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Burgeoning Polymer Nano Blends for Improved Controlled Drug Release: A Review

Authors Maghsoudi S, Taghavi Shahraki B, Rabiee N, Fatahi Y, Dinarvand R, Tavakolizadeh M, Ahmadi S, Rabiee M, Bagherzadeh M, Pourjavadi A, Farhadnejad H, Tahriri M, Webster TJ, Tayebi L

Received 3 March 2020

Accepted for publication 1 May 2020

Published 19 June 2020 Volume 2020:15 Pages 4363—4392

DOI https://doi.org/10.2147/IJN.S252237

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Anderson Oliveira Lobo

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Saeid Maghsoudi,1 Bahareh Taghavi Shahraki,1 Navid Rabiee,2 Yousef Fatahi,3– 5 Rassoul Dinarvand,3,4 Maryam Tavakolizadeh,6 Sepideh Ahmadi,7,8 Mohammad Rabiee,9 Mojtaba Bagherzadeh,2 Ali Pourjavadi,6 Hassan Farhadnejad,10 Mohammadreza Tahriri,11 Thomas J Webster,12 Lobat Tayebi11

1Department of Medicinal Chemistry, Shiraz University of Technology, Shiraz, Iran; 2Department of Chemistry, Sharif University of Technology, Tehran, Iran; 3Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 4Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 5Universal Scientific Education and Research Network (USERN), Tehran, Iran; 6Polymer Research Laboratory, Department of Chemistry, Sharif University of Technology, Tehran 11365-9516, Iran; 7Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 8Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 9Biomaterial Group, Department of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran; 10Department of Pharmaceutics and Pharmaceutical Nanotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 11School of Dentistry, Marquette University, Milwaukee, WI 53233, USA; 12Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA

Correspondence: Thomas J Webster; Mohammadreza Tahriri Tel +1 617 373 6585
Email [email protected]; [email protected]

Abstract: With continual rapid developments in the biomedical field and understanding of the important mechanisms and pharmacokinetics of biological molecules, controlled drug delivery systems (CDDSs) have been at the forefront over conventional drug delivery systems. Over the past several years, scientists have placed boundless energy and time into exploiting a wide variety of excipients, particularly diverse polymers, both natural and synthetic. More recently, the development of nano polymer blends has achieved noteworthy attention due to their amazing properties, such as biocompatibility, biodegradability and more importantly, their pivotal role in controlled and sustained drug release in vitro and in vivo. These compounds come with a number of effective benefits for improving problems of targeted or controlled drug and gene delivery systems; thus, they have been extensively used in medical and pharmaceutical applications. Additionally, they are quite attractive for wound dressings, textiles, tissue engineering, and biomedical prostheses. In this sense, some important and workable natural polymers (namely, chitosan (CS), starch and cellulose) and some applicable synthetic ones (such as poly-lactic-co-glycolic acid (PLGA), poly(lactic acid) (PLA) and poly-glycolic acid (PGA)) have played an indispensable role over the last two decades for their therapeutic effects owing to their appealing and renewable biological properties. According to our data, this is the first review article highlighting CDDSs composed of diverse natural and synthetic nano biopolymers, blended for biological purposes, mostly over the past five years; other reviews have just briefly mentioned the use of such blended polymers. We, additionally, try to make comparisons between various nano blending systems in terms of improved sustained and controlled drug release behavior.

Keywords: polymer blends, drug delivery, wound dressing, PLGA, chitosan, starch

Introduction

The past two decades have seen widespread progress in the development of drug delivery vehicles. However, over the past several years, despite the significant advances in developing novel excipients for releasing specific drugs in a sustainable and controllable way, limitations on experimental achievements have remained a major concern. Thus, there is an urgent need for proposing new drug delivery approaches to ameliorate this pressing issue.

Drug delivery systems (DDSs) consisting of biocompatible and biodegradable materials that take into account distinct physiological and physiochemical changes, are of special interest because they can significantly release biological agents at the right place and/or at a rate adjusted to disease progression.1 DDSs can be categorized either as diffusion-controlled, chemically-controlled, swelling-controlled or modulated-release systems.2 Novel DDSs which release drugs at a controlled rate, slowly, and in a targeted manner have been promising.3 For more than ten years, numerous articles of various concentrated topics have been devoted to the field of DDSs and several advancements have been made. Nevertheless, it should be kept in mind that many therapeutic agents may cause severe side effects as they need to be delivered at a prolonged exposure time which results in reducing their toxicity by releasing smaller concentrations over longer drug exposure, particularly, as antitumor and antibacterial agents.4,5

Polymers in Controlled Nano Drug Delivery Systems

Controlled drug delivery systems (CDDSs) bring about a variety of positive points, including improved drug administration, efficacy and patient compliance, tailored therapeutic activity, reduced side effects, toxicity and drug administration frequency, as well as improved premature degradation.1,6,7 In all circumstances, the main purpose of CDDSs is a sensible combination between biocompatible, soft and biodegradable polymers and drugs such that drugs can be released in a sustained or controlled manner over a long time span (Figure 1).8 In order to acquire novel and beneficial controlled drug release, different approaches among polymers have emerged—such as injectable hydrogels,9 direct implantation,10 crosslinked micelles,11 injectable suspension12 and depots.13

Figure 1 A simple depiction of CDDSs at different time points.Abbreviation: CDDSs, controlled drug delivery systems.

As time goes by, biopolymers of various nanometer sizes, shapes, and surface properties have played a crucial role as CDDSs14 and their synergic effects have ameliorated drug entrapment and mechanical property concerns.15 It is an indisputable fact that polymers—either natural or synthetic—have become predominantly important materials as CDDSs, providing the weight, consistency and volume for the beneficial administration of drugs.16 Stimuli-responsive polymers could mitigate the many dilemmas with biological systems, demonstrating a significant response to modifications in chemical and physical stimuli such as pH, temperature, concentration, pressure, ionic strength, light and redox potential.17 Hence, these responses can lead to swelling, precipitation and dissolution, along with a change in hydrophilicity and hydrophobicity.18 As our body is influenced by external stimuli by adjusting to changing external conditions, rationally designed new responsive polymers are of particular importance to meet such criteria. For CDDs applications, devices must be able to deliver agents at the right place in response to a stimulus and be easily administered aside from possessing non-toxic, biocompatible and biodegradable materials.19 Here, we attempt to include the most recent publications of stimuli-responsive polymers in CDDSs by introducing one of the most notable types of these materials used for CDDSs, namely crosslinked polymer networks termed hydrogels.

Over the past years, nanotechnology-based devices have been attractive tools for discovering optimally safe and beneficial drug candidates. Scientists have taken advantages from various nanoscale delivery vehicles for targeted and controlled drug release applications since nanoparticles can avoid immune system clearance and penetrate cells and tissues where conventional delivery systems cannot. Recently, many organic and inorganic nanomaterials and devices have been utilized as delivery systems to develop potential therapeutic modalities. Additional advantages of these vehicles can be improving drug therapeutic activity through prolonging drug half-life, enhancing hydrophobicity of drugs, reducing potential immunogenicity and more importantly, releasing drugs in a controllable and limited manner.20,21

Polymeric nanofibers ranging from 50 to 1000 nm, in particular, due to their unique properties (including specific surface area per unit mass, greater porosity with small pore sizes, significant mechanical properties based on architectural arrangement and magnificent flexibility) are of great interest to release drugs locally and slowly for numerous biomedical applications, such as wound dressings.22,23 Nanofibrous mats are also very good candidates for sustained release applications for antibiotic, antibacterial, antifungal or anticancer agents as they can beneficially encapsulate drugs in dressings and/or scaffolds.24

Polymer nanoparticles (NPs) have also revolutionized the field of CDDSs due to their larger surface areas per volume compared to conventional particles leading to enhanced drug encapsulation, better loading capacity, stability, local release and can be easily attached to a variety of compounds.25 It is interesting to mention that drug delivery is directly affected by the morphology and shape factors of the nanoparticle systems. Moreover, it is a proven fact that particles of nanometer to sub-micron size significantly outperform microparticles in DDSs. While larger particles possess large cores contributing to faster polymer degradation permitting drugs to be better encapsulated and slowly diffuse out, smaller particles with their greater surface areas allow the drug to be at or near the particle surface, causing even faster drug release. Furthermore, the geometry of the nanoparticle can influence drug release. For instance, discs and rod-shaped nanocarriers have superior blood circulation properties over spherical particles, enabling longer circulation times and better targeting.26

In the majority of these situations, drug loaded nanofibers have emerged remarkably in favor of a blended polymeric solution, resulting in sustained and burst release.27 Biocompatible and biodegradable synthetic polymers (such as PLGA, PLA, PGA, poly (vinyl alcohol) PVA, poly (ε-caprolactone) (PCL), poly (ethylene glycol) (PEG), poly (L-lysine) (PLL) and polyphosphoesters (PPEs)) and natural ones (namely cellulose, CS, starch and gelatin) have opened many avenues for improving medical and pharmaceutical applications, and when fabricating them at the nanoscale, they have revolutionized controlled drug delivery research.28,29

Polymeric Hydrogels and Micelles as Drug Delivery Vehicles

Hydrophilic gels, so-called hydrogels, are a crosslinked network of polymers of considerable absorbent compositions, produced by both natural and synthetic polymers. The distinctive characteristic of hydrogels include their soft material environment due to their high degree of hydrophilicity, which promotes the uptake of water.30,31 This high water content makes hydrogels very promising for the significant loading of hydrophilic drugs for CDDS applications which mimics biological tissues (Figure 2).32 Furthermore, their porous configuration allow drugs to be loaded into the gel matrix giving rise to drug release gradually based on the diffusion coefficient of the small and/or macro molecule in the gel network.19 For more information on hydrogels, we refer the reader to a comprehensive review by Li et al,9 as here we emphasize only their nano aspects.

Figure 2 Drug release from hydrogels: (A) drug is released by dissolving from the hydrogel, (B) drug is incorporated into the hydrogel to maintain its native structural integrity and function, (C) stimuli-responsive hydrogels loaded with a drug as a drug carrier, and (D) entrapment of a drug in a degradable hydrogel allowing the drug to diffuse out of the hydrogel.

Three-dimensional hydrogels—such as copolymeric hydrogels—bring a number of exceptional applications in CDDSs.3335 For instance, enzyme-mediated redox chain initiation including glucose oxidase (GOX) was used to build three-dimensional hydrogels through stable aqueous conditions under ambient temperature and atmospheric circumstances. This process was completed via an easy interfacial polymerization approach for producing nanometer-scale constructs and consistent PEG-based hydrogel layers safe for use after incubation in water for 16 weeks. Moreover, such three-dimensional hydrogel layers were able to load both biological agents and fluorescent nanoparticles predicted to be a suitable technique for CDDSs.36 This study revealed that three-dimensional hydrogels could be a remarkable approach for evaluating controlled drug release profiles owing to the fact that they possess a uniform, conformal coating and multilayer nano structure. Besides, in order to obtain a high degree of swelling for the beneficial release of drugs in a controlled manner, it is highly recommended to use synthetic nanostructured polymers over natural ones, as they possess much better water-soluble properties and their nanoscale properties provide for increased surface area which leads to greater control.37

Polymeric micelles have been a superior strategy in tackling the delivery of poorly water-soluble drugs in a controlled manner at target sites. They are formulated by the spontaneous self-assembly of amphiphilic block copolymers in an aqueous solution.38 Polymeric micelles are naturally nanostructured and provide for much better stability, tailorability and no toxicity. Because of their special core-shell structure, the hydrophobic part paves the way for the encapsulation of hydrophobic drugs. The hydrophilic part, however, could protect the hydrophobic section from the biological invasion owing to its brush-like nano-structure. With respect to the hydrophobic nature of the micelle core, water-insoluble drugs can be encapsulated and solubilized in the micellar core by either chemical conjugation or physical entrapment to reach their desired target (Figure 3).39 Several studies have reported the progression of polymeric micelles in CDDSs.40,41

Figure 3 Polymeric micelles in CDDSs. Hydrophilic block copolymers can establish micelles in an aqueous solvent with a hydrophobic core sterically stabilized by a hydrophilic shell. The drug is localized in the hydrophobic core separated from the outside environment by a hydrophilic shell. Abbreviation: CDDSs, controlled drug delivery systems.

The State of the Art of Nano Polymer Blends in CDDSs

Polymer blends are simple and successful combinations of at least two polymers to provide a new and economical excipient with different physical properties without the preparation of particular copolymers.42,43 They provide new products with various applications in the pharmaceutical and biomedical fields. This straightforward and time-saving approach can combine the flavor of different polymers and benefit not only drug and gene delivery, but also many technological advancements such as organic solar cells, thick plastics and membrane separation.44,45 The blending of polymers can reduce the undesired side effects of many drugs, particularly, those biological agents in which drug release is very important. In that way, the timing of drug release and drug dosage should be regulated and improved. However, in terms of drug delivery, some key factors should be taken into consideration, including intrinsic miscibility among two polymers, the interaction between the active pharmaceutical ingredients (API) with polymers and the critical situation of the environment during storage.46 Fundamentally, drug delivery in the presence of blended polymers is a complicated process suggested by three mechanisms: polymer relaxation, degradation, and diffusion (Figure 4).47

Figure 4 Schematic illustration of drug release from a typical nanoparticle/nanocomposite/polymeric based material. Notes: Reprinted with permission Merino S, Martin C, Kostarelos K, Prato M, Vazquez E. Nancsite hydrogels: 3D polymer–nanoparticle synergies for on-demand drug delivery. ACS Nano. 2015;9(5);4686-4697. Copyright 2015 American Chemical Society.211

Different classifications of biological products, ranging from proteins to antibodies, can be incorporated into copolymers based on their properties either indirectly or physically and even be chemically surface-immobilized.49 Even though the properties of natural polymers are less similar to synthetic polymers, there has been some evidence of the interaction between them, most of which have led to polymer hydrogel compounds as three-dimensional heavy networks formed by a polymer backbone, water and crosslinking agents in CDDSs.50 Indeed, hydrogels are produced by hydrophilic monomers with crosslinkers used for a wide variety of medical applications, particularly for controlled drug release in vivo and in vitro.51 Polymer combinations are usually used for enhancing the poorly water-soluble delivery of pharmaceutical ingredients.

The Aim of Using Nano Polymer Blends in CDDSs

The reasons why polymer blending outclass single polymers could be the reduction or even removing of long and costly procedures necessary for producing new polymers that not merely lead to new and great properties, but also improve material processability and polymerization steps.52 Besides, polymer blending has made a breakthrough in tailoring the important disadvantages of polymers such as biodegradability, physico-mechanical, poor mechanical and thermal properties. For instance, the biodegradability of polymer matrices can be improved through blending of biodegradable and non-biodegradable polymers and changing their composition.53,54

Generally, polymer blends can be categorized as (i) miscible, (ii) compatible and (iii) immiscible. As miscible blends do not provide preferred properties, their applications in industry is not favorable. The significant feature of polymer blends is their phase behavior in which polymers mostly produce immiscible and incompatible blends resulting in a coarse phase morphology with a particulate minority phase dispersed in a matrix and poorly distributed. Moreover, polymer mixtures are more likely to be in two separate layers, like oil and water, owing to the unfavorably low value of entropy. Therefore, morphologies of polymer blends are determined by their processing and thermal history. After blending of two polymers, they are prone to obtain a small-scale arrangement of the phases, called the “microstructure”. The blend properties, eventually, are greatly affected by the size scale of the microstructure, giving rise to a pressing issue between processing flow conditions and microstructure. As a consequence, the compatibilization of polymer blends plays a crucial role in altering the interfacial properties in an immiscible polymer blend. The major advantage of this approach can be a decrease in the interfacial tension coefficient and the generation and stabilization of the satisfactory morphology.52,5557 Among different compatibilizers, the role of nanoparticles to improve the final morphology of the polymer blend has gained popularity. Nanostructured blends achieved by cross-linking the major phase and/or minor phase are of ideal interest in producing materials with smart properties. The myriad of benefits of nanostructured polymeric blends in CDDSs may be better device fabrication, modification of device characteristics, enhanced drug loading and the use of the dispersed phase domains for improved drug release properties.58 Among nanostructured materials, nanostructured hydrogels have received much attention in the field of nanotechnology.59 The rate of drug release from nanostructured hydrogels can be controlled through various approaches, such as modifying the cross-linking density or controlling the ratio of hydrophilic to hydrophobic monomers.60

The compositions of different types of polymers—such as PLGA, PLA, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), surfactants, etc.—can increase the rate of drug water solubility and their release.61,62 Further, creating such polymers to be nanostructured can increase surface area and increase water solubility. For instance, Liu et al utilized an ethylene-vinyl acetate copolymer (EVA) blended with PLA and PEG as a stent coating drug carrier for delivering paclitaxel (PTX), and as a result, they demonstrated that these blends released PTX in a highly tunable and controlled way.63 In another example, hydroxypropyl methylcellulose acetate succinate (HPMCAS) was blended with dodecyl (C12)-tailed poly (N-isopropylacrylamide) (PNIPAm) for improving low water-soluble drugs, such as phenytoin.45 It should be noted that among synthetic and natural polymers used in drug delivery, synthetic–natural polymer blends have attracted more attention than either synthetic–synthetic or natural–natural polymer blends providing a satisfying platform to combine mechanical and bioactive properties.48

With all of these considerations, the potential applications of polymer blends as carrier materials in CDDSs has been inextricably bound with several difficulties in the design and development of devices in comparison to forms coated with just one group of polymers. However, owing to advancements in CDDSs in the last two decades, the optimal architecture and application of CDDSs with tunable drug release profiles have been achieved.

The main aim of this review is to provide recent developments in nano polymer blends with an emphasis on controlled and sustained delivery, carrier fabrication, drug loading efficacy, and physicochemical properties. Here, we make comparisons between the role of natural and synthetic polymers in CDDSs. In particular, the manner of controlled release from CS, cellulose, and starch, as well as PLGA, PLA, and PGA will be discussed from research over the last five years in the sections that follow. In most sections, we bring additional applications of different nano polymer blends to a diversity of drug delivery systems and medical devices through succinct tables. We give particular attention to approaches for CDDSs for hydrophilic drugs that are highly loaded in their fiber forms. Furthermore, future potentials and challenges of nano polymer blends are also discussed.

In Table 1, we provide advantages and disadvantages of the above natural and synthetic polymers.

Table 1 Advantages and Disadvantages of the Mentioned Natural and Synthetic Polymers

Types of Polymers Used in CDDSs

Natural Polymers

Natural polymers—which are fundamentally polysaccharides—play a versatile role in medical applications, including CDDSs, regarding the regulation of the dosage form and improvements in physicochemical parameters. They serve as excipients in pharmaceutical companies due to their low cost, biodegradability, biocompatible structures, availability and having safe properties.64,65 These polymers are water-soluble, biogenic, enzymatically degradable, chemically flexible and consist of large molecules which originate from nature—namely plants, microorganisms, and animals.16 Furthermore, these polymers can be classified into two major groups: (1) protein polymers, such as collagen and gelatin, and (2) polysaccharides, like CS, glycogen, cellulose, and starch.66 During recent years, there has been a great deal of interest in biodegradable polysaccharides for CDDSs exploited as drug carriers or enhancers of the viscosity in liquids or emulsions.8

Current studies on biocompatible and biodegradable natural polymers have led to a considerable evolution of more novel types of wound dressings and applications in the biomedical area. Among them, natural polysaccharides—such as CS, cellulose, and starch—have garnered attention because of their organized structures, and thus, they are preferable for producing polymer-based composites and biopolymers. This section aims to demonstrate recent progress in CS, cellulose and starch blends and their application in CDDSs.

Applications of Chitosan (CS) and Its Blend Derivatives in CDDSs

CS is the second most plentiful polysaccharide with abundant bio-applications. It can be produced from the alkaline N-deacetylation of chitin but it is also a biopolymer found in insects, fungi and more greatly, in the shells of crustaceans.67,68 With respect to medical applications, CS has gained popularity because of its great properties, specifically in its ability to blend with polymers. Therefore, CS can blend with numerous natural and synthetic polymers, displaying a diversity of features that enhance its utility as a drug delivery vehicle based on its mucoadhesive nature.69 Recently, CS blends have been successfully utilized for drug and vaccine delivery,70,71 cranial defects,72 anti-cancer activity,73,74 anti‐adhesion therapy,75 antibacterial activity,76 anti-aging therapy77 and anti-inflammatory wound dressing activity.78 As with the aforementioned polymers, nano CS possesses increased surface area per volume compared to conventional CS, and thus has even greater biological properties.

For wound healing applications, stimuli-responsive CS and poly (N-vinyl-2- pyrrolidone) (PVP) were blended with 74% neutralized poly ascorbic acid (PAA). The obtained hydrogels showed not only antimicrobial properties against E. coli but also demonstrated significant behavior for delivering silver sulfadiazine with approximately 90% of release in a controlled manner within 80 min.79 Texier et al showed intermolecular interactions between CS and PEG sponges as a chemical crosslinking of the PEG network in the CS matrix via nucleophilic thiolyne addition. The morphology of the composite demonstrated that these novel crosslinked-sponges possess high stability with a porous structure for topical drug delivery at physiological conditions.80 In a recent study, CS and PVP were combined to effectively deliver betamethasone-17-valerate (BMV) for treating recurrent aphthous stomatitis (RAS). The existence of PVP with CS can enhance both thermal stability and swelling ratio for the release of BMV at roughly 80%.81 Polymer blending here enabled PVP with a higher swelling ability to increase tensile strength leading to an efficient mucoadhesive drug delivery system.

In another study, Jesus and colleagues developed a blended material produced by CS and PCL NPs in order to improve the controlled release of vaccine, protein, and antigen, as well as reduce their cytotoxicity. Notably, over a span of 6 months, ovalbumin (OVA) adsorption on PCL/CS NPs led to an expected loss of protein ellipticity along with an alteration to a marked β-sheet content, but it did not induce protein-unordered conformation. The release of the drug was reported over 6 h.70 Carboxymethyl CS (CMCS) was blended with gelatin, a biodegradable and biocompatible polypeptide, as a controlled release polymeric hydrogel, in order to analyze the release of 5-Fluorouracil (5-FU). The blended microspheres were examined with different analytical techniques to understand the interaction of the polymer and 5-FU. As a result, the in vitro release of 5-FU increased to 12 h at a physiological pH,82 with an expected enhancement for nanospheres.

To tackle problems of infection and traumatic musculoskeletal injuries, Berretta et al developed a blend of CS and PEG pastes to provide biocompatibility, biodegradability and the local delivery of vancomycin and amikacin to a larger distribution of eluted antibiotics to prevent or even treat musculoskeletal wounds and bone infections. Therefore, preliminary studies showed satisfying results for the CS/PEG copolymers with the mentioned antibiotic drugs, which resulted in degradability, biocompatibility, injectability and prevention of infection for musculoskeletal-type wounds.83 The injectable, cytocompatible and biodegradable gels based on an easy blending of 4.0% carboxymethyl hexanoyl CS (CHC) with 4.0% hyaluronic acid (HA) was described. These injectable in situ gels were not made by high temperature nor crosslinking reagents and förster resonance energy transfer (FRET) controlled the mechanism of gel formation. With this blend, a turbid colloidal suspension and subsequently supermolecular hydrogels were obtained immediately to sustain and provide pH-dependent delivery of berberine as an anti-apoptotic and anti-arthritis herbal medicine. In vitro degradation was evaluated through dipping of the gels in various buffer solutions at 37 °C of hyaluronidase and lysozyme. The weight loss ratio of the gels in pH 6.0 buffer was 7.8%, 40.5%, 45.1% and 62.1% in the buffer and lysozyme, hyaluronidase and both enzymes, respectively. Sustained drug delivery was achieved at pH 6.0 showing that the gel was more stable at pH 6.0. Moreover, the gels greatly swelled within a day, preceded by a sharp reduction in mass in a pH 7.4 buffer. Besides, the drug-loaded blends kept chondrocytes safe against sodium nitroprusside-induced apoptosis and arthritis resulting in an improvement of the anti-apoptotic efficiency of berberine. From another perspective, another research group focused on preparing LbL assembled multilayer films using the above mentioned feature of CMC and chitosan, which helped them study the chemistry of those biocompatible polysaccharides by investigating both cross-linked and non-cross-linked nanostructures (Figure 5).84 

Figure 5 (A) Chemical structures of chitosan and carboxymethyl cellulose sodium salt. (B) Schematic illustration of the cross-linking-induced structural change of the LbL-assembled CMC/CHI multilayer film and its effect on the loading of drugs with different molecular weights.Notes: Reprinted with permission Park S, Choi D, Jeong H, Heo J, Hong J. Drug loading and release behavior depending on the induced porosity of chitosan/cellulose multilayer Nanofilms. Mole Pharm. 2017;14(10):3322-3330. Copyright 2017 American Chemical Society. 84Abbreviations: CMC,carboxymethyl hexanoyl chitosan; LbL, Layer-by-Layer.

Moreover, Rokhdadeh et al formulated pluronic F127/CS blend microspheres and glutaraldehyde as a crosslinker. These blended compounds showed high physical activity and drug-polymer harmony in comparison to CS microspheres with excellent mucosal DDSs. It is noteworthy to indicate that the release profile of the 5-FU as a model drug improved to 1 day.85 More recently, a novel composite developed by Anirudhan et al consisted of blends of biodegradable thiolated CS-PEG contained with medical clay (MMT), named TCS-PEG/MMT, and was used for the oral drug delivery of insulin. Consequently, after 8 h, almost 70% of insulin was released at a basic pH of 7.4, which revealed the controlled release of the drug.86 Tolbutamide (TOL), a significant hypoglycemic drug, was released in a controlled manner loaded with CS/PLGA NPs with the solvent evaporation method. Thermal gravity analysis (TGA) and transmission electron microscope (TEM) proved that not only did this copolymer enhance the bioavailability of the drug, but it decreased TOL dosage. Additionally, TOL was released by CS/PLGA-TOL NPs at a pH of 7.4 and in a phosphate buffer solution (PBS) in a sustained manner.87

Arya et al utilized curcumin (Cur), a herbal anti-cancer drug, loaded PLGA NP surfaces coated with a blend of CS/PEG in order to increase bioavailability and reduce limitations in conventional chemotherapy. These Cur nanoparticles showed a controlled release rate of Cur after 6 days, followed by a biphasic phenomena, together with higher cytotoxicity, improved anti-migratory, as well as anti-invasive and apoptosis-inducing ability of the CS/PEG blend in various pancreatic cancer cell lines in comparison with the native counterpart.73 In another study, the controlled release behavior of Metformin (Met) was reported by Shariatinia et al. This group developed a highly efficient film from a blend of CS and poly (ethylene glycol)-block-poly (propylene glycol)-block-poly (ethylene) consisting of mesoporous MCM-41 or MCM-41-APS (APS=aminopropylsilane) nanoparticles for the controlled release of Met. The release of the drug increased considerably within 22–24 h (burst release), after which the release of the drug was slowed to release over 15 days (controlled release). Moreover, the film including 4% MCM-41-APS and 10% Met revealed improved tensile strength, hydrophilicity, biocompatibility, and drug release.88 In Table 2, additional applications of CS blends are summarized for the controlled release of various drugs.

Table 2 Other Applications of CS Blends in CDDSs

Applications of Cellulose and Its Blend Derivative in CDDSs

Cellulose is a fibrous and water-soluble organic material with a linear homopolymer of β-1,4-linked anhydro-D-glucose units having abundant hydroxyl groups, which possess a high ability to blend with different kinds of materials.89 Cellulose and its derivatives (such as microcrystalline cellulose (MCC), ethyl cellulose (EC), methylcellulose (MC), HPMC, HPC, carboxymethyl cellulose (CMC), and several other forms) have been widely used in CDDSs as significant carriers.9092 Blends of different cellulose derivatives with other excipients participate in coating and enteric coating roles in pharmaceutical industries by releasing biological molecules in a controlled manner.93

The effect of blending cellulose and PEG for loading vitamin C as a typical drug was reported by Shen and colleagues. In this experiment, pH and temperature responses were conducted and an effective controlled drug release was reported. An interesting point in this report is that it used cellulose and showed pH responsive-based drug release in multi-pulses, which means that according to the Grayson et al experiment,94 this blend could be regarded as a valuable device for CDDSs.95 β-cyclodextrin (β-CD) and CMC hydrogels were blended for the controlled release of the antiviral drug, acyclovir. The degree of swelling and crystallinity, which are two remarkable factors for drug release,96 demonstrated improved drug loading and sustained release capability.97

Here, nanomedicine has also provided significant improvements. Specifically, electrospun nanofibers have extensively been used in CDDSs due to their particular advantages as highly effective nanofibers.98,99 Electrospinning is a fiber production process that makes micro/nanometer-sized polymeric fibers. Their applications in sustained drug release can be achieved if surface modification is performed on blends of electrospun fibers.100 It needs uncomplicated equipment compared to other fiber fabrication methods, such as wet chemistry methods and molecular beam lithography. Because the process can create diverse polymer construct properties such as compatibility, high surface to volume ratio, high porosity, and straightforward encapsulation of therapeutic molecules, it has been widely used in CDDSs specifically in regenerative medicine and wound dressings. The electric force in electrospinning is used to control the surface tension and polymer solution viscosity to make electrospun fibers.101,102

Recently, El-Newehy et al developed a polymer blend made of HPC with PVA and PVP to release diclofenac sodium (DS) as a model drug based on electrospun nanofibers. In this study, in vitro entrapment efficiency and the sustained release of DS were controlled by UV spectroscopy when loaded into electrospun nanofibers of HPC with PVA and PVP, at a pH of 7.4 and at body temperature; in the first two hours, the amount of the DS released from the electrospun fiber was 63, 61, 58, and 46% of its DS content from HPC/PVA 100/0, 75/25, 50/50 and 25/75, respectively, whereas it released 85, 69, 63, and 57% of its DS content after three hours, respectively. However, the rate of release was diminished by increasing the PVA concentration because PVA in the nanofiber mats controls the DS release by forming hydrogen bonds with DS. Therefore, the blends of PVA and PVP with HPC enhanced the mechanical properties of the HPC nanofibers mats which could clearly be fruitful for biomedical therapy.103

In terms of a nanomedicine approach, CMC and PVA were blended and loaded with ZnO nanoparticles and erythromycin (EM), the selected antibacterial drug (both alone and in combination), for achieving a more beneficial antibiotic activity with regards to a synergistic effect. Electrospinning procedures and crosslinking with 2% glutaraldehyde vapor and a 3% AlCl3 alcoholic solution were used for fabrication. Therefore, EM-loaded PVA-CMC/ZnO nanocomposite mats demonstrated a good ability for not only sustained drug release but also for wound dressings owing to their satisfactory antibiotic efficacy. It should be noted that the release of EM was completed after three days (another CMC delivery system is presented in Figure 6).22

Moreover, the controlled release of donepezil hydrochloride was investigated by Gencturk et al. They developed potential and non-toxic electrospun polyurethane/HPC (PU/HPC) nanofibers for transdermal CDDSs according to in vitro preliminary permeation data. Approximately 90% of donepezil hydrochloride in the nanofibers released slowly over 6h.104 Zhu et al developed smooth and cylindrical nanoscale fibers of poly (N-isopropylacrylamide) (PNIPAAm) and EC blends loaded with ketoprofen (KET) with considerable intermolecular interactions between them. The intermolecular interactions between the drug and blend were very good and KET release was reported at different ratios. Heating changed unexpectedly as observed from the water contact angle on the PNIPAAm and blend nanofibers, and the fibers underwent a fast hydrophilic/hydrophobic transition. At a 1:2 weight ratio of PNIPAAm/EC in the fibers, KET release at 25 °C was much faster than at 37 °C owing to this drastic change in properties. For the 1:1 ratio, the release rate from the fibers was relatively low at 37 °C. Finally, for the 1:4 weight ratio of PNIPAAm/EC, the materials lost most of their thermoresponsive properties. But not only were these blended fibers safe and appropriate for cell growth, but more importantly, the electrospun-blends of PNIPAAm/EC fibers played a beneficial role in the controlled release of poorly water-soluble drugs for tissue engineering applications.105

Core-shell nanofiber drug carriers were reported via a graft blending of NaCMC, poly (ethylene oxide) (PEO) and methyl acrylate (TCMC) loaded with TCH to build TCMC/PEO/TCH(CS) core-shell polymeric nanofibers, which were fabricated by coaxial electrospinning as a novel controlled drug delivery system. Spectroscopy analyses demonstrated that the release of TCH was slow and at a controllable rate within 72 h. Additionally, core-shell TCMC4/PEO(CS) electrospun nanofibers exhibited outstanding antibacterial effects against both gram-positive and gram-negative bacteria, as well as good cell viability. For toxicity and biocompatibility of the TCMC4/PEO/TCH(CS) and TCMC4/PEO(CS) core-shell electrospun nanofibrous mats, an MTT assay was used and showed that cell viability on the nanofibrous reached 100% after a day. While after two days, the TCMC4/PEO(CS) revealed no cytotoxicity and the TCMC4/PEO/TCH(CS) nanofibers demonstrated a decrease in the viability of human fibroblasts (HDF) reporting that the released TCH at 24 h and 48 h affected cell viability.106

Further, different quantities of cellulose nanocrystals (CNCs) were blended with gelatin hydrogels with glutaraldehyde used as a crosslinker, due to its high reactivity toward the -NH2 group of gelatin, and on account of the weak mechanical properties of gelatin. Figure 6 shows a schematic of a typical preparation process of a nanocarrier based on carboxymethyl cellulose (CMC) based on the reaction between different functional groups as well as loading of the drug into the main core of the nanocarrier along with conjugation to the surface. In another study, different proportions of CNCs (0.5, 5, 15, 20 and 25%) were selected to investigate the effects of CNCs on the swelling ratio, as well as dynamic mechanical properties of gelatin-based hydrogels to make semi-interpenetrating polymer networks (semi-IPNs). Semi-IPNs ameliorated not only the mechanical properties of the hydrogel and drug release, but it also controlled swelling ratio. Theophylline was incorporated as a drug model in this study. As a consequence, the highest swelling ratio and drug release and efficacy were related to 5% CNC at pH 3. Nevertheless, the best drug loading for sustained and controlled drug release was associated with 15% CNC. Drug release rates continuously decreased with time owing to the thickness of the hydrogel that acted as a diffusion barrier. It should be noted that the hydrogel with the higher swelling ratio resulted in higher drug release percentages, and as a result, the 5% CNC-gelatin hydrogel showed the highest drug release percentage while the 25% CNC-gelatin hydrogel showed the lowest drug release percentage.107

Figure 6 Schematic representation of the preparation of a carboxymethyl cellulose (CMC) based drug delivery system.Notes: Reprinted with permission Lai, WF, Shum HC. Hypromellose-graft-chitosan and its polyelectrolyte complex as novel systems for sustained drug delivery. ACS Applied Materials & Interfaces. 2015;7(19):10501-10510. Copyright 2015 American Chemical Society.108Abbreviation: CMC, carboxymethyl cellulose.

HPMC of diverse viscosities has been thoroughly used in the pharmaceutical industry for the controlled release of drugs. Its considerable swellability, hydrophilicity and non-ionic nature has paved the way for blending with various excipients, in the form of hydrogels, to achieve the controlled release of biological products.109111 In this case, HPMC was blended with different kinds of polymers, such as PVP,112 CS,113 EC,114 gelatin, and xanthan gum115 and in most cases, these blends showed remarkable controlled release activity.116119

Dharmalingam et al designed a combination of HPMC and NaCMC in the presence of citric acid (CA) as a crosslinking agent (citric acid crosslinked HPMC-NaCMC hydrogel films) in order to evaluate the controlled release of methylene blue and TCH for wound healing applications. The loading efficacy for the drugs reversed for different ratios of CA at a pH 7.4 and 37 °C. Specifically, when the concentration of CA in the hydrogel increased from 5 to 10 to 20%, the loading efficacy of methylene blue increased (approximately 35, 45 and 55%, respectively), whereas the pattern for TCH was the complete reverse (approximately 10, 8 and 6 %, respectively). Moreover, this increase led to a reduction of the swelling ratio, the water contact angle (surface hydrophilicity) and tensile strength of the hydrogel films, while the elongation at break (%) increased. Additionally, both drugs released in a controlled manner for more than 3 days, demonstrating that the HPMC/NaCMC hydrogels were highly satisfactory not only for controlled drug release but for effective wound healing as an excellent antibacterial agent.120

Similarly, atenolol-controlled release was investigated by Lotfipour et al in an experiment with different concentrations of soluble and insoluble binary blended polymers, including Eudragit RSPO, EC, and NaCMC with HPMC. The controlled release profile of atenolol from different weight ratios of matrices containing the blends of HPMC and other excipients was confirmed with diffusion and erosion processes, depending on the type of polymer and concentration.121 Blends of HPMC with SA were also investigated for the release profile of three drugs: BSA, Met, and indomethacin (IDM), with different molecular weights and solubility properties. Due to the large pores in the HPMC-SA hydrogels, small and water-soluble Met, had a burst release within just 2.5 h. Nevertheless, other drugs and BSA and IDM as two water-insoluble compounds had better-controlled release profiles in which the macromolecular drug BSA had the best-sustained release profile for blockage by a semi-interpenetrating polymeric network and IDM showed controlled release after 12 h.122 In Table 3, additional applications of cellulose blends are summarized for their controlled release of various drugs.

Table 3 Other Applications of Cellulose Blends in CDDSs

Applications of Starch and Its Blend Derivatives in CDDSs

Starch is a natural polymeric carbohydrate and is the most abundant storage polymer used extensively in the pharmaceutical industry because of its high availability, affordability, and biodegradability.123,124 It is constituted by amylose (typically 18–33%) and amylopectin (typically 67–82%), which are highly applicable for many pharmaceutical and food applications.125,126 Scientists have a positive attitude towards developing starch-related compounds as magnificent materials with advantages of greater biocompatibility and non-toxicity.127

Importantly, however, native starch separated from various sources has some significant drawbacks such as narrow shear and thermal resistance, thermal decomposition and a high proclivity for retrogradation.128 Therefore, the combination between starch and other biodegradable and biocompatible polymers has addressed these problems, making it enormously beneficial in tissue engineering, drug delivery and for the effective release of biologically active compounds.129 Different starch-based DDSs have been projected for therapeutic effects and these DDSs can be associated with various drug carrier strategies.130

Blending starch and its derivatives (such as sodium starch glycolate and pregelatinized starch) with both compatible and non-compatible polymers can be an advantageous strategy in order to improve the properties and stability of starch-based films.131 Many studies have reported the ability of starch to blend with a variety of materials to advance ionotropically gelled multiple-unit systems for the enhancement of drug encapsulation, swelling, stability and controlled release of biological agents.132136 Ayorinde et al reported blends of natural starches with HPMC for orally dissolving films of amlodipine besylate (AB). They utilized Bambara nut (BAM) and the African yam bean (AYB) starches separately blended with HPMC. AB was included by dispersion and films were made by solvent evaporation. The AYB/HPMC, BAM/HPMC demonstrated high viscosity, and among all ratios, it was the BAM/HPMC (1: 1) and AYB//HPMC (2: 1) that most effectively released all of the AB content within 30 h. This activity can be traced back to the individual physicochemical properties of BAM and AYB (such as thickness, variation of mass, disintegration time, folding endurance, and surface pH) influencing the dissolution of the drug from films and, thus, increasing AYB concentration for a better sustained drug release while drug release was reduced with increasing BAM concentrations.137

Dual crosslinking (DC) has been exploited as a beneficial strategy for tailoring drug delivery approaches.138 The ionic crosslinking and DC were evaluated as a novel mucoadhesive DDS by de Oliveira Cardoso et al. In this experiment, blends of natural polysaccharides, gellan gum and retrograded starch hydrogels loaded with KET were proposed resulting in hydrogels with various rheological and mechanical properties and improvements in texture, as well as sustained drug release rate.139 The blending of starch and gelatin and their predominant effect on controlled drug release—for methylthioninium,140 ascorbic acid141 and vancomycin hydrochloride142—have been reported.

High amylose has a chemical reaction affinity due to its hydroxyl groups (esterification, etherification, and oxidation) that can modulate their solubility, swelling, film and gel formation and biodegradability rates.143 In this sense, a crosslinked interaction between high amylose starch and pectin incorporated by DS for additional applications in CDDSs was reported by Soares et al. The analytical results, including thermal analysis and X-ray diffraction, showed that while both thermal stability and crystallinity increased, the mechanical strength of the structures reduced due to drug loading. If we consider the suffix WD and CD as the samples without a crosslinker and the samples containing DS respectively, the greatest recovery (R %) indicated that the larger the amount of pectin in WD and CD samples they had (1:4 samples), the stronger and more elastic gels that were achieved. Moreover, drug loading did not qualitatively influence the rheological behavior which remained as gels, contributing that the extra drug can weaken the polymer network, and further interactions between the DS and carboxyl groups of the polymers could prevent hydrogen bonding.144

In another novel study, starch grafted with PEG (starch-g-PEG) and disulfide crosslinked micelles through lipoic acid (LA) loaded with the anti-cancer drug doxorubicin (DOX) were used for stimuli-responsive intracellular drug delivery. Another study, as is illustrated in Figure 7, used H40-star-PLA-SS-PEP as the main self-assembly polymeric structure for the preparation of the nanocarrier with the ability of loading DOX on its structure, and also on the surface. By comparing this study with the previous one, it can be concluded that in the absence of reductive glutathione (GSH), only a small amount of DOX could release, whereas, for the 10.0 mM of GSH, roughly 90% of DOX was efficiently released. Furthermore, the disulfide crosslinked micelles demonstrated a quicker DOX release in glutathione monoester (GSH-OEt) pretreated HeLa cells compared to non-pretreated and buthionine sulfoximine (BSO) pretreated cells, and as a result, disulfide crosslinked starch-g-PEG micelles paved the way for drug release.145,146

Figure 7 Illustration of Reduction-Stimulus Micelles Based on H40-star-PLA-SS-PEP for Intracellular DOX Release Triggered by Glutathione (GSH) Tripeptide.Notes: Reprinted with permission Liu J, Pang Y, Huang W, et al. Bioreducible micelles self-assembled from amphiphilic hyperbranched multiarm copolymer for glutathione-mediated intracellular drug delivery. Biomacromolecules. 2011;12(5):1567-1577. Copyright 2011 American Chemical Society.146Abbreviations: DOX, doxorubicin; GSH, glutathione

In a significant study, Setti et al developed a stable emulsion comprised of MaterBi® (a blend of thermoplastic starch and PCL) as the hydrophobic phase and SA as the hydrophilic phase for the controlled delivery of two commercial drugs: Neomercurocromo® and Cur. Homogenous polymer films were achieved by an ultrasonic processor without using any surfactants. Different MaterBi®/alginate fractions were tested, and finally, in vitro studies showed that these films were able to release both drugs separately and simultaneously in controllable rates compared to a pure PCL polymer. They made three sample films from the matrix of MaterBi®: (1) uncrosslinked and (2) crosslinked 50 wt% alginate 50 wt% MaterBi® films as well as (3) 30 wt% alginate 70 wt% MaterBi®. Over a span of 3 hours, the sample (1) released more hydrophilic drugs (Neomercurocromo®) while for (2), both drugs were released in lower amounts than their particular counterpart and finally for (3), Cur release was lower whereas for the Neomercurocromo®, release increased. Moreover, cell viability assays confirmed the biocompatibility of the films and suitability for superficial cell proliferation against human dermal fibroblasts in adult cells, and even for applications in wound healing and in the field of hygienic packaging of special pharmaceutical products.147

The superior advantages of starch nanocomposites — in comparison to conventional composites — include their optimal thermal, renewability, biodegradability, and mechanical and barrier properties, which have been widely used in the pharmaceutical industry as coating materials for CDDSs. However, our strongly held belief is that more research should be conducted for improving their controlled and local release area focussed on the physicochemical properties of starch and how to manufacture and make starch nanoparticles.

Synthetic Polymers Used in CDDSs

The role of synthetic polymers is of greatest importance in CDDSs as both a polymeric drug itself or as a carrier for small molecule drugs/bio-macromolecules, as such proteins embrace a significant function in releasing a drug, peptide or oligo or poly (nucleic acid) and can be regarded as stimuli-responsive polymers.17 Several studies have focused on using synthetic polymeric matrices in many biomedical industries due to their remarkable physical, resistance and mechanical properties.127,148 It is worth noticing that in the case of polymer blending, natural polymers often do not show gratifying results because of their preparation problems; thus, synthetic polymers are more favorable than natural polymers in many cases.149 Among those used for the sustained release and CDDSs, PLGA, PLA, and PGA have been emphasized more, owing to their approval by the US Food and Drug Administration (FDA) and the European Medicines Authorities (EMA) for human use.150 It should be mentioned that among all synthetic polymers, PEG has been blended more with the above compounds because it can increase hydrophilicity, avoid immune system clearance and provide a controlled release time, and in this way, much work has been published.151

The aforementioned polymers are usually blended with natural polymers to produce new hybrid products with suitable physicochemical and thermo-mechanical properties for promoting their fabrication into biomedical devices for prolonged release systems,152,153 which prevent fabrication and handling issues for medical applications.48 Novel synthetic polymers are being increasingly used in pharmaceutical sections as coating materials that provide for adequate mechanical properties and better polymeric electrospinnability. Over the past years, modified synthetic polymeric hydrogels have been blended with some natural polymers to achieve advanced biopolymers, which have paved the way for CDDSs. In this section, we illustrate the recent applications of PLGA, PLA and PGA and their blends with different excipients in numerous biomedical devices.

Applications of PLGA Blends in CDDSs

PLGA, a polyester of hydroxy acids, is one the most biocompatible, biodegradable and injectable polymers approved by the FDA for many biomedical and therapeutic applications, ranging from DDSs to tissue engineering.154156 Although PLGA is a glassy synthetic polymer, it has a quite rigid structure along with remarkable mechanical strength, permitting its use as CDDSs. Besides, PLGA copolymers possess high ratios of lactic acid which are less hydrophilic than functional groups in PGA, absorbing less water and consequently are more slowly degradable. Most importantly, PLGA hydrogels degrade in a dynamic process through hydrolytic cleavage of its poly (ester) backbone.157 To enhance the efficacy of PLGA in CDDSs, many modifications have emerged, such as PLGA copolymers containing blocks and alternating polymers through different hydrophilic moieties—namely PEG or PEO.158

However, PLGA has brittle and low elongation characteristics, so the blending of PCL with PLGA has emerged for developing nanofibers with sufficient flexibility, good porosity, slow degradability and a better biological nature.159 Individually controlled release of some hydrophilic antiretroviral drugs—including Tenofovir (TFV), Raltegravir (RAL), Maraviroc (MVC) and Azidothymidine (AZT)—was accomplished in vitro through uniaxial electrospun PLGA/PCL nanofibers. By utilizing representative scanning electron micrographs (SEM), different ratios of compositions demonstrated a shift in drug release from a burst to sustained release, as fibers with a high PCL concentration showed fast release (24 h), while fibers with high PLGA content could ameliorate limitations for the sustained release of TFV (30 days). In another study, scientists showed that different preparation procedures could lead to different surface morphologies, and in the following, different properties and biomedical applications. For instance, the addition of metal nanoparticles (such as Ag) or even metal salts into a polymeric structure as a dopant in the first phase of synthesis and in the last phase of synthesis can create two different surface morphologies of an obtained scaffold (Figure 8).160,161

Figure 8 Schematic illustration of the preparation procedure of PP-pDA-Ag-COL scaffolds. PLGA/PCL scaffolds were prepared by electrospun technology. Ag nanoparticles were in situ reduced by polydopamine and then coated by collagen I.Notes: Reprinted with permission Qian Y, Zhou X, Zhang F, Diekwisch TGH, Luan X, Yang J. Triple PLGA/PCL Scaffold Modification Including Silver Impregnation, Collagen Coating, and Electrospinning Significantly Improve Biocompatibility, Antimicrobial, and Osteogenic Properties for Orofacial Tissue Regeneration. ACS Appl Mater Interfaces. 2019;11(41):37381-37396. Copyright 2011 American Chemical Society.161

To overcome the drawbacks of PLGA hydrogels, such as short blood circulation and quick uptake by the reticuloendothelial system (RES), PEG-MS and PL/PEG compositions have been developed.162 These copolymers have largely been utilized in medicine, notably, for CDDSs for proteins and drugs. Their suitable interaction with drugs has alleviated drug loading content (DLC) problems even though producing surface-modified PEG-MS and PL/PEG loaded with drugs is a highly complicated issue because there are a few surface attachments of PEG in the production of PLGA/PEG.163,164 Jin et al developed sialic acid (SA) modified lung-targeted microspheres (MS) conjugated with PLGA/PEG (SA-PLGA/PEG-MS) to achieve the controlled release of triphenylphosphonium cation (TPP) coated with Cur (Cur-TPP) for treating acute lung injury (ALI) through emulsion solvent evaporation techniques. In vitro drug release studies indicated that 63 and 20% TPP- Cur had a prolonged (72 h) and burst (3 h) release, respectively, from both SA-PEG-MS and PL/PEG-MS and PLGA/PEG-MS. In another study, the sustained cumulative release of a typical drug from a starch-g-PEG/LA-based nanocarrier was investigated in typical biological conditions showing highly-dependant behavior to the structure of the polymer-based nanocarrier and also the drug loading ability (Figure 9).165

Figure 9 In vitro sustained cumulative release of DOX from starch-g-PEG/LA. Notes: Reprinted with permission from Jin F, Liu D, Yu H, et al. Sialic acid-functionalized PEG–PLGA microspheres loading mitochondrial-targeting-modified curcumin for acute lung injury therapy. Mol Pharm. 2018;16(1):71–85. Copyright 2018 American Chemical Society.165Abbreviation: PEG, polyethylene glycol;

Recently, Sánchez-López et al designed Memantine-PEG-PLGA (MEM-PEG-PLGA) with the expectation of targeting the blood-brain barrier (BBB) for Alzheimer’s treatment. In this experiment, the MEM was well distributed in the matrix of PLGA. DLC results were promising due to the growth of the thermogravimetric (Tg) parameter of the polymeric solution, although there was not a clear result concerning the strength of the interaction between the drug and hydrogels. Both in vivo and in vitro studies showed that the PLGA/PEG hydrogels delivered MEM in a controlled release manner to the target tissue, and the improvement in the drug therapeutic effect demonstrated a stable drug amount into the target organ.166

Likewise, in vitro, DOX release was controlled when loaded with a high affinity single-stranded EpCAM RNA aptamer conjugated to PLGA-PEG copolymers. In favor of PLGA-PEG nanopolymersomes, the cytotoxicity (P < 0.01) toward MCF-7 was greater than non-targeted nanopolymersomes, and the drug was released in a controlled and sustained manner.167 Farajzadeh and colleagues conducted a study to evaluate the synergistic inhibitory effect of Met and Cur loaded PLGA/PEG against T47D breast cancer cells. The morphology and dynamic light scattering (DLS) results were utilized to improve the nanoformulations. The drugs were encapsulated into the PLGA/PEG at a 1000:1 molar ratio, and the release profile of free drugs with the drug-NPs (Met-NP and Cur-NP) were compared. Impressively, the drugs were released in a sustained manner for more than 120 h without any initial burst release. This combination not only killed the T47D breast cancer cells more quickly than free drugs, but it also decreased cytotoxicity and side effects to patients.168

Novel PEG-PLGA/PLGA nanofibers were prepared and then loaded with gentamycin through a solid-oil-in water method to investigate the role of hydrogels in CDDSs. Drug release kinetics from the polymeric nanofibers were investigated by fitting the drug release data within four kinetic equations: zero order, first order, Higuchi and Korsmeyer-Peppas models. As a result, gentamycin content increased to 10.5 w/w% resulting in enhanced antibacterial activity as well as complete sustained release after 10 h.169 The anti-cancer activity of 9-cis-retinoic acid incorporated PEG-coated PLGA NPs was reported by Cosco et al. The dynamic Franz-type diffusion cell (comprised of a donor and a receptor) separated by a cellulose acetate membrane was evaluated for drug release. Therefore, the rapid and prolonged release of 9-cis-retinoic acid after 10 h and 48 h, respectively, were reported.170

It should be noted that blending has not always come with sustained release. For instance, electrospun nanofibers of PEGylated PLGA (PEG-PLGA) were selected to evaluate the release kinetics of amoxicillin (AMX). When recording the absorbance of the drug at 228 nm through a Lambda 25 UV–vis spectrophotometer, the release profiles of AMX from PLGA/AMX and PLGA-PEG/AMX nanofibers were obtained. This study showed that PLGA-PEG could release the drug in a faster manner than PLGA nanofibers. The reason is interesting: on account of the hydrophilicity of both AMX and PEG, and on the other hand, the hydrophobicity of PLGA in that its hydrophilicity was improved by PEG, AMX is more likely to disperse uniformly in the PLGA-PEG/AMX nanofibers than in the PLGA/AMX nanofibers. The greater surface area of the nanofibers also played a critical role. Furthermore, 3% PLGA/AMX exhibited a smaller release of AMX than 5% AMX/PLGA fibers (2 days) while the release profile for AMX for 3% PLGA-PEG/AMX was higher than for 5% PLGA-PEG/AMX nanofibers because of the low quantity of incorporation which was dispersed much more uniformly in the 3% PLGA-PEG/AMX than in the 5% PLGA-PEG/AMX nanofibers.171 In Table 4, additional applications of PLGA blends are summarized for the controlled release of various drugs.

Table 4 Other Applications of PLGA-Based Hydrogels in CDDSs

Applications of PLA Blends in CDDSs

Undoubtedly, PLA— as a tremendously versatile and aliphatic polyester discovered by Carothers in 1932172—is a biopolymer with much potential for biomedical applications. It can be produced by lactic acid (obtained by the fermentation of sugars originating from renewable resources) polymerization or through the ROP of lactic acid. Therefore, it is astonishingly biocompatible, biodegradable, eco-friendly and sustainable.173,174 PLA, additionally, has been extensively used in producing tissue scaffolds and drug carriers because of its degradability in carbon dioxide and water in vivo.175 PLA possesses three stereoisomers: semi-crystallized poly(D-lactide acid) (PDLA), poly(L-lactide acid) (PLLA) and amorphous poly(DL-lactide acid) (PDLLA), each with different structures as carriers for drug delivery.176 During recent years, various PLA blends have been introduced for CDDSs as beneficial copolymers for a wide range of medical and pharmaceutical applications.173,177,178 In the last years, many PEGylated PLA hydrogels have been synthesized and investigated for their application in CDDSs.151 Sirc et al have demonstrated the controlled release of some drugs based on PLA/PEG hydrogels. They reported not only the sustained release for Cyclosporine A (controlled release for a day)179 but more recently for PTX. The compositions of PLA/PEG-PTX were architected by a needleless electrospinning technique. HPLC-UV analysis ensured the advantages of this hydrogel on the prolonged and efficient release of PTX, including the sustained release of PTX in favor of additional ratios of PEG (15 wt %), remarkable cytotoxicity of PLA/PEG-PTX fibers against a human fibrosarcoma HT1080 cell line, as well as an increased antiangiogenic effect.

Most significantly, an in vivo study illustrated that PTX (at a concentration of PTX 0.1mg/cm2) loaded PLA-PEG(20) (PLA-PTX(10)-PEG(20)) prevented tumor recurrence, which paved the way for beneficial and safe local recurrence of tumor treatment.180 PEG-b-PLA NPs were designed through an organocatalyzed ring-opening polymerization process for assessing the in vitro drug release kinetics of Rhodamine B base (RhB), by utilizing two various surfactants to achieve diversely charged NPs: (i) choline chloride (CC) for positive charges and (ii) sodium dodecyl sulphate (SDS) for negative charges. With respect to the previously synthesized hydrogel, AC6, RhB loaded within AC6-NPs_SDS showed a prolonged release time of over a day (Figure 10).181

Figure 10 (A) Preparation of the drug loaded carrier and (B) the sustained release of RhB in AC6-NPs. Reproduced from Mauri E, Negri A, Rebellato E, Masi M, Perale G, Rossi F. Hydrogel-nanoparticles composite system for controlled drug delivery. Gels. 2018;4(3):74. Creative Commons license and disclaimer available from: http://creativecommons.org/licenses/by/4.0/legalcode.181Abbreviations: DCM, dichloromethane; NPs, nanoparticles; SDS, sodium dodecyl sulfate.

The controlled release of an important cephalosporin antibiotic drug, cefixime (Cfx), was assessed by Sherif et al who developed an effective composition prepared from PLA/PCL blends, including nano-hydroxyapatite (n-HA)—a prime mineral material of bone tissue in mammals—loaded with β-cyclodextrin (β-CD) and Cfx (PLA/PCL-βCD-Cfx) in the electrospun membranes. To evaluate the controlled release profile, PLA/PCL-nHA membranes were placed into 30 mL of a PBS solution. In the presence of βCD, the release of the drug was controlled to about half after 24 h, which exhibited a promising delivery approach of Cfx over a proper time period.182 Correspondingly, the Herrero group reported effective controlled BSA release from electrospun membranes of PLA/PCL blends possessing micron fiber diameters. Electrospinning parameters—such as flow rate, voltage, distance to the collector and solvents—played a crucial role in determining drug loading and release. As a consequence, PLA/PCL was able to cumulatively release BSA for up to three weeks.172 This study also highlights the additional significant improvement that could be obtained through the use of nanometer fibers, rather than the aforementioned studied micron fibers, due to their significantly greater surface area.

Several publications have reported the promising benefits of biodegradable copolymer use for CDDSs of pesticides and fertilizers, such as reducing environmental hazards, improving agricultural product yields, decreasing environmental contamination and reducing phytotoxicity.183186 Under these advantages, Wang et al reported CDDSs for pesticides, azoxystrobin, and difenoconazole, by exploiting the solvent evaporation method to obtain low toxicity and synergetic effects by utilizing microsphere poly (butylene succinate) (PBS) blended with PLA (70/30 w/w) as shells. Compared to the difenoconazole-ascomycete (5:8) 32.5% w/v suspension concentrate (SC) with 17 days of release, it was the PLA/PBS microsphere which helped the cumulative release of the drugs for up to 25 days at a concentration ratio of about 85%.187

Numerous studies have researched the advantages of PLA/PLGA copolymers, including their biodegradability and mechanical properties as well as their effective role in CDDSs of opioid antagonists, anti-cancer, anti-diarrheal, anti-bacterial, anti-psychotic, anti-inflammatory and anti-diabetic drugs for intramuscular, subcutaneous, periodontal and oral administration.188192 Milovanovic et al used a PLA/PLGA matrix with supercritical carbon dioxide (scCO2) as an effective solvent to proceed with the production of PLA/PLGA foams for the controlled delivery of thymol (a model drug) in a single-step procedure according to supercritical impregnation and foaming. The tested foams could release thymol in a controlled manner based on DSC and FTIR analyses between 3 to 6 weeks in PBS at 37 °C. Furthermore, the maximum thymol release rate (6.62%) of this foam demonstrated controlled release of the drug (3 days) at a pH value of 1.1.193 Hence, high surface area, tunable pore size and pore interconnectivity of pores could lead to remarkable controlled release carriers.

PLA would be an excellent candidate for polymer blending for a diverse number of medical applications. However, the commercial use of PLA blends has been restricted and is a long way from scale-up to date. Stable and effective formulations of PLA blends need to be more of a focus. In Table 5, additional applications of PLA-based NPs are summarized for the controlled release of various drugs.

Table 5 Other Applications of PLA-Based Hydrogels in CDDSs

Applications of PGA Blends for CDDSs

PGA is a safe and non-immunogenic polymer that was initially explored for the delivery of small products and antitumor agents in Phase III trials. PGA nanoparticles have been widely used as polymer-carriers for CDDSs due to their superb biodegradability and biocompatibility properties, which are being utilized for the targeted delivery of poorly soluble or unstable bioactive compounds bringing about low side effects and high drug loading efficacy.194196 Nevertheless, PGA has some limitations in CDDSs, such as insolubility in common solvents, problems in fabrication, high melting temperature (220 °C) and high crystallinity of approximately 50%.197,198

Accordingly, a naturally occurring anionic polypeptide γ-PGA—linked by the peptide bond among the α-amino and the abundant γ-carboxyl groups30—produced mostly using Bacillus subtilis bacteria199, has gained popularity on account of its satisfactory water solubility, favorable fiber-formation, film-forming ability, plasticity, and most greatly, for its activity in controlled drug release.175 Notably, γ-PGA with a negatively charged structure can blend with a positively charged polymer, providing electrostatic interactions to make biocompatible and biodegradable compositions, see Figure 11.200

Figure 11 The composition between γ-PGA as the negatively charged polymer and the positively charged polymer CS. Reproduced from Khalil I, Burns A, Radecka I, et al. Bacterial-derived polymer poly-y-glutamic acid (y-PGA)-based micro/nanoparticles as a delivery system for antimicrobials and other biomedical applications. Int J Mol Sci. 2017;18(2):313. Creative Commons license and disclaimer available from: http://creativecommons.org/licenses/by/4.0/legalcode.200Abbreviation: γ-PGA, poly-γ-glutamic acid.

Novel injectable and stimuli-responsive γ-PGA/collagen hydrogels loaded with DOX and granulocyte-macrophage colony-stimulating factor (GM-CSF) were developed by Cho et al. The γ-PGA ameliorated the innate temperature-based phase transition nature of collagen to a limited viscous sol and non-flowing gel states at room and body temperatures, respectively.

Chung et al exploited a spin-coating technique for the controlled release of bone morphogenetic protein 2 (BMP-2) incorporated with polyelectrolyte multilayers of CS/γ-PGA coated on a Ti6Al4V substrate. To fully decompose ex vivo, the prepared film required a 5–8 µm thickness and more than 45 days. Consequently, a 50% release of BMP-2 was observed to have an initial burst release within 3 h, while after that, the controlled release of BMP-2 over a span of 5 days was reported.202

In a recent study, aldehyde hyaluronic acid (HA-CHO) hydrazide-modified γ-PGA (γ-PGA-ADH) was synthesized to form HA/γ-PGA hydrogels through a Shiff base reaction. The controlled release of BSA as a biological compound with a variety of composition ratios was confirmed after 30 h during either diffusion or case-II relaxation mechanisms.203 Temperature and pH-responsive hydrogels based on poly (NIPAAm-co-poly (γ-glutamic acid) - Allyl glycidyl ether) (poly (NIPAAm-co- γ-PGA -AGE)) were synthesized by crosslinking polymerization to evaluate the controlled release of naproxen. In this study, γ-PGA-Allyl glycidyl ether (γ-PGA-AGE), which was obtained by the reaction of γ-PGA and AGE through ring-opening grafting, played an indispensable role in preparing the thermo/pH-sensitive NIPAAm-co- γ-PGA -AGE hydrogels. The cytocompatibility of the hydrogels was enhanced by increasing the ratio of γ-PGA-AGE. After 36 h, naproxen was released at 88 and 81% according to r= 0.20 and r= 0.15 hydrogels, respectively, while for r= 0.05 and r= 0.10, up to 12 h was required to reach the maximum release rate. As a result, the poly (NIPAAm-co-γ-PGA-AGE) hydrogels can be considered as a controlled drug release carrier.30

A novel diblock copolymer d-α-tocopheryl polyethylene glycol 1000 succinate-b-poly(e-caprolactone-ran-glycolide) (TPGSb-(PCL-ran-PGA) (TPP) was synthesized by ring-opening polymerization incorporated with potential antifungal drug itraconazole (ITZ) to form ITZ-TPP NPs by a modified double emulsion technique. Not only did this composition enhance antifungal activity of ITZ with no clear cytotoxicity on HeLa cells and fibroblasts nor any obvious inhibitory activity against fungal growth, more importantly, it showed a controlled release from 23.75 and 56% of the encapsulated drug during the first 3 days and more than 12 days, respectively.197 Liu et al developed polymersomes of folic acid (FA), which were effective for the controlled and targeted release of DOX, and the diblock PGA/PCL (FA-PGA-b-PCL) for ultrasensitive transverse (T2) MRI. Afterward, ultra-small superparamagnetic iron oxide NPs (SPIONs) were explored in situ as hydrophilic PGA coronas of FA-PGA-b-PCL to obtain magnetic polymersomes. Thus, a lower water diffusion coefficient and higher fruitful diameter were achieved, which could be a potential advantage resulting in greater T2 relaxivity of the FA-PGA-b-PCL. Besides, in terms of controlled release, DOX loaded FA-PGA-b-PCL released in a controlled manner for about 15 days. Both in vitro and in vivo tests reported that DOX was delivered and released significantly into the nucleus of HeLa cells with great efficiency (ie, tumor volume decreased gradually after two weeks) owing to the certain recognition and binding between FA on the surface of the polymersomes and the FA receptors on cancer cell membranes, indicating that these DOX-loaded magnetic polymersomes are favorable for numerous biomedical applications.204

Many studies have highlighted the different strategies of modern drug delivery to overcome the serious dilemma of platinum (II) drugs for cancer therapy, such as drug resistance, detoxification and side effects.205208 Recently, Yang et al developed a novel micelle of methoxy PEG-PGA and newly synthesized cisplatin derivative PyPt M (PyPt) as PyPt drugs in the polymeric core and PEG as the shell. PyPt is a poorly water-soluble drug, however, its aquated species can interact with mPEG-b-PLG—with the protection of PyPt from glutathione (GSH) detoxification—to enhance solubility in order to increase cellular uptake and the cytotoxicity of M (PyPt) compared to free cisplatin and PyPt. Consequently, the benefits of M (PyPt) include less detoxification of GSH in PyPt, resulting in a high affinity to bind DNA, higher apoptosis, improved cisplatin efficacy and resistance. Moreover, the M (PyPt) demonstrated the potential controlled release of Pt in tumor micro-environments, which prohibited the division of cancer cells. However, basically, the preparation of a nano polymer blend system is the same for any study and investigation, and follows basic rules in this matter (Figure 12).209

Figure 12 Schematic illustration of the preparation of a typical polymer nano blend system.

The controlled release necessary for overcoming biological barriers related to the oral administration of peptides was reported by Niu and co-workers. In this scenario, they created core-shell nanoparticles in which the core was a hydrophobically-modified cell-penetrating peptide (CPP) and insulin and the shell was a selected model peptide along with the copolymer PGA-PEG in order to preserve the drug and carrier from the inclement conditions of the intestine. Moreover, they chose octaarginine (r8) as the CPP, which can interact with insulin through electrostatic and hydrophobic forces. One way to design PGA-PEG enveloped r8-insulin nano-complexes (ENCPs) is to dissolve PGA-PEG in water, followed by evaporating water in a round flask under reduced pressure at 37 °C, then adding r8-insulin nano-complexes (NCPs) to the flask for about a 10 min rotation until the NCPs were enveloped with the film, followed by the adjustment of ENCPs at a pH of 7. ENCPs had such fascinating advantages, such as the potential controlled release of insulin in vivo (release from the ENCPs was slower than the NCPs alone), better protection of insulin from enzymatic degradation and to solidify in simulated intestinal fluid (SIF).210

Conclusions and Future Prospects

This review scrutinized recent developments and the characterization of nano polymeric blends for CDDSs. Recently, CDDSs have attracted much attention due to their massive advantages over conventional drug therapy. They are distinguished by a variety of categories, such as diffusion-controlled, chemically controlled, solvent activated and modulated release systems.50 CDDSs have been additionally reported in which drugs can be dissolved or dispersed in the films. The effective delivery of a drug at a controlled rate over an accurate time frame to a selected target organ has been the absolute necessity in drug delivery technology and pharmacokinetics.

Polymer blends have demonstrated a good response to external stimuli—such as pH, temperature, ionic factor, electric field and magnetic field—which can be regarded as a novel class of carriers or coating materials for sustained drug release and for CDDSs. Synthetic as well as naturally occurring polymers can blend to generate a hybrid polymer with new physical and chemical properties. Examples of naturally occurring polymers include CS, cellulose, and starch, while on the other hand, PLGA, PLA and PGA are salient examples of synthetic polymers.

Different types of drugs can be fabricated into biocompatible and biodegradable polymers with various strategies. During past years, there has been a promising need for the development of polymer blends, and these necessities will continue to steadily increase in the future. Moreover, polymer blends loaded with a drug could release a drug over a prolonged time by reducing the drug dosage and unwanted toxic effects. Consequently, these compositions are ideal candidates for CDDSs. However, functionality and drug release mechanisms of these systems are highly complicated, more than that of just one polymer. Thus, it is worth implementing a practical decision to reduce time and a cost-intensive series of trial and error experiments in order to accurately assess therapeutic efficacy and ameliorate the clinical practice of polymer blends. It is of critical importance to evaluate such systems more clinically and pathologically in animal models.

Therefore, in summary, even though improvements and enhancements have been reported by numerous researchers worldwide, there are still too many challenges that must be solved before the widespread use of nano polymer blends are realized in medicine. In addition, the field of CDDSs suggests a large variety in scope and prospect to develop novel technologies with high performance and potential economically viable solutions, issues commonly ignored in today’s published papers.

Disclosure

The authors report no conflicts of interest in this work.

References

1. Moghanjoughi AA, Khoshnevis D, Zarrabi A. A concise review on smart polymers for controlled drug release. Drug Deliv Transl Res. 2016;6(3):333–340. doi:10.1007/s13346-015-0274-7

2. Schmitt H, Creton N, Prashantha K, Soulestin J, Lacrampe M, Krawczak P. Melt‐blended halloysite nanotubes/wheat starch nanocomposites as drug delivery system. Polymer Eng Sci. 2015;55(3):573–580. doi:10.1002/pen.23919

3. Tiwari G, Tiwari R, Sriwastawa B, et al. Drug delivery systems: an updated review. Int J Pharm Investig. 2012;2(1):2. doi:10.4103/2230-973X.96920

4. Krukiewicz K, Zawisza P, Herman AP, Turczyn R, Boncel S, Zak JK. An electrically controlled drug delivery system based on conducting poly (3, 4-ethylenedioxypyrrole) matrix. Bioelectrochemistry. 2016;108:13–20. doi:10.1016/j.bioelechem.2015.11.002

5. Iturrioz-Rodríguez N, Correa-Duarte MA, Fanarraga ML. Controlled drug delivery systems for cancer based on mesoporous silica nanoparticles. Int J Nanomedicine. 2019;14:3389. doi:10.2147/IJN.S198848

6. Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM. Polymeric systems for controlled drug release. Chem Rev. 1999;99(11):3181–3198. doi:10.1021/cr940351u

7. Senapati S, Mahanta AK, Kumar S, Maiti P. Controlled drug delivery vehicles for cancer treatment and their performance. Signal Trans Target Ther. 2018;3(1):1–19. doi:10.1038/s41392-017-0004-3

8. Pushpamalar J, Veeramachineni AK, Owh C, Loh XJ. Biodegradable polysaccharides for controlled drug delivery. ChemPlusChem. 2016;81(6):504–514. doi:10.1002/cplu.201600112

9. Li J, Mooney DJ. Designing hydrogels for controlled drug delivery. Nat Rev Mater. 2016;1(12):16071. doi:10.1038/natrevmats.2016.71

10. Maulvi FA, Lakdawala DH, Shaikh AA, et al. In vitro and in vivo evaluation of novel implantation technology in hydrogel contact lenses for controlled drug delivery. J Controlled Rel. 2016;226:47–56. doi:10.1016/j.jconrel.2016.02.012

11. Khoee S, Rahimi S. Reversible core–shell crosslinked micelles for controlled release of bioactive agents. In: Nanoarchitectonics in Biomedicine. Alexandru Mihai Grumezescu. Elsevier; 2019:119–167.

12. Hyland SJ, Deliberato DG, Fada RA, Romanelli MJ, Collins CL, Wasielewski RC. Liposomal bupivacaine versus standard periarticular injection in total knee arthroplasty with regional anesthesia: a prospective randomized controlled trial. J Arthroplasty. 2019;34(3):488–494. doi:10.1016/j.arth.2018.11.026

13. Khan S, Akhtar N, Minhas MU. Fabrication, rheological analysis, and in vitro characterization of in situ chemically cross‐linkable thermogels as controlled and prolonged drug depot for localized and systemic delivery. Polym Adv Technol. 2019;30(3):755–771.

14. Hussain M, Xie J, Hou Z, et al. Regulation of drug release by tuning surface textures of biodegradable polymer microparticles. ACS Appl Mater Interfaces. 2017;9(16):14391–14400. doi:10.1021/acsami.7b02002

15. Hasnain MS, Nayak AK, Singh M, Tabish M, Ansari MT, Ara TJ. Alginate-based bipolymeric-nanobioceramic composite matrices for sustained drug release. Int J Biol Macromol. 2016;83:71–77. doi:10.1016/j.ijbiomac.2015.11.044

16. Ngwuluka N, Ochekpe N, Aruoma O. Naturapolyceutics: the science of utilizing natural polymers for drug delivery. polymers. 2014;6(5):1312–1332. doi:10.3390/polym6051312

17. Schmaljohann D. Thermo-and pH-responsive polymers in drug delivery. Adv Drug Deliv Rev. 2006;58(15):1655–1670. doi:10.1016/j.addr.2006.09.020

18. Srikanth P, Narayana R, Wasim Raja S, Brito Raj S. A review on oral controlled drug delivery. Advan Pharm. 2013;3:51–58.

19. Wei M, Gao Y, Li X, Serpe MJ. Stimuli-responsive polymers and their applications. Polym Chem. 2017;8(1):127–143. doi:10.1039/C6PY01585A

20. Shi J, Votruba AR, Farokhzad OC, Langer R. Nanotechnology in drug delivery and tissue engineering: from discovery to applications. Nano Lett. 2010;10(9):3223–3230. doi:10.1021/nl102184c

21. Mir M, Ishtiaq S, Rabia S, et al. Nanotechnology: from in vivo imaging system to controlled drug delivery. Nanoscale Res Lett. 2017;12(1):500. doi:10.1186/s11671-017-2249-8

22. Darbasizadeh B, Fatahi Y, Feyzi-barnaji B, et al. Crosslinked-polyvinyl alcohol-carboxymethyl cellulose/ZnO nanocomposite fibrous mats containing erythromycin (PVA-CMC/ZnO-EM): fabrication, characterization and in-vitro release and anti-bacterial properties. Int J Biol Macromol. 2019;141:1137–1146. doi:10.1016/j.ijbiomac.2019.09.060

23. Patel GC, Yadav BK. Polymeric nanofibers for controlled drug delivery applications. In: Organic Materials as Smart Nanocarriers for Drug Delivery.  Alexandru Mihai Grumezescu. Elsevier; 2018:147–175.

24. Nazari T, Moghaddam AB, Davoodi Z. Optimized polylactic acid/polyethylene glycol (PLA/PEG) electrospun fibrous scaffold for drug delivery: effect of graphene oxide on the cefixime release mechanism. Mater Res Express. 2019;6(11):115351. doi:10.1088/2053-1591/ab508d

25. Silva-Abreu M, Calpena AC, Andrés-Benito P, et al. PPARγ agonist-loaded PLGA-PEG nanocarriers as a potential treatment for Alzheimer’s disease: in vitro and in vivo studies. Int J Nanomedicine. 2018;13:5577. doi:10.2147/IJN.S171490

26. Muhamad L II, Selvakumaran S, Lazim NAM. Designing polymeric nanoparticles for targeted drug delivery system. Nanomed. 2014;287:287.

27. Jin G, Prabhakaran MP, Kai D, Ramakrishna S. Controlled release of multiple epidermal induction factors through core–shell nanofibers for skin regeneration. Eur J Pharm Biopharm. 2013;85(3):689–698. doi:10.1016/j.ejpb.2013.06.002

28. Ulery BD, Nair LS, Laurencin CT. Biomedical applications of biodegradable polymers. J Polym Sci B Polym Phys. 2011;49(12):832–864.

29. Tian H, Tang Z, Zhuang X, Chen X, Jing X. Biodegradable synthetic polymers: preparation, functionalization and biomedical application. Prog Polym Sci. 2012;37(2):237–280. doi:10.1016/j.progpolymsci.2011.06.004

30. Yang N, Wang Y, Zhang Q, Chen L, Zhao Y. γ-Polyglutamic acid mediated crosslinking PNIPAAm-based thermo/pH-responsive hydrogels for controlled drug release. Polym Degrad Stab. 2017;144:53–61. doi:10.1016/j.polymdegradstab.2017.07.028

31. Vashist A, Ahmad S. Hydrogels: smart materials for drug delivery. Oriental J Chem. 2013;29(3):861–870. doi:10.13005/ojc/290303

32. Patil J, Kamalapur M, Marapur S, Kadam D. Ionotropic gelation and polyelectrolyte complexation: the novel techniques to design hydrogel particulate sustained, modulated drug delivery system: a review. Digest J Nanomater Biostruct. 2010;5(1):241–248.

33. H-j L, Ahn S-H, Kim GH. Three-dimensional collagen/alginate hybrid scaffolds functionalized with a drug delivery system (DDS) for bone tissue regeneration. Chem Mater. 2012;24(5):881–891. doi:10.1021/cm200733s

34. Guan J, He H, Hansford DJ, Lee LJ. Self-folding of three-dimensional hydrogel microstructures. J Phys Chem B. 2005;109(49):23134–23137. doi:10.1021/jp054341g

35. Nguyen LH, Gao M, Lin J, Wu W, Wang J, Chew SY. Three-dimensional aligned nanofibers-hydrogel scaffold for controlled non-viral drug/gene delivery to direct axon regeneration in spinal cord injury treatment. Sci Rep. 2017;7:42212. doi:10.1038/srep42212

36. Johnson LM, DeForest CA, Pendurti A, Anseth KS, Bowman CN. Formation of three-dimensional hydrogel multilayers using enzyme-mediated redox chain initiation. ACS Appl Mater Interfaces. 2010;2(7):1963–1972. doi:10.1021/am100275n

37. Ahmed EM. Hydrogel: preparation, characterization, and applications: A review. J Advan Res. 2015;6(2):105–121. doi:10.1016/j.jare.2013.07.006

38. Xu W, Ling P, Zhang T. Polymeric micelles, a promising drug delivery system to enhance bioavailability of poorly water-soluble drugs. J Drug Deliv. 2013;2013.

39. Ahmad Z, Shah A, Siddiq M, Kraatz H-B. Polymeric micelles as drug delivery vehicles. RSC Adv. 2014;4(33):17028–17038. doi:10.1039/C3RA47370H

40. Sang X, Yang Q, Wen Q, Zhang L, Ni C. Preparation and controlled drug release ability of the poly [N-isopropylacryamide-co-allyl poly (ethylene glycol)]-b-poly (γ-benzyl-l-glutamate) polymeric micelles. Mater Sci Eng C. 2019;98:910–917. doi:10.1016/j.msec.2019.01.056

41. Feng X-R, Ding J-X, Gref R, Chen X-S. Poly (β-cyclodextrin)-mediated polylactide-cholesterol stereocomplex micelles for controlled drug delivery. Chin J Polymer Sci. 2017;35(6):693–699. doi:10.1007/s10118-017-1932-7

42. Parameswaranpillai J, Thomas S, Grohens Y. Polymer blends: state of the art, new challenges, and opportunities. Characterization Polymer Blends. 2015;1–6.

43. Makhijani K, Kumar R, Sharma SK. Biodegradability of blended polymers: a comparison of various properties. Crit Rev Environ Sci Technol. 2015;45(16):1801–1825. doi:10.1080/10643389.2014.970682

44. Ferreira SBDS, Moco TD, Borghi-Pangoni FB, Junqueira MV, Bruschi ML. Rheological, mucoadhesive and textural properties of thermoresponsive polymer blends for biomedical applications. J Mech Behav Biomed Mater. 2016;55:164–178. doi:10.1016/j.jmbbm.2015.10.026

45. Li Z, Johnson LM, Ricarte RG, et al. Enhanced performance of blended polymer excipients in delivering a hydrophobic drug through the synergistic action of micelles and HPMCAS. Langmuir. 2017;33(11):2837–2848. doi:10.1021/acs.langmuir.7b00325

46. Tipduangta P, Belton P, Fabian L, et al. Electrospun polymer blend nanofibers for tunable drug delivery: the role of transformative phase separation on controlling the release rate. Mol Pharm. 2015;13(1):25–39. doi:10.1021/acs.molpharmaceut.5b00359

47. Buwalda SJ, Vermonden T, Hennink WE, Hydrogels for Therapeutic Delivery: Current Developments and Future Directions. Biomacromolecules.2017;18(2):316–330.

48. Munj HR, Lannutti JJ, Tomasko DL. Understanding drug release from PCL/gelatin electrospun blends. J Biomater Appl. 2017;31(6):933–949. doi:10.1177/0885328216673555

49. Son YJ, Kim WJ, Yoo HS. Therapeutic applications of electrospun nanofibers for drug delivery systems. Arch Pharm Res. 2014;37(1):69–78. doi:10.1007/s12272-013-0284-2

50. Bajpai AK, Shukla SK, Bhanu S, Kankane S. Responsive polymers in controlled drug delivery. Prog Polym Sci. 2008;33(11):1088–1118. doi:10.1016/j.progpolymsci.2008.07.005

51. Ma C, Shi Y, Pena DA, Peng L, Yu G. Thermally responsive hydrogel blends: a general drug carrier model for controlled drug release. Angewandte Chemie International Edition. 2015;54(25):7376–7380. doi:10.1002/anie.201501705

52. La Mantia F, Morreale M, Botta L, Mistretta M, Ceraulo M, Scaffaro R. Degradation of polymer blends: a brief review. Polym Degrad Stab. 2017;145:79–92. doi:10.1016/j.polymdegradstab.2017.07.011

53. Ibrahim BA, Kadum KM. Influence of polymer blending on mechanical and thermal properties. Modern Appl Sci. 2010;4(9):157. doi:10.5539/mas.v4n9p157

54. Dubey KA, Chaudhari CV, Bhardwaj YK, Varshney L. Polymers, blends and nanocomposites for implants, scaffolds and controlled drug release applications. Advan Biomater Biomed Appl Springer. 2017;1–44.

55. Van Puyvelde P, Velankar S, Moldenaers P. Rheology and morphology of compatibilized polymer blends. Curr Opin Colloid Interface Sci. 2001;6(5–6):457–463. doi:10.1016/S1359-0294(01)00113-3

56. de Luna MS, Filippone G. Effects of nanoparticles on the morphology of immiscible polymer blends–Challenges and opportunities. Eur Polym J. 2016;79:198–218. doi:10.1016/j.eurpolymj.2016.02.023

57. Ryan AJ. Designer polymer blends. Nat Mater. 2002;1(1):8–10. doi:10.1038/nmat720

58. Thomas S, Shanks R, Chandran S. Nanostructured Polymer Blends. William Andrew; 2013.

59. Deo KA, Lokhande G, Gaharwar AK. Nanostructured hydrogels for tissue engineering and regenerative medicine. Encyclopedia of Tissue Engineering and Regenerative Medicine Oxford, UK: Academic Press. 2019;21.

60. Montoro SR, de Fátima Medeiros S, Alves GM. Nanostructured hydrogels. In: Nanostructured Polymer Blends. E. Calo. Elsevier; 2014:325–355.

61. J-E L, Johansson L, Norman A-C, Wettström K. Interactions between surfactants and polymers. I: HPMC. In: Trends in Colloid and Interface Science V. M. Corti. Springer; 1991:73–77.

62. Martins RM, CAd S, Becker CM, Samios D, Christoff M, Bica CI. Anionic surfactant aggregation with (hydroxypropyl) cellulose in the presence of added salt. J Braz Chem Soc. 2006;17(5):944–953. doi:10.1590/S0103-50532006000500019

63. Liu X, Lei L, Hou J-W, et al. Evaluation of two polymeric blends (EVA/PLA and EVA/PEG) as coating film materials for paclitaxel-eluting stent application. J Mater Sci Mater Med. 2011;22(2):327–337. doi:10.1007/s10856-010-4213-3

64. Satturwar PM, Fulzele SV, Dorle AK. Biodegradation and in vivo biocompatibility of rosin: a natural film-forming polymer. AAPS PharmSciTech. 2003;4(4):434–439. doi:10.1208/pt040455

65. Kulkarni Vishakha S, Butte Kishor D, Rathod Sudha S. Natural polymers–A comprehensive review. Int J Res Pharm Biomed Sci. 2012;3(4):1597–1613.

66. Gavasane AJ, Pawar HA. Synthetic biodegradable polymers used in controlled drug delivery system: an overview. Clin Pharmacol Biopharm. 2014;3(2):1–7. doi:10.4172/2167-065X.1000121

67. Muxika A, Etxabide A, Uranga J, Guerrero P, De La Caba K. Chitosan as a bioactive polymer: processing, properties and applications. Int J Biol Macromol. 2017;105:1358–1368. doi:10.1016/j.ijbiomac.2017.07.087

68. Muslim T, Rahman MH, Begum HA, Rahman MA. Chitosan and carboxymethyl chitosan from fish scales of Labeo rohita. Dhaka Univ J Sci. 2013;61(1):145–148. doi:10.3329/dujs.v61i1.15116

69. Ahsan SM, Thomas M, Reddy KK, Sooraparaju SG, Asthana A, Bhatnagar I. Chitosan as biomaterial in drug delivery and tissue engineering. Int J Biol Macromol. 2018;110:97–109. doi:10.1016/j.ijbiomac.2017.08.140

70. Jesus S, Fragal EH, Rubira AF, Muniz EC, Valente AJ, Borges O. The inclusion of chitosan in poly-ε-caprolactone nanoparticles: impact on the delivery system characteristics and on the adsorbed ovalbumin secondary structure. AAPS PharmSciTech. 2018;19(1):101–113. doi:10.1208/s12249-017-0822-1

71. Arthanari S, Mani G, Peng MM, Jang HT. Chitosan–HPMC-blended microspheres as a vaccine carrier for the delivery of tetanus toxoid. Artif Cells Nanomed Biotechnol. 2016;44(2):517–523. doi:10.3109/21691401.2014.966193

72. Munhoz M, Hirata H, AMdG P, Martins VC, Cunha M. Use of collagen/chitosan sponges mineralized with hydroxyapatite for the repair of cranial defects in rats. Injury. 2018;49(12):2154–2160. doi:10.1016/j.injury.2018.09.018

73. Arya G, Das M, Sahoo SK. Evaluation of curcumin loaded chitosan/PEG blended PLGA nanoparticles for effective treatment of pancreatic cancer. Biomed Pharmacother. 2018;102:555–566. doi:10.1016/j.biopha.2018.03.101

74. Abaza A, Hegazy E, Mahmoud GA, Elsheikh B. Characterization and antitumor activity of chitosan/poly (vinyl alcohol) blend doped with gold and silver nanoparticles in treatment of prostatic cancer model. J Pharm Pharmacol. 2018;2018(6):659–667.

75. Ko JE, Ko YG, Kim WI, Kwon OK, Kwon OH. Nanofiber mats composed of a chitosan‐poly (d, l‐lactic‐co‐glycolic acid)‐poly (ethylene oxide) blend as a postoperative anti‐adhesion agent. J Biomed Mater Res B Appl Biomater. 2017;105(7):1906–1915. doi:10.1002/jbm.b.33726

76. Gómez Chabala L, Cuartas C, López M. Release behavior and antibacterial activity of chitosan/alginate blends with aloe vera and silver nanoparticles. Mar Drugs. 2017;15(10):328. doi:10.3390/md15100328

77. Rajashree S, Rose C. Studies on an anti-aging formulation prepared using aloe vera blended collagen and chitosan. Int J Pharm Sci Res. 2018;9:582–588.

78. Tamer TM, Valachová K, Hassan MA, et al. Chitosan/hyaluronan/edaravone membranes for anti-inflammatory wound dressing: in vitro and in vivo evaluation studies. Mater Sci Eng C. 2018;90:227–235. doi:10.1016/j.msec.2018.04.053

79. Rasool A, Ata S, Islam A. Stimuli responsive biopolymer (chitosan) based blend hydrogels for wound healing application. Carbohydr Polym. 2019;203:423–429. doi:10.1016/j.carbpol.2018.09.083

80. Racine L, Costa G, Bayma-Pecit E, Texier I, Auzély-Velty R. Design of interpenetrating chitosan and poly (ethylene glycol) sponges for potential drug delivery applications. Carbohydr Polym. 2017;170:166–175. doi:10.1016/j.carbpol.2017.04.060

81. Sizílio R, Galvão J, Trindade G, et al. Chitosan/pvp-based mucoadhesive membranes as a promising delivery system of betamethasone-17-valerate for aphthous stomatitis. Carbohydr Polym. 2018;190:339–345. doi:10.1016/j.carbpol.2018.02.079

82. Kanth V, Kajjari P, Madalageri P, Ravindra S, Manjeshwar L, Aminabhavi T. Blend hydrogel microspheres of carboxymethyl chitosan and gelatin for the controlled release of 5-fluorouracil. Pharmaceutics. 2017;9(2):13. doi:10.3390/pharmaceutics9020013

83. Berretta JM, Jennings JA, Courtney HS, Beenken KE, Smeltzer MS, Haggard WO. Blended chitosan paste for infection prevention: preliminary and preclinical evaluations. Clin Orth Related Res. 2017;475(7):1857–1870. doi:10.1007/s11999-017-5231-y

84. Park S, Choi D, Jeong H, Heo J, Hong J. Drug loading and release behavior depending on the induced porosity of chitosan/cellulose multilayer Nanofilms. Mole Pharm. 2017;14(10):3322–3330.

85. Rokhade AP, Shelke NB, Patil SA, Aminabhavi TM. Novel hydrogel microspheres of chitosan and pluronic F-127 for controlled release of 5-fluorouracil. J Microencapsul. 2007;24(3):274–288. doi:10.1080/02652040701281365

86. Anirudhan TS, Parvathy J. Novel thiolated chitosan-polyethyleneglycol blend/Montmorillonite composite formulations for the oral delivery of insulin. Bioactive Carbohydrates Dietary Fibre. 2018;16:22–29. doi:10.1016/j.bcdf.2018.02.003

87. Shi Y, Jia L, Du Q, Niu J, Zhang D. Surface-modified PLGA nanoparticles with chitosan for oral delivery of tolbutamide. Colloids Surf B Biointerfaces. 2018;161:67–72. doi:10.1016/j.colsurfb.2017.10.037

88. Shariatinia Z, Zahraee Z. Controlled release of metformin from chitosan–based nanocomposite films containing mesoporous MCM-41 nanoparticles as novel drug delivery systems. J Colloid Interface Sci. 2017;501:60–76. doi:10.1016/j.jcis.2017.04.036

89. Habibi Y, Lucia LA, Rojas OJ. Cellulose nanocrystals: chemistry, self-assembly, and applications. Chem Rev. 2010;110(6):3479–3500. doi:10.1021/cr900339w

90. Jackson JK, Letchford K, Wasserman BZ, Ye L, Hamad WY, Burt HM. The use of nanocrystalline cellulose for the binding and controlled release of drugs. Int J Nanomedicine. 2011;6:321. doi:10.2147/IJN.S25646

91. Baumann MD, Kang CE, Stanwick JC, et al. An injectable drug delivery platform for sustained combination therapy. J Controlled Rel. 2009;138(3):205–213. doi:10.1016/j.jconrel.2009.05.009

92. Khan GM, Zhu J-B. Studies on drug release kinetics from ibuprofen–carbomer hydrophilic matrix tablets: influence of co-excipients on release rate of the drug. J Controlled Rel. 1999;57(2):197–203. doi:10.1016/S0168-3659(98)00122-9

93. Duarte ARC, Gordillo M, Cardoso MM, Simplício AL, Duarte CM. Preparation of ethyl cellulose/methyl cellulose blends by supercritical antisolvent precipitation. Int J Pharm. 2006;311(1–2):50–54. doi:10.1016/j.ijpharm.2005.12.010

94. Grayson ACR, Choi IS, Tyler BM, et al. Multi-pulse drug delivery from a resorbable polymeric microchip device. Nat Mater. 2003;2(11):767–772. doi:10.1038/nmat998

95. Shen Q, Liu D-S. Cellulose/poly (ethylene glycol) blend and its controllable drug release behaviors in vitro. Carbohydr Polym. 2007;69(2):293–298. doi:10.1016/j.carbpol.2006.10.012

96. Khan S, Ranjha NM. Effect of degree of cross-linking on swelling and on drug release of low viscous chitosan/poly (vinyl alcohol) hydrogels. Polymer Bull. 2014;71(8):2133–2158. doi:10.1007/s00289-014-1178-2

97. Malik NS, Ahmad M, Minhas MU. Cross-linked β-cyclodextrin and carboxymethyl cellulose hydrogels for controlled drug delivery of acyclovir. PLoS One. 2017;12(2):e0172727. doi:10.1371/journal.pone.0172727

98. Agrahari V, Agrahari V, Meng J, Mitra AK. Electrospun nanofibers in drug delivery: fabrication, advances, and biomedical applications. In: Emerging Nanotechnologies for Diagnostics, Drug Delivery and Medical Devices. Ashim K. Mitra. Elsevier; 2017:189–215.

99. Nguyen TTT, Chung OH, Park JS. Coaxial electrospun poly (lactic acid)/chitosan (core/shell) composite nanofibers and their antibacterial activity. Carbohydr Polym. 2011;86(4):1799–1806. doi:10.1016/j.carbpol.2011.07.014

100. Bhattarai RS, Bachu RD, Boddu SH, Bhaduri S. Biomedical applications of electrospun nanofibers: drug and nanoparticle delivery. Pharmaceutics. 2019;11(1):5. doi:10.3390/pharmaceutics11010005

101. Weng L, Xie J. Smart electrospun nanofibers for controlled drug release: recent advances and new perspectives. Curr Pharm Des. 2015;21(15):1944–1959. doi:10.2174/1381612821666150302151959

102. Cheng H, Yang X, Che X, Yang M, Zhai G. Biomedical application and controlled drug release of electrospun fibrous materials. Mater Sci Eng C. 2018;90:750–763. doi:10.1016/j.msec.2018.05.007

103. El-Newehy MH, El-Naggar ME, Alotaiby S, El-Hamshary H, Moydeen M, Al-Deyab S. Green electrospining of hydroxypropyl cellulose nanofibres for drug delivery applications. J Nanosci Nanotechnol. 2018;18(2):805–814. doi:10.1166/jnn.2018.13852

104. Gencturk A, Kahraman E, Güngör S, Özhan G, Özsoy Y, Sarac A. Polyurethane/hydroxypropyl cellulose electrospun nanofiber mats as potential transdermal drug delivery system: characterization studies and in vitro assays. Artif Cells Nanomed Biotechnol. 2017;45(3):655–664. doi:10.3109/21691401.2016.1173047

105. Hu J, Li H-Y, Williams GR, Yang -H-H, Tao L, Zhu L-M. Electrospun poly (N-isopropylacrylamide)/ethyl cellulose nanofibers as thermoresponsive drug delivery systems. J Pharm Sci. 2016;105(3):1104–1112. doi:10.1016/S0022-3549(15)00191-4

106. Esmaeili A, Haseli M. Optimization, synthesis, and characterization of coaxial electrospun sodium carboxymethyl cellulose-graft-methyl acrylate/poly (ethylene oxide) nanofibers for potential drug-delivery applications. Carbohydr Polym. 2017;173:645–653. doi:10.1016/j.carbpol.2017.06.037

107. Ooi SY, Ahmad I, Amin MCIM. Cellulose nanocrystals extracted from rice husks as a reinforcing material in gelatin hydrogels for use in controlled drug delivery systems. Ind Crops Prod. 2016;93:227–234. doi:10.1016/j.indcrop.2015.11.082

108. Lai, WF, Shum HC. Hypromellose-graft-chitosan and its polyelectrolyte complex as novel systems for sustained drug delivery. ACS Applied Materials & Interfaces. 2015;7(19):10501–10510

109. De Simone V, Dalmoro A, Lamberti G, Caccavo D, d’Amore M, Barba AA. HPMC granules by wet granulation process: effect of vitamin load on physicochemical, mechanical and release properties. Carbohydr Polym. 2018;181:939–947. doi:10.1016/j.carbpol.2017.11.056

110. Siepmann J, Peppas N. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv Drug Deliv Rev. 2012;64:163–174. doi:10.1016/j.addr.2012.09.028

111. Melaj MA, Daraio ME, Vazquez A. Controlled release on sand bed columns and biodegradability in soil of chitosan: hydroxypropyl methylcellulose films. J Appl Polym Sci. 2019;136(20):47532. doi:10.1002/app.47532

112. Karavas E, Georgarakis E, Bikiaris D. Felodipine nanodispersions as active core for predictable pulsatile chronotherapeutics using PVP/HPMC blends as coating layer. Int J Pharm. 2006;313(1–2):189–197. doi:10.1016/j.ijpharm.2006.01.015

113. Siddaramaiah KP, Divya K, Mhemavathi B, Manjula D. Chitosan/HPMC polymer blends for developing transdermal drug delivery systems. J Macromol Scie Part A. 2006;43(3):601–607. doi:10.1080/10601320600575231

114. Attama A, Akpa P, Onugwu L, Igwilo G. Novel buccoadhesive delivery system of hydrochlorothiazide formulated with ethyl cellulose-hydroxypropyl methylcellulose interpolymer complex. Sci Res Essays. 2008;3(8):334–343.

115. Azhar SA, Kumar PR, Sood V, Shyale S. Studies on directly compressed ondansetron hydrochloride mucoadhesive buccal tablets using gelatin, chitosan and xanthan gum along with HPMC K4M. J Appl Pharm Sci. 2012;2(5):1.

116. Saeidipour F, Mansourpour Z, Mortazavian E, Rafiee-Tehrani N, Rafiee-Tehrani M. New comprehensive mathematical model for HPMC-MCC based matrices to design oral controlled release systems. Eur J Pharm Biopharm. 2017;121:61–72. doi:10.1016/j.ejpb.2017.09.007

117. Lee K-H, Park C, Oh G, Park J-B, Lee B-J. New blends of hydroxypropylmethylcellulose and Gelucire 44/14: physical property and controlled release of drugs with different solubility. J Pharm Invest. 2018;48(3):313–321. doi:10.1007/s40005-017-0322-z

118. Wilson MR, Jones DS, Andrews GP. The development of sustained release drug delivery platforms using melt‐extruded cellulose‐based polymer blends. J Pharm Pharmacol. 2017;69(1):32–42. doi:10.1111/jphp.12656

119. Zabihi F, Yang M, Leng Y, Zhao Y. PLGA–HPMC nanoparticles prepared by a modified supercritical anti-solvent technique for the controlled release of insulin. J Supercrit Fluids. 2015;99:15–22. doi:10.1016/j.supflu.2015.01.023

120. Dharmalingam K, Anandalakshmi R. Fabrication, characterization and drug loading efficiency of citric acid crosslinked NaCMC-HPMC hydrogel films for wound healing drug delivery applications. Int J Biol Macromol. 2019;134:815–829. doi:10.1016/j.ijbiomac.2019.05.027

121. Lotfipour F, Nokhodchi A, Saeedi M, Norouzi-Sani S, Sharbafi J, Siahi-Shadbad M. The effect of hydrophilic and lipophilic polymers and fillers on the release rate of atenolol from HPMC matrices. Il Farmaco. 2004;59(10):819–825. doi:10.1016/j.farmac.2004.06.006

122. Hu Y, Zhang S, Han D, Ding Z, Zeng S, Xiao X. Construction and evaluation of the hydroxypropyl methyl cellulose-sodium alginate composite hydrogel system for sustained drug release. J Polymer Res. 2018;25(7):148. doi:10.1007/s10965-018-1546-y

123. Masina N, Choonara YE, Kumar P, et al. A review of the chemical modification techniques of starch. Carbohydr Polym. 2017;157:1226–1236. doi:10.1016/j.carbpol.2016.09.094

124. Madhumitha G, Fowsiya J, Mohana Roopan S, Thakur VK. Recent advances in starch–clay nanocomposites. Int J Polymer Anal Charact. 2018;23(4):331–345.

125. Kaur L, Singh J, Liu Q. Starch–a potential biomaterial for biomedical applications. In: Nanomaterials and Nanosystems for Biomedical Applications. M. Reza Mozafari. Springer; 2007:83–98.

126. Waterschoot J, Gomand SV, Fierens E, Delcour JA. Starch blends and their physicochemical properties. Starch‐Stärke. 2015;67(1–2):1–13.

127. Kim H-Y, Park SS, Lim S-T. Preparation, characterization and utilization of starch nanoparticles. Colloids Surf B Biointerfaces. 2015;126:607–620. doi:10.1016/j.colsurfb.2014.11.011

128. Song R, Murphy M, Li C, Ting K, Soo C, Zheng Z. Current development of biodegradable polymeric materials for biomedical applications. Drug Des Devel Ther. 2018;12:3117.

129. Sionkowska A. Current research on the blends of natural and synthetic polymers as new biomaterials. Prog Polym Sci. 2011;36(9):1254–1276.

130. Chen J, Chen L, Xie F, Li X. Starch-based DDSs with stimulus responsiveness. In: Drug Delivery Applications of Starch Biopolymer Derivatives. Jin Chen. Springer; 2019:41–99.

131. Acosta S, Chiralt A, Santamarina P, Rosello J, González-Martínez C, Cháfer M. Antifungal films based on starch-gelatin blend, containing essential oils. Food Hydrocoll. 2016;61:233–240. doi:10.1016/j.foodhyd.2016.05.008

132. Nayak AK, Pal D. Natural starches‐blended ionotropically gelled microparticles/beads for sustained drug release. In: Handbook of Composites from Renewable Materials. Vijay Kumar Thakur. John Wiley & Sons. 2017:527–559.

133. Perez JJ, Francois NJ. Chitosan-starch beads prepared by ionotropic gelation as potential matrices for controlled release of fertilizers. Carbohydr Polym. 2016;148:134–142. doi:10.1016/j.carbpol.2016.04.054

134. Huo W, Xie G, Zhang W, et al. Preparation of a novel chitosan-microcapsules/starch blend film and the study of its drug-release mechanism. Int J Biol Macromol. 2016;87:114–122. doi:10.1016/j.ijbiomac.2016.02.049

135. Kumar R, Ashfaq M, Verma N. Synthesis of novel PVA–starch formulation-supported Cu–Zn nanoparticle carrying carbon nanofibers as a nanofertilizer: controlled release of micronutrients. J Mater Sci. 2018;53(10):7150–7164.

136. Zhong B, Wang S, Dong H, et al. Halloysite tubes as nanocontainers for herbicide and its controlled release in biodegradable poly (vinyl alcohol)/starch film. J Agric Food Chem. 2017;65(48):10445–10451. doi:10.1021/acs.jafc.7b04220

137. Ayorinde J, Odeniyi M, Balogun-Agbaje O. Formulation and evaluation of oral dissolving films of amlodipine besylate using blends of starches with hydroxypropyl methyl cellulose. Polym Med. 2016;46:45–51.

138. Kulkarni RV, Mangond BS, Mutalik S, Sa B. Interpenetrating polymer network microcapsules of gellan gum and egg albumin entrapped with diltiazem–resin complex for controlled release application. Carbohydr Polym. 2011;83(2):1001–1007.

139. de Oliveira Cardoso VM, Cury BSF, Evangelista RC, Gremião MPD. Development and characterization of cross-linked gellan gum and retrograded starch blend hydrogels for drug delivery applications. J Mech Behav Biomed Mater. 2017;65:317–333.

140. Phromsopha T, Baimark Y. Preparation of starch/gelatin blend microparticles by a water-in-oil emulsion method for controlled release drug delivery. Int J Biomater. 2014;2014.

141. Dos Santos Garcia VA, Borges JG, Maciel VBV, et al. Gelatin/starch orally disintegrating films as a promising system for vitamin C delivery. Food Hydrocoll. 2018;79:127–135.

142. Rivadeneira J, Di Virgilio AL, Audisio MC, Boccaccini AR, Gorustovich AA. 45s5 bioglass® concentrations modulate the release of vancomycin hydrochloride from gelatin–starch films: evaluation of antibacterial and cytotoxic effects. J Mater Sci. 2017;52(15):9091–9102.

143. Rioux B, Ispas-Szabo P, Aı̈t-Kadi A, Mateescu M-A JJ. Structure–properties relationship in cross-linked high amylose starch cast films. Carbohydr Polym. 2002;50(4):371–378.

144. Soares GA, de Castro AD, Cury BS, Evangelista RC. Blends of cross-linked high amylose starch/pectin loaded with diclofenac. Carbohydr Polym. 2013;91(1):135–142. doi:10.1016/j.carbpol.2012.08.014

145. Zhang A, Zhang Z, Shi F, et al. Disulfide crosslinked PEGylated starch micelles as efficient intracellular drug delivery platforms. Soft Matter. 2013;9(7):2224–2233. doi:10.1039/c2sm27189c

146. Liu J, Pang Y, Huang W, et al. Bioreducible micelles self-assembled from amphiphilic hyperbranched multiarm copolymer for glutathione-mediated intracellular drug delivery. Biomacromolecules. 2011;12(5):1567–1577.

147. Setti C, Suarato G, Perotto G, Athanassiou A, Bayer IS. Investigation of in vitro hydrophilic and hydrophobic dual drug release from polymeric films produced by sodium alginate-MaterBi® drying emulsions. Eur J Pharm Biopharm. 2018;130:71–82. doi:10.1016/j.ejpb.2018.06.019

148. Kamaly N, Yameen B, Wu J, Farokhzad OC. Degradable controlled-release polymers and polymeric nanoparticles: mechanisms of controlling drug release. Chem Rev. 2016;116(4):2602–2663. doi:10.1021/acs.chemrev.5b00346

149. Gültekin HE, DEĞİM Z. Biodegradable polymeric nanoparticles are effective systems for controlled drug delivery. FABAD J Pharm Sci. 2013;38(2):107–118.

150. Palma E, Pasqua A, Gagliardi A, Britti D, Fresta M, Cosco D. Antileishmanial activity of amphotericin B-loaded-PLGA nanoparticles: an overview. Materials. 2018;11(7):1167. doi:10.3390/ma11071167

151. Perinelli DR, Cespi M, Bonacucina G, Palmieri GF. PEGylated polylactide (PLA) and poly (lactic-co-glycolic acid)(PLGA) copolymers for the design of drug delivery systems. J Pharm Invest. 2019;1–16.

152. Saini P, Arora M, Kumar MR. Poly (lactic acid) blends in biomedical applications. Adv Drug Deliv Rev. 2016;107:47–59. doi:10.1016/j.addr.2016.06.014

153. Cascone MG, Sim B, Sandra D. Blends of synthetic and natural polymers as drug delivery systems for growth hormone. Biomaterials. 1995;16(7):569–574. doi:10.1016/0142-9612(95)91131-H

154. Xing Z-C, Koo T-H, Kim Y-J, Kwon O-H, Kang I-K. Surface modification of PLGA nanofibrous biocomposites using flavonoids for biomedical applications. J Adhes Sci Technol. 2013;27(12):1382–1392. doi:10.1080/01694243.2012.697371

155. Enayati M, Mobedi H, Hojjati‐Emami S, Mirzadeh H, Jafari‐Nodoushan M. In situ forming PLGA implant for 90 days controlled release of leuprolide acetate for treatment of prostate cancer. Polym Adv Technol. 2017;28(7):867–875. doi:10.1002/pat.3991

156. Chereddy KK, Vandermeulen G, Préat V. PLGA based drug delivery systems: promising carriers for wound healing activity. Wound Repair Regener. 2016;24(2):223–236. doi:10.1111/wrr.12404

157. Sequeira JA, Santos AC, Serra J, Veiga F, Ribeiro AJ. Poly (lactic-co-glycolic acid)(PLGA) matrix implants. In: Nanostructures for the Engineering of Cells, Tissues and Organs. Alexandru Mihai Grumezenscu. Elsevier; 2018:375–402.

158. Mir M, Ahmed N, ur Rehman A. Recent applications of PLGA based nanostructures in drug delivery. Colloids Surf B Biointerfaces. 2017;159:217–231. doi:10.1016/j.colsurfb.2017.07.038

159. Zhao W, Li J, Jin K, Liu W, Qiu X, Li C. Fabrication of functional PLGA-based electrospun scaffolds and their applications in biomedical engineering. Mater Sci Eng C. 2016;59:1181–1194. doi:10.1016/j.msec.2015.11.026

160. Carson D, Jiang Y, Woodrow KA. Tunable release of multiclass anti-HIV drugs that are water-soluble and loaded at high drug content in polyester blended electrospun fibers. Pharm Res. 2016;33(1):125–136. doi:10.1007/s11095-015-1769-0

161. Qian Y, Zhou X, Zhang F, Diekwisch TGH, Luan X, Yang J. Triple PLGA/PCL Scaffold Modification Including Silver Impregnation, Collagen Coating, and Electrospinning Significantly Improve Biocompatibility, Antimicrobial, and Osteogenic Properties for Orofacial Tissue Regeneration. ACS Appl Mater Interfaces. 2019;11(41):37381–37396.

162. Huo ZJ, Wang SJ, Wang ZQ, et al. Novel nanosystem to enhance the antitumor activity of lapatinib in breast cancer treatment: therapeutic efficacy evaluation. Cancer Sci. 2015;106(10):1429–1437. doi:10.1111/cas.12737

163. Wilkosz N, Łazarski G, Kovacik L, et al. Molecular insight into drug-loading capacity of PEG–PLGA nanoparticles for itraconazole. J Phys Chem B. 2018;122(28):7080–7090. doi:10.1021/acs.jpcb.8b03742

164. Liu S, Jia H, Yang J, et al. Zinc coordination substitute amine: a noncationic platform for efficient and safe gene delivery. ACS Macro Lett. 2018;7(7):868–874. doi:10.1021/acsmacrolett.8b00374

165. Jin F, Liu D, Yu H, et al. Sialic acid-functionalized PEG–PLGA microspheres loading mitochondrial-targeting-modified curcumin for acute lung injury therapy. Mol Pharm. 2018;16(1):71–85. doi:10.1021/acs.molpharmaceut.8b00861

166. Sánchez-López E, Ettcheto M, Egea MA, et al. Memantine loaded PLGA PEGylated nanoparticles for Alzheimer’s disease: in vitro and in vivo characterization. J Nanobiotechnology. 2018;16(1):32. doi:10.1186/s12951-018-0356-z

167. Maghsoudi S, Shahraki BT, Rabiee N, et al. Recent advancements in aptamer-bioconjugates: sharpening stones for breast and prostate cancers targeting. J Drug Deliv Sci Technol. 2019;53:101146. doi:10.1016/j.jddst.2019.101146

168. Farajzadeh R, Pilehvar-Soltanahmadi Y, Dadashpour M, et al. Nano-encapsulated metformin-curcumin in PLGA/PEG inhibits synergistically growth and hTERT gene expression in human breast cancer cells. Artif Cells Nanomed Biotechnol. 2018;46(5):917–925. doi:10.1080/21691401.2017.1347879

169. Dorati R, DeTrizio A, Spalla M, et al. Gentamicin SULFATE PEG-PLGA/PLGA-H nanoparticles: screening design and antimicrobial effect evaluation toward clinic bacterial isolates. Nanomaterials. 2018;8(1):37. doi:10.3390/nano8010037

170. Cosco D, Molinaro R, Morittu V, Cilurzo F, Costa N, Fresta M. Anticancer activity of 9-cis-retinoic acid encapsulated in PEG-coated PLGA-nanoparticles. J Drug Deliv Sci Technol. 2011;21(5):395–400. doi:10.1016/S1773-2247(11)50064-4

171. Zhang L, Wang Z, Xiao Y, et al. Electrospun PEGylated PLGA nanofibers for drug encapsulation and release. Mater Sci Eng C. 2018;91:255–262. doi:10.1016/j.msec.2018.05.045

172. Herrero-Herrero M, Gómez-Tejedor J-A V-LA. PLA/PCL electrospun membranes of tailored fibres diameter as drug delivery systems. Eur Polym J. 2018;99:445–455. doi:10.1016/j.eurpolymj.2017.12.045

173. Singhvi M, Zinjarde S, Gokhale D. Poly‐Lactic acid (PLA): synthesis and biomedical applications. J Appl Microbiol. 2019;127(6):1612–1626. doi:10.1111/jam.14290

174. Jain A, Khan W, Kyzioł A. Particulate systems of PLA and its copolymers. In: Materials for Biomedical Engineering. Elsevier. 2019:349–380.

175. Fang Y, Zhu X, Wang N, et al. Biodegradable core-shell electrospun nanofibers based on PLA and γ-PGA for wound healing. Eur Polym J. 2019;116:30–37. doi:10.1016/j.eurpolymj.2019.03.050

176. Zhang Y, Luo S, Liang Y, et al. Synthesis, characterization, and property of biodegradable PEG-PCL-PLA terpolymers with miktoarm star and triblock architectures as drug carriers. J Biomater Appl. 2018;32(8):1139–1152. doi:10.1177/0885328217751247

177. Marudova M, Yorov T. Chitosan/poly (lactic acid) blends as drug delivery systems. Int J Polymeric Mater Polymeric Biomater. 2019;68(1–3):99–106. doi:10.1080/00914037.2018.1525728

178. Bode C, Kranz H, Fivez A, Siepmann F, Siepmann J. Often neglected: PLGA/PLA swelling orchestrates drug release: HME implants. J Controlled Rel. 2019;306:97–107.

179. Sirc J, Hampejsova Z, Trnovska J, et al. Cyclosporine a loaded electrospun poly (D, L-lactic acid)/poly (ethylene glycol) nanofibers: drug carriers utilizable in local immunosuppression. Pharm Res. 2017;34(7):1391–1401. doi:10.1007/s11095-017-2155-x

180. Hobzova R, Hampejsova Z, Cerna T, et al. Poly (d, l-lactide)/polyethylene glycol micro/nanofiber mats as paclitaxel-eluting carriers: preparation and characterization of fibers, in vitro drug release, antiangiogenic activity and tumor recurrence prevention. Mater Sci Eng C. 2019;98:982–993. doi:10.1016/j.msec.2019.01.046

181. Mauri E, Negri A, Rebellato E, Masi M, Perale G, Rossi F. Hydrogel-nanoparticles composite system for controlled drug delivery. Gels. 2018;4(3):74. doi:10.3390/gels4030074

182. Sharif F, Tabassum S, Mustafa W, et al. Bioresorbable antibacterial PCL‐PLA‐nHA composite membranes for oral and maxillofacial defects. Polymer Composites. 2019;40(4):1564–1575. doi:10.1002/pc.24899

183. Roy A, Singh SK, Bajpai J, Bajpai AK. Controlled pesticide release from biodegradable polymers. Central Eur J Chem. 2014;12(4):453–469. doi:10.2478/s11532-013-0405-2

184. Rychter P, Lewicka K, Rogacz D. Environmental usefulness of PLA/PEG blends for controlled‐release systems of soil‐applied herbicides. J Appl Polym Sci. 2019;136(33):47856. doi:10.1002/app.47856

185. Krishnamoorthy V, Rajiv S. Tailoring electrospun polymer blend carriers for nutrient delivery in seed coating for sustainable agriculture. J Clean Prod. 2018;177:69–78. doi:10.1016/j.jclepro.2017.12.141

186. Rychter P, Lewicka K, Pastusiak M, Domański M, Dobrzyński P. PLGA–PEG terpolymers as a carriers of bioactive agents, influence of PEG blocks content on degradation and release of herbicides into soil. Polym Degrad Stab. 2019;161:95–107. doi:10.1016/j.polymdegradstab.2019.01.002

187. Wang Y, Li C, Wang Y, Zhang Y, Li X. Compound pesticide controlled release system based on the mixture of poly (butylene succinate) and PLA. J Microencapsul. 2018;35(5):494–503. doi:10.1080/02652048.2018.1538265

188. Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE. Biodegradable polymeric nanoparticles as drug delivery devices. J Controlled Rel. 2001;70((1–2): 1–20). doi:10.1016/S0168-3659(00)00339-4

189. Bode C, Kranz H, Fivez A, Siepmann F, Siepmann J. Often neglected: PLGA/PLA swelling orchestrates drug release: HME implants. J Controlled Rel. 2019;306:97–107.

190. Moroishi H, Sonotaki S, Murakami Y. PLA-and PLA/PLGA-emulsion composite biomaterial sheets for the controllable sustained release of hydrophilic compounds. Materials. 2018;11(12):2588. doi:10.3390/ma11122588

191. Bee S-L, Hamid ZA, Mariatti M, et al. Approaches to improve therapeutic efficacy of biodegradable PLA/PLGA microspheres: a review. Polymer Rev. 2018;58(3):495–536. doi:10.1080/15583724.2018.1437547

192. Wang Y, Wen Q, Choi S. FDA’s regulatory science program for generic PLA/PLGA-based drug products. Am Pharm Rev. 2016;19(4):5–9.

193. Milovanovic S, Markovic D, Mrakovic A, et al. Supercritical CO2-assisted production of PLA and PLGA foams for controlled thymol release. Mater Sci Eng C. 2019;99:394–404. doi:10.1016/j.msec.2019.01.106

194. Tukappa A, Ultimo A, de la Torre C, Pardo T, Sancenón F, Martínez-Máñez R. Polyglutamic acid-gated mesoporous silica nanoparticles for enzyme-controlled drug delivery. Langmuir. 2016;32(33):8507–8515. doi:10.1021/acs.langmuir.6b01715

195. Mottaghitalab F, Farokhi M, Shokrgozar MA, Atyabi F, Hosseinkhani H. Silk fibroin nanoparticle as a novel drug delivery system. J Controlled Rel. 2015;206:161–176. doi:10.1016/j.jconrel.2015.03.020

196. Chen Y, Zhang L, Liu Y, et al. Preparation of PGA–PAE-micelles for enhanced antitumor efficacy of cisplatin. ACS Appl Mater Interfaces. 2018;10(30):25006–25016. doi:10.1021/acsami.8b04259

197. Qiu L, Hu B, Chen H, et al. Antifungal efficacy of itraconazole-loaded TPGS-b-(PCL-ran-PGA) nanoparticles. Int J Nanomedicine. 2015;10:1415.

198. Shalaby SW. Composite absorbable/biodegradable rings for controlled drug delivery. Google Patents. 2016.

199. Cho S-H, Hong JH, Noh Y-W, Lee E, Lee C-S, Lim YT. Raspberry-like poly (γ-glutamic acid) hydrogel particles for pH-dependent cell membrane passage and controlled cytosolic delivery of antitumor drugs. Int J Nanomedicine. 2016;11:5621. doi:10.2147/IJN.S117862

200. Khalil I, Burns A, Radecka I, et al. Bacterial-derived polymer poly-y-glutamic acid (y-PGA)-based micro/nanoparticles as a delivery system for antimicrobials and other biomedical applications. Int J Mol Sci. 2017;18(2):313. doi:10.3390/ijms18020313

201. Cho S-H, Kim A, Shin W, et al. Photothermal-modulated drug delivery and magnetic relaxation based on collagen/poly (γ-glutamic acid) hydrogel. Int J Nanomedicine. 2017;12:2607. doi:10.2147/IJN.S133078

202. Chung R-J, Ou K-L, Tseng W-K, Liu H-L. Controlled release of BMP-2 by chitosan/γ-PGA polyelectrolyte multilayers coating on titanium alloy promotes osteogenic differentiation in rat bone-marrow mesenchymal stem cells. Surf Coat Technol. 2016;303:283–288. doi:10.1016/j.surfcoat.2016.03.081

203. Ma X, Xu T, Chen W, Qin H, Chi B, Ye Z. Injectable hydrogels based on the hyaluronic acid and poly (γ-glutamic acid) for controlled protein delivery. Carbohydr Polym. 2018;179:100–109. doi:10.1016/j.carbpol.2017.09.071

204. Liu Q, Song L, Chen S, Gao J, Zhao P, Du J. A superparamagnetic polymersome with extremely high T2 relaxivity for MRI and cancer-targeted drug delivery. Biomaterials. 2017;114:23–33. doi:10.1016/j.biomaterials.2016.10.027

205. Surowiak P, Materna V, Kaplenko I, et al. Augmented expression of metallothionein and glutathione S-transferase pi as unfavourable prognostic factors in cisplatin-treated ovarian cancer patients. Virchows Archiv. 2005;447(3):626–633. doi:10.1007/s00428-005-1228-0

206. Min Y, Mao CQ, Chen S, Ma G, Wang J, Liu Y. Combating the drug resistance of cisplatin using a platinum prodrug based delivery system. Angewandte Chemie International Edition. 2012;51(27):6742–6747. doi:10.1002/anie.201201562

207. Xiao H, Noble GT, Stefanick JF, et al. Photosensitive Pt (IV)–azide prodrug-loaded nanoparticles exhibit controlled drug release and enhanced efficacy in vivo. J Controlled Rel. 2014;173:11–17. doi:10.1016/j.jconrel.2013.10.020

208. Song H, Kang X, Sun J, et al. Nanoparticle delivery of sterically hindered platinum (iv) prodrugs shows 100 times higher potency than that of cisplatin upon light activation. Chem Commun. 2016;52(11):2281–2283. doi:10.1039/C5CC09534D

209. Yang X, Yu Y, Huang X, et al. Delivery of platinum (II) drugs with bulky ligands in trans-geometry for overcoming cisplatin drug resistance. Mater Sci Eng C. 2019;96:96–104. doi:10.1016/j.msec.2018.10.092

210. Niu Z, Samaridou E, Jaumain E, et al. PEG-PGA enveloped octaarginine-peptide nanocomplexes: an oral peptide delivery strategy. J Controlled Rel. 2018;276:125–139. doi:10.1016/j.jconrel.2018.03.004

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