<p>Novel Drug Delivery Systems for Loading of Natural Plant Extracts and Their Biomedical Applications</p>

Heshu Sulaiman Rahman; Hemn Hassan Othman; Nahidah Ibrahim Hammadi; Swee Keong Yeap; Kawa Mohammad Amin; Nozlena Abdul Samad; Noorjahan Banu Alitheen

doi:10.2147/IJN.S227805

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Review

Novel Drug Delivery Systems for Loading of Natural Plant Extracts and Their Biomedical Applications

Authors Rahman HS , Othman HH , Hammadi NI , Yeap SK, Amin KM , Abdul Samad N, Alitheen NB

Received 19 August 2019

Accepted for publication 10 October 2019

Published 15 April 2020 Volume 2020:15 Pages 2439—2483

DOI https://doi.org/10.2147/IJN.S227805

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Thomas Webster

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Heshu Sulaiman Rahman,^1,² Hemn Hassan Othman,³ Nahidah Ibrahim Hammadi,⁴ Swee Keong Yeap,⁵ Kawa Mohammad Amin,⁶ Nozlena Abdul Samad,⁷ Noorjahan Banu Alitheen⁸

¹Department of Physiology, College of Medicine, University of Sulaimani, Sulaymaniyah 46001, Republic of Iraq; ²Department of Medical Laboratory Sciences, College of Health Sciences, Komar University of Science and Technology, Sulaymaniyah, Republic of Iraq; ³Department of Pharmacology and Toxicology, College of Pharmacy, University of Sulaimani, Sulaymaniyah 46001, Republic of Iraq; ⁴Department of Histology, College of Veterinary Medicine, University of Al-Anbar, Ramadi, Republic of Iraq; ⁵China-ASEAN College of Marine Sciences, Xiamen University Malaysia, Sepang, Malaysia; ⁶Department of Microbiology, College of Medicine, University of Sulaimani, Sulaymaniyah 46001, Republic of Iraq; ⁷Integrative Medicine Cluster, Institut Perubatan dan Pergigian Termaju (IPPT), Sains@BERTAM, Universiti Sains Malaysia, Kepala Batas 13200, Pulau Pinang, Malaysia; ⁸Department of Cell and Molecular Biology, Faculty of Biotechnology and Bio-Molecular Sciences, Universiti Putra Malaysia, Selangor, Malaysia

Correspondence: Noorjahan Banu Alitheen
Department of Cell and Molecular Biology, Faculty of Biotechnology and Bio-Molecular Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
Tel +60 126866947
Email [email protected]

Heshu Sulaiman Rahman
Department of Physiology, College of Medicine, University of Sulaimani, Sulaymaniyah 46001, Republic of Iraq
Tel +964 7726159598
Email [email protected]

Abstract: Many types of research have distinctly addressed the efficacy of natural plant metabolites used for human consumption both in cell culture and preclinical animal model systems. However, these in vitro and in vivo effects have not been able to be translated for clinical use because of several factors such as inefficient systemic delivery and bioavailability of promising agents that significantly contribute to this disconnection. Over the past decades, extraordinary advances have been made successfully on the development of novel drug delivery systems for encapsulation of plant active metabolites including organic, inorganic and hybrid nanoparticles. The advanced formulas are confirmed to have extraordinary benefits over conventional and previously used systems in the manner of solubility, bioavailability, toxicity, pharmacological activity, stability, distribution, sustained delivery, and both physical and chemical degradation. The current review highlights the development of novel nanocarrier for plant active compounds, their method of preparation, type of active ingredients, and their biomedical applications.

Keywords: nanomedicine, natural plant metabolite, biomedical application, carrier formulation, drug delivery

Introduction

Based on the recently reported data, more than 70% of new drugs formulated are showing poor water solubility, which becomes the limiting factor in the absorption drug after oral admission.¹ The limitation in the bioavailability of natural products active components includes poor solubility of the ingredient, poor stability due to gastric and colonic acidity, poor metabolism by the effect of gut microflora, poor absorption across the intestinal wall, poor active efflux mechanism and first-pass metabolic effects are among the factors that make the failure of clinical trials.^2,3

In this respect, developed novel drug delivery system and carriers for herbal drugs should ideally accomplish some prerequisites such as proper delivering of the drug at a rate oriented by the needs of the body, over the period of treatment and it should pass the active entity of herbal drug to the site of action.⁴ Many approaches have been adopted to increase drug solubility, sustainability, bioavailability and gastrointestinal permeability.⁵ Nanocarrier has gained tremendous attention in the development of new pharmaceutical carrier and delivery systems. One of the strategies to thwart this problem is to encapsulate natural plant metabolites into the biodegradable and biocompatible nanoparticle.⁶

Employment of innovative drug delivery systems including utilization of nanocarrier delivery to overcome the physicochemical and pharmacokinetic limitation of phytochemicals enhanced the controlled release and even efficacy of the bioactivities. This innovation shows the promising future of nanomedicine as a potential solution for impressive hindrance and handling of various chronic diseases.⁷

Additionally, altering the main features of nanocarriers such as their constituents (organic, inorganic or hybrid), sizes (small, medium or large), shapes (sphere, rod or cube) and surface properties (charge, functional groups, PEGylation or attachment of targeting moieties) are considered as a leading cause for tuning the physiochemical properties of nanocarriers. The overall aim of employing nanocarriers in drug delivery is to treat an unwellness effectively with the lowest side effects and potential outcomes.⁸

Nanomedicine has recently earned enhanced attraction for its ability to efficaciously diagnose and treat various ailments.⁹ Therefore, the aim of this review is to display the types of nanocarrier loaded natural plant products and focus on their role in various disease therapies with the promising use of nanomedicine.

Design of the Review

In this review, nanocarriers were being classified based on the types of nanocarrier, i.e. i) organic nanocarriers; ii) inorganic nanocarriers; iii) hybrid nanocarriers; and iv) biological nanocarriers. References were searched in Scopus data based using each class of nanocarriers as the keyword. Articles after the year 2010 were selected (unless the significant references for a particular type of nanocarrier, which were downloaded separately) and sorted based on the specific type of carrier for each of the above classes.

Nanocarrier

Nanocarrier is hopefully utilized to overcome the difficulty and issues related to conventional drug delivery systems such as their nonspecificity, side effects, burst release and detrimental destroying of large populations of the normal cells. Nanocarrier improves the bioavailability and therapeutic efficiency of drugs, as well as providing a preferential accumulation at the target site.¹⁰ Nowadays, a large number of nanocarriers have been produced but only some of them are clinically authorized for the delivery of materials because of their motivated actions at the targeted sites, especially antitumor agents.¹¹

The particles of a nanocarrier vary in size, and those ranged from 10 to 100 nm give the most acceptable physicochemical characteristics. The main advantages of nanonization are improving solubility, reducing medicinal doses and side effects, and increasing the absorbency of medicinal herbs compared with the respective crude extract preparations.¹²

Types of Nanocarrier

Organic Nanocarrier

Lipid and Polymer-Based Nanocarrier

Lipids act as a suitable penetration enhancer of drugs in the digestive tract by supporting solubilization of the drug in the stomach surroundings and thereby reducing the first-pass metabolism by diffusion of the drug through a lymphatic to the circulatory system.¹⁰

Solid Lipid Nanoparticle (SLN)

SLN is a colloidal drug carrier that developed in the early 1990s in which the particle size ranges from 50 to 1000 nm (Figure 1A). SLN is processed by using emulsifier(s) to stabilize the dispersion that composed of melted solid lipid(s) in water.¹³ The high-pressure homogenization (HPH) technique and microemulsification are the most commonly used methods for preparing SLN.¹⁴

Figure 1 A schematic illustration of nanostructured Lipid Carrier (NLC) on right and solid lipid nanoparticles (SLN) on left Notes: Reproduced from Hsu CY, Wang PW, Alalaiwe A, Lin ZC, Fang JY. Use of lipid Nanocarriers to improve Oral delivery of vitamins. Nutrients. 2019;11(1):68-97³²⁵

The main advantages of SLN are providing a highly lipophilic lipid matrix for drugs to be dispersed in,¹⁵ allowing the encapsulation, embedding with a wide range of molecules (such as drugs, antigens, proteins, and nucleotides) and also promoting the delivery of therapeutic loading into specific tissues and cells. Improving the in vitro and in vivo stability and reducing the adverse effects are also among the acceptable features of SLN.¹⁶ SLN is quite similar to nanoemulsions except that both solid and liquid lipids (oils) are used in the formulation of SLN whereas only liquid lipids are used in nanoemulsions.

The most extensively employed SLN is puerarin-loaded SLN in rats that characterized by rapid absorption, relatively improved bioavailability and increased tissue concentrations in targeted organs (heart and brain).^15,17 Another group developed triptolide-loaded SLN as an antioxidant and anti-inflammatory product that showed a significant reduction in glutathione (GSH) and myeloperoxidase (MPO) activities. The aim of this development was to improve solubility, reduce toxicity, hyperemia, and irritation to the gastrointestinal tract (GIT)¹⁸ through minimizing direct contact with the mucosal surface, gradual drug-releasing, and avoiding high local drug concentrations. More examples in this respect are addressed in Table 1.^15,17–21

Nanostructured Lipid Carrier (NLC)

It is considered as a second-generation lipid nanoparticle that contains a mixture of solid and liquid lipids (Figure 1B) and was originally developed from SLN but with more lipid matrix imperfections.²² A wide variety of solid lipids have been utilized such as hydrogenated palm oil (HPO), glyceryl monostearate, stearic acid, and cetyl alcohol whereas the most commonly used liquid lipids are olive oil, mustard oil, castor oil, and cod liver oil. The preferable stabilizer in this system is thimerosal.²³

Generally, NLC preferred over the SLN because of better controlling of the drug release, more stability, enhanced drug-loading capacity, and minimized drug ejection during depository.²⁴ Thus, various active ingredients have been incorporated into NLC in studies focused on modifying water solubility, enhancing gastrointestinal absorption and oral bioavailability, controlling release, lengthening circulation time by reducing identification by the reticuloendothelial system (RES), and co-delivery.¹² Therefore, it is realized that NLC is a better carrier for oral delivery of several natural and chemically synthesized compounds.

In this respect, silymarin loaded NLC is the best example that has been used clinically to overcome many hepatic diseases as its low solubility, permeability, and bioavailability often occur with its therapy. NLC loaded tripterine, curcumin, and triptolide are also other successful examples of corroborated absorption enhancement by this system which may be due to their small particle size, lipid components, and surfactant contents.²⁵

Cardomom essential oil (CEO) loaded NLCs have successfully been synthesized using food-grade lipids including cocoa butter and olive oil. The CEO loaded NLCs had a small size (90%), loading capacity (>25%) and provides good physical and chemical stability. This work overcame the limitation of applying the CEO to aqueous-based foods.²⁶ Currently, various novel and innovative NLC have been produced as a carrier to target anticancer functions such as zerumbone,²⁷ thymoquinone^28,29 and citral³⁰ and as a worthy drug observably increased antitumor activity in leukemia and breast tumor cells in vitro and in vivo. More examples of compounds loaded NLC are presented in Table 1.^31–37

Table 1 Nanocarrier Encapsulated Herbal Formulations

Nanoemulsion (NE)

It refers to an optically single isotropic and thermodynamic stable transparent (translucent) nonhomogeneous colloidal dispersion system (Figure 2) with a droplet size of less than 100 nm. Generally, the NE is composed of stabilized oil and water with the aid of surfactant and cosurfactant an interfacial film molecule.⁹

Figure 2 A schematic illustration of oil (O) in water (W) nanoemulsion. Notes: Reproduced from Agnihotri N, Soni GC, Chanchal DK, Tiwari S. A Scientific Review On Nanoemulsion For Targeting Drug Delivery System. Int J Life Sci Rev. 2019;5(2):16-29³²⁶

After the lipophilic drugs loaded into either oil/water or oil/water/oil suspension, the oil driblets are engulfed by the macrophage and find in a high concentration in the spleen, liver, and kidneys since the quantity of the liquefied medicate is too big. Whereas the hydrophilic drug is encapsulated into water/oil or water/oil/water nanoemulsion, it can be well condensed in the lymphatic system through subcutaneous or intramuscular insertion due to the higher internal membrane permeability.^9,38

This system is characterized by targeted sustained release, the stability of the solubilized components, enhanced the permeability of materials to the mucous and skin, solubilized components of varied lipophilicity, improved drug absorption, lowered viscosity with inducing less pain or allergic reactions and simpleness of production and decontamination as well.³⁹ Moreover, the intestinal absorption of NE is attributed to the lymphatic conveyance processes that ameliorate the oral bioavailability of encapsulated materials.^40,41

NE serves as an attractive vehicle for the delivery of drugs and essential oils (especially as repellent and antimicrobial agents, nucleic acids as well as imaging agents).^39,42,43 In the last few years ago, a modern system has upgraded the transdermal remedial use of NE, such as Transcutol^®P, phospholipid, alkyl polyglycosides, PEGylated fatty acid ester, and fatty alcohol.^44–46

Herbal drugs including camptothecin, rutin, genistein, resveratrol, and oils of Brucea javanica, coixenolide, and zedoary have been loaded into NE for various applications.^47,48 With great application prospects of NE, Syagrus romanzoffiana fruit pulp extracts were incorporated into O/W NE using the phase inversion method to evaluate antioxidant activity.⁴⁹ More examples of herbal loaded NE are presented in Table 1.^51–53

Nanocapsule (NC)

It is a nanovesicular colloidal dispersion system (Figure 3) that exhibits a typical core-shell structure in which the drug is confined to a reservoir or within a cavity surrounded by a polymer membrane or coating.⁵² The cavity can contain the active substance in liquid (an oily or an aqueous core) or solid form or as a molecular in which the core-shell structure and composition are the main features of NC especially controlling the drug release.⁵⁴ Likewise, this formula can be lipophilic or hydrophobic according to the preparation method and raw materials used. The main aim in developing this formula is to alter the oral bioavailability of ailing hydrophilic active components.⁵⁵

Figure 3 A schematic illustration of silver-loaded titanium dioxide nanocapsule. Notes: Adapted from Hérault N, Wagner J, Abram SL, et al. Silver-Containing Titanium Dioxide Nanocapsules for Combating Multidrug-Resistant Bacteria. Int J Nanomed. 2020;15:1267-1281³²⁷

Figure 4 A schematic illustration of Polyethylene glycate (PEG)-aptamer-liposome-doxorubicin (DOX); a type of lipid drug-conjugate. Notes: Reproduced from Dou XQ, Wang H, Zhang J, et al. Aptamer–drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity. Int J Nanomed. 2018;13:763-776³²⁸

Additionally, as asserted by different authors, other advantages of NC as a carrier system include high drug encapsulation efficiency due to optimized drug solubility in the core, low polymer content compared to other systems, drug polymeric shell protection against degradation factors like pH and light and the reduction of tissue irritation due to the polymeric shell.⁵⁶ Recently, a ligand-modified or multifunctional NC that carries the active substance on their surfaces or imbibed in the polymeric membrane has been developed to attain higher delivery of therapies to the targeted site more actively.⁵⁴ Different preparation methods such as nanoprecipitation, emulsion–diffusion, double emulsification, emulsion-coacervation, polymer-coating, and layer-by-layer were employed to develop various types of this carrier.⁵⁵

In this area, the well-known anticancer natural herbal product, artemisinin (ART) (from Artemisia annua) crystals were encapsulated with polyelectrolytes (chitosan, gelatin, and alginate) for the purpose of controlled release through self-assembly of polyelectrolytes on drug crystals, and improved hydrophilicity of the crystal using the layer-by-layer technique.⁵⁴ More examples of herbal loaded NE are presented in Table 1.^57–62

Lipid Drug Conjugate (LDC) or Polymer Drug Conjugate (PDC)

The union of agents with polymers is a new approach to modify drug property and its pharmacokinetics. LDCs are lipidic drugs that covalently or noncovalently coupled to a lipid moiety, such as diglyceride, phosphoglyceride and fatty acid (Figure 4).⁶³ In several instances, LDC may also be known as Pharmacosomes especially when the drug is conjugated with a phospholipid. LDC is the most accepted lipid-based nanoparticle, especially when considered drug is hydrophilic in nature in which it is converted into water-insoluble lipid-drug conjugate by conjugating it with a lipid component.⁶⁴

LDC is characterized by possessing controlled drug release, drug targeting, an increase in gastrointestinal permeability, an increment in bioavailability.⁶⁵ Additionally, adding targeted motifs to the polymer to produce functionalized polymer–drug conjugate can also be constructed. One of the appreciable natural products with high edible polyphenolic content is resveratrol that is widely known to be used for improving age-related diseases such as cancers of various organs and Alzheimer’s disease. Resveratrol efficacy was halted significantly due to its instability, and solubility especially in vivo model. Thus, resveratrol conjugated transferrin (Tf)-modified polyethylene glycol-polylactic acid (PEG-PLA) nanoparticle (Tf-PEG-PLA-RSV) was developed to target transferrin receptor overexpression in C6 glioma cells in vitro and to inhibit tumor maturation in rats induced with C6 glioma.⁶⁶ More examples of herbal loaded NE are presented in Table 1.^67–71

Liposome

A liposome is a spherical shaped polar lipid nanoparticle that encapsulates an aqueous core by single or multiple natural or synthetic lipid bilayer membranes, in which it freely diffuses into its interior (Figure 5A).⁷² A liposome is known to have both hydrophilic and lipophilic groups on the same molecules and thus it can load both hydrophilic and lipophilic materials and can have single or multiple homocentric membranes as well.⁷³

The pharmacokinetic profiles of drugs, herbs, vitamins, and enzymes can be modified extraordinarily by encapsulating them with liposomes for the purpose of preparing vaccines, cosmetics, and nutraceuticals.⁷⁴ Because of liposome’s unique feature of having phospholipid bilayers as well as accommodating both water-soluble and lipid-soluble agents, it is able to enhance the solubility, bioavailability, delivery, intracellular uptake and biodistribution performance of the products both in vitro and in vivo.^75,76 Additionally, defending of active drug from environmental factors, overwhelming primal destruction of the loaded material, less costly and prompt treatment with minimum systemic morbidness that has magnified their use in biomedicine formulations.⁴

The most commonly used polymers to elongate their half-life, as well as stability, are PEG and poly(lactic-co-glycolic acid) (PLGA). On the other hand, antibodies or ligands can be conjugated to liposome in order to enhance their target specificity, such as incorporating of curcumin into liposomes coated with PSMA antibodies by Thangapazham et al to enhance targeted delivery of curcumin for prostate cancer. They used LNCaP and C4-2B human prostate cancer cell lines in their study and realized that treatment of cells with liposomal curcumin leading to at least 70–80% inhibition of cellular proliferation without affecting their viability, with a 10-fold dose advantage over free curcumin.⁷⁷ More examples of herbal loaded NE are presented in Table 1.^78–83

Transferosome

The conventional liposomes do not deeply penetrate the skin and remain confined to the outer layer of stratum corneum. Thus, new classes of lipid vesicles such as transferosomes have been developed as an enhanced type of liposomes,¹¹ which is an ultra-flexible lipid-based elastic vehicle with highly deformable membranes that enhance the sending of materials to deeper skin tissues through a nonoccluded method which penetrates the intercellular lipid lamellar regions of stratum corneum due to the hydration or osmotic force of the skin.⁸⁴

It is composed of phospholipid and a single chain surfactant that provides elasticity and deformability to the vesicles (Figure 5B) that can be used topically for the purpose of supplying the nutrients locally to maintain the skin.⁸⁵ This unique infrastructure endows transfer some to entrap hydrophilic, lipophilic, and amphiphilic drugs and thereof it can be utilized as drug carriers for small molecules, peptides, proteins, and herbal components as well as it can accommodate drug molecules with a wide range of solubility.⁹ On the other hand, chemically, transfersomes are not stable because of their predisposition to oxidative degradation and the purity of natural phospholipids is another criterion militating against the adoption of transfersomes as drug delivery vehicles.⁸⁶

Figure 5 A schematic illustration of liposome (A), transferosome (B), niosome (C) and ethosome (D).Notes: Adapted with permission from Frontier in Pharmacology. Sercombe L, Veerati T, Moheimani F, Wu SY, Sood AK, Hua S. Advances and challenges of liposome assisted drug delivery. Front. Pharmacol. 2015;6:286.³²⁴

Additionally, transferosomes are not difficult to scale up, as the process is simple, easy to scale up without using pharmaceutically unsatisfactory additives.⁸⁷ In this respect, ginsenoside Rh1 from Red ginseng (the steamed root of Panax ginseng C. A. Mayer) transferosome has been developed for skin maintenance that provided significantly higher skin penetration and higher topical absorption in comparison to ethosome and conventional liposome using rat dorsal skin in vitro.⁸⁸ More examples of herbal loaded transferosomes are presented in Table 1.^89–93

Niosome

Niosome is a nonionic nanosphere vesicle with a diameter of 100 nm to 2 um, in which its center is watery that surrounded by layers of nonionic amphiphilic lipids in lamellar phase (Figure 5C).⁹⁴ It is prepared by thin-film hydration method, sonication, microfluidization, multiple membrane extrusion, reverse phase evaporation technique, remote loading, bubble method and proniosome pre-formulation technique.⁹⁵

Niosome is almost similar to liposome in structure but with more penetrating capability, more stability and therapeutic index of a drug, and less toxicity, thus it could offer more advantages over liposome.⁹⁶ The advantages of niosome include cost-effectiveness, high solubility and flexibility and controlled release of its content. Therefore, they have been utilized widely as a targeting vehicle for neoplasia or as peptide carrier, hemoglobin carrier, and transdermal delivery.⁹⁷

In tropical application, niosomes were also showed prolonged circulation, sustained release and retention in the skin and facilitated the permeation of the drug into the skin.⁹⁸ Niosomes were reported to be more stable without significant toxicity than liposomes especially when used topically for treatment of skin diseases. In this regard, niosome loaded resveratrol for topical treatment of skin cancers is one of the potential candidate.^99,100 Similarly, the topical gel from Zingiber cassumunar Roxb. extract loaded niosome for anti-inflammatory activity-enhanced skin permeation and stability of compound D was developed using croton oil-induced ear edema model in male ICR mice.¹⁰¹ More examples of herbal loaded niosome are shown in Table 1.^102–106

Ethosome

It is a novel liposome that defined as a soft, non–invasive lipid-based elastic vesicles (Figure 5D) developed for topical, transdermal and systemic applications with the high efficient ability of both hydrophilic and lipophilic drugs and active ingredient delivery to deeper skin layers and blood circulation.^8,10

Ethosome is composed of water, certain phospholipids (phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, and phosphatidylglycerol), and a relatively high concentration of alcohol (30–45%) (ethanol and isopropyl alcohol).^109,110 This composition provides higher deformability and entrapment efficiency to ethosome that enhances topical drug delivery of highly concentrated active ingredients and transdermal transport efficiency and prolongs the physical stability of ethosomes via flexibility of the lecithin bilayer when compared to liposome.¹⁰⁹

The disadvantage of ethosome is size growing from tens nanometers to micrometers due to its poor stability that caused by alcohol evaporation and then loaded compounds leaks out after a while. To control this shortcoming, alcohol can be situated with a combination of trehalose and propylene glycol.¹²

In this connection, curcumin-encapsulated PEGlycated and traditional liposomes and ethosomes were developed and tested for their potency as a transporter for the carrying of products to the skin. PEGlycated liposomes presented the most accepted ex vivo transdermal drug delivery system in rat skin and showed a higher suppression of paw edema in the rat model of induced inflammation.¹¹⁰ More examples of herbal loaded NE are presented in Table 1.^88,111,112

Dendrimer

A dendrimer is a tree-like synthesized polymer that was characterized as having a single central core that gives frequent branches of variously armed macromolecules (external capping and multifunctional groups) (Figure 6) to achieve better targeting to specific sites. Generally, they are made up of natural or synthetic components such as sugars, nucleotides and amino acids.^113,114

Figure 6 A schematic illustration of dendrimer. Notes: Reproduced from ud Din F, Aman W, Ullah I, et al. Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. Int J Nanomed. 2017;12:7291-7309⁸

The unique feature of this polymer is that its structure and hydrophilicity are easily controllable during formation to get higher solubility, permeability, biocompatibility, biodistribution, clearance and consequently reducing side effects.¹¹⁵

Instantly, the polyamidoamine (PAMAM) dendrimers have recently been studied as carriers as they can be developed in various shapes, sizes and surfaces, in order to get functionalized nanoscale formulas.¹¹⁶ Thus, this dendrimer can offer to target ligands to promote particular binding to cellular receptors.¹¹⁷ Additionally, the small size of this dendrimer renders it to be promptly cleared from the body through the renal and escape from the reticuloendothelial system.¹¹⁸ Furthermore, broad internal cavities of PAMAM dendrimers allow them to complex hydrophobic drugs either by a covalent or non-covalent conjunction.^119,120

In this regard, a group of researchers investigated the effectiveness of quercetin-loaded PAMAM dendrimers after oral administration as a Biopharmaceutical Classification System (BCS) class II molecule. They assessed the water solubility of quercetin in 4 generated dendrimers with 5 different concentrations. Consequently, they found that all generations with respective concentrations of PAMAM dendrimers showed potential positive effects on solubility enhancement and in vitro quercetin dual releasing pattern of an initial quicker release then sustained release. Furthermore, the efficacy of this dendrimer on a carrageenan-induced paw edema model to evaluate the acute activity of this nanocarrier in response to inflammation was also evaluated.¹²¹ More examples of herbal loaded NE are presented in Table 1.^122–128 However, many other dendrimers such as polyamidoamine organosilicon (PAMAMOS), polypropyleneimine (PPI), and glycodendrimers have been developed and studied but with less common use.¹²⁰

Micelle

It is a nanosized (10–100 nm) polymer particles or colloidal dispersion (Figure 7) that consists of a single core-shell with narrow and small-sized self-assembly of synthetic amphiphilic di- or tri-block copolymers with both hydrophobic and hydrophilic segments in aqueous media.^129,130 Solubilization enhancement, intracellular drug accumulation, and protection against degradation are provided by the inner hydrophobic core, while the hydrophilic layer providing improved biocompatibility and active site-specific cell targeting, as well as thermal, pH, and photosensitivity properties.¹³¹

Figure 7 A schematic illustration of micelle.Notes: Reproduced from ud Din F, Aman W, Ullah I, et al. Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. Int J Nanomed. 2017;12:7291-7309⁸

In order to achieve a higher accumulation of drugs at the tumor site and achieve a prolonged circulation in blood, micelles must maintain good stability in the body. This proper stability can be achieved in two paths that are dynamic stability in which the micelle being decomposed into the single polymer chain, and the other is thermodynamic stability in which depends on the anti-dilution capacity of polymeric micelles.¹³¹

The best-studied block copolymers for use in micelle construction are polyethylene glycol (PEG)-block-poly3-caprolactone (PCL), PEG-b-polylactide-coglycolide, and PEG-b-poly-c-benzyl L-glutamate. Among them, PEG-PCL is the most preferable one due to its acceptable features such as biodegradability, safety, and high loading for lipid-soluble biomaterials.¹³²

In this respect, artemisinin encapsulated PEG-PCL micelle introduced with LyP-1 (cyclizine-amino acid peptide) has been developed that recognizes and binds to the p32/gC1qR receptor and consequently expressed highly in specific cancer cells of tissues and lymph vessels. This polymeric micelle modification enhances the artemisinin delivery to extremely metastasized mammary adenocarcinoma and its surrounding lymphatic tissues both in vitro and in vivo successfully.¹³³

Generally, polymeric micelles are penetrating the tumors via active or passive targeting mechanisms in which the latter enhanced permeability and retention effects produced after intravenous administration of particles, while active targeting depends on the basic receptor-mediated interaction between the ligand-modified on the surface of micelles and the molecular markers specifically over-expressed in the cancer cells, such as folate receptors, integrins, and epidermal growth factor receptors.^134,135 More examples of herbal loaded NE are presented in Table 1.^136–140

Nanosphere (NS)

Nanosphere is a colloidal aqueous solution with amorphous or crystalline nature having a size range between 10 and 200 nm (Figure 8) that composed of a polymeric core encapsulating active ingredients and/or adsorbing them onto the nanoparticles.^141,142

Figure 8 A schematic illustration of nanosphere.Notes: Reproduced from Harper 3D.¹⁴²

The main virtue of this system includes delayed drug release, regular plasma drug concentrations, more stability in biological fluids, high protection from enzymatic and chemical degradation, improved bioavailability, potential antitumor efficiency, enhance complete entrapment of the drug, and reduced toxicity.¹⁴³ These most outstanding features of NS are directly due to hydrophobic surfaces of these particles that are highly susceptible to opsonization and clearance by the reticuloendothelial system.¹²

Biodegradable NS includes albumin NS, modified starch NS, gelatin NS, polypropylene dextran NS and polylactic acid NS. In addition, there are 2 more types of NS, immune NS and magnetic NS. Immunomagnetic NS can be prepared by combining the above two kinds of NS, which could significantly improve its targeting.¹⁴⁴

Most nanospheres are prepared with biodegradable, biocompatible, and synthetic polymers such as polylactic acid (PLA), polyglycolic acid (PGA), and their co-polymer polylactide-coglycolide (PLGA) using emulsion evaporation technique.¹⁴⁴ Moreover, NS can be also prepared using pre-formed polymers by nanoprecipitation (omitting the oil in the formulation) or interfacial deposition of polymer (containing the oil). The type of polymer is also important for evaluating the rate of release by NS. Because of the small size of NS, they can be administered orally, locally, and systemically.^12,145

Interestingly, oridonin (ORI)-loaded poly(D, L-lactic acid) (PLA) modified with a functionalized polymer [RGD (Arg-Gly-Asp peptides)] to improve antitumor activity is generated that comes with tissue targeting, and better in vivo tumor inhibitory effects than oridonin alone or ORI loaded PLA nanoparticles.¹⁴⁶ More examples of herbal loaded NE are presented in Table 1.^{142,143,147–149}

Nanocrystals

They are pure drug crystals with nanosized particles (Figure 9) in which toxic side effects resulting from the encapsulating/solubilizing excipients may be eliminated.¹⁵⁰ The best known features of nanocrystals are high drug-loading capacity and platform stability that render them to be widely used to deliver poorly hydrophilic materials in the form of a colloidal dispersion.¹⁵¹ Cells of the mononuclear phagocytic system can recognize the nanocrystal particles in the bloodstream as an exogenous material which results in passive accumulation in liver, spleen, and lung.^61,152

Figure 9 A schematic illustration of fentofibrate nanocrystals (FNB-NCs). Notes: Reproduced from Kevadiya BD, Chen L, Zhang L, Thomas MB, Davé RN. Fenofibrate Nanocrystal Composite Microparticles for Intestine-Specific Oral Drug Delivery System. Pharmaceuticals. 2019;12(3):109-124³²⁹

Nanocrystals are generally developed by the “bottom-up” (such as Nanomorph™, Soliqs/Abbott), “top-down” technologies (such as Dissocubes^®, SkyePharma) or combination technologies (such as NANOEDGE, Baxter). However, the top-down technique is the procedure of choice for nanocrystals in products developed in the pharmaceutical, cosmetic or clinical trials mainly due to the simple and easy scale-up which better serves the industry.⁶¹

The nanocrystals are made by wet milling methods, such as bead milling or high-pressure homogenization technique that improves the oral bioavailability and enhanced the transdermal efficacy of poorly soluble drugs.¹⁵³ Physically, the biodistribution of nanocrystals is affected by particle size, morphology and surface modification. Additionally, in order to target nanocrystals to specific pathogenic sites, ligand conjugation and stimuli-responsive polymers can be used.¹⁵⁴

In 2011, a group of researchers prepared a natural product derived nanocrystal focused on Camptothecin (CPT) active compound that was isolated from the bark and stem of Camptotheca acuminata, a tree native to China used as a cancer treatment in Traditional Chinese Medicine.¹⁵⁵ In their study, they examined the particle characteristics, cellular cytotoxicity, and animal anticancer effect. Finally, they realized that CPT nanocrystals were more potent to MCF-7 human breast cancer cells than CPT alone in vitro. Additionally, CPT nanocrystals exhibited significant suppression of tumor growth in MCF-7 xenografted BALB/c mice model and the drug concentration in the tumor site was 5 times more at 24 hrs by using the nanocrystal treatment than by using the CPT solution. Storage stability study indicated that the nanocrystals were stable for at least 6 months.¹⁵⁵ More examples of herbal loaded NE are presented in Table 1.^156–163

Phytosome or Herbosome

Water-soluble phytochemicals such as flavonoids and polyphenols are poorly absorbed in the body due to their large molecular size which did not allow them to be absorbed by passive diffusion, as well as their poor lipid solubility makes a serious limiting to their pass across the lipid-rich biological membranes, subsequent poor bioavailability.¹⁶⁴

Phytosome is a patented formula developed to incorporate medicinal plant active ingredients and water-soluble phytochemicals into phospholipids to create lipid-compatible molecular complexes in order to immensely modify their absorption and bioavailability.¹⁶⁵ The novelty of phytosome formulation is that there is a molecular complex and chemical bonding between phosphatidylcholine and the plant materials at a ratio of either 1:1 or a 2:1 relying on the substance(s) conjugated, whereas no chemical bonds are formed in liposome and thousands of phosphatidylcholine molecules enclosing the water-soluble compound can be observed freely.¹⁶⁶

Phytolipid delivery system is a specifically modified phytosome for delivering of herbal drugs that made by incorporation of standardized plant extracts or water-soluble phytochemicals into phospholipids to produce lipid-compatible complexes to enhance better absorption and bioavailability without resorting the pharmacological or structural changes of the ingredients.¹⁶⁷

The phytosomes are small-sized particles (Figure 10) that produce better transiting from a water-soluble condition into the lipid-soluble condition of the enterocyte cell membrane and then into the cell, lastly arriving the blood and protecting the valuable ingredients of the herbal drug from gastric enzyme destruction and gut bacteria.¹⁶⁸

Figure 10 A schematic illustration of phytosome. Notes: Reproduced Karthivashan G, Masarudin MJ, Kura AU, Abas F, Fakurazi S. Optimization, formulation, and characterization of multiflavonoids-loaded flavanosome by bulk or sequential technique. Int J Nanomed. 2016;11:3417-3434¹⁶⁹

Figure 11 A schematic illustration of APC-SNEDDS dissolved in distilled water. APC: Akebia saponin D-phospholipid complex. Notes: Reproduced from Shen J, Bi J, Tian H, et al. Preparation and evaluation of a self-nanoemulsifying drug delivery system loaded with akebia saponin D–phospholipid complex. Int J Nanomed. 2016;11:4919-4929¹⁸³

The recently produced phytosome-loaded herbal content is optimizing a sequential technique by a group of researchers from Malaysia to encapsulate several flavonoids in a single phytosome that named flavonosome. Three widely constituted and therapeutically valuable flavonoids named quercetin (Q), kaempferol (K), and apigenin (A) were tested in the ethyl acetate fraction of Moringa oleifera leaf extract and encapsulated in a single flavonosome (QKA–phosphatidylcholine) via 4 various techniques. After checking for many physicochemical properties, they suggested that this three-in-one flavonosome with sustained activity is a good candidate as an antioxidant, hepatoprotective, and heat supplement agent.¹⁶⁹ More examples of herbal loaded NE are presented in Table 1.^170–175

Self Nanoemulsifying Drug Delivery System (SNEDDS)

SNEDDS is a lipid-based anhydrous isotropic mixture of oil, surfactant(s) and cosurfactant(s) with a particle size of 20–200 nm (Figure 11).^9,176 It produces fine oil-in-water nanoemulsions upon gentle agitation after dilution in aqueous media, such as gastrointestinal fluids; thus, it can be given orally in soft or hard gelatin capsules. This leads to in situ solubilization of drug that can subsequently be absorbed by lymphatic pathways, bypassing the hepatic first-pass effect.¹⁷⁷ On the other hand, efforts were made to overcome the limited aqueous solubility, low ocular bioavailability and short pre-ocular retention and absorption of drugs by introducing SNEDD in the form of eye drop.¹⁷⁸

Physically stability upon storage, easy to produce, improved dissolution rates and absorption that results in more reproducible blood–time profiles are among the most accepted features of SNEDDS. Additional advantages of SNEDDS over conventional emulsions and other lipid carriers are the significantly reduced energy requirement for their preparation and easier to manufacture in a large scale.¹⁷⁹

Among the successful example of previously prepared crude plant extract-loaded SNEDDS is a persimmon (Diospyros kaki) leaf extract (PLE) loaded SNEDDS that was characterized to compare its in vitro dissolution and relative bioavailability with a commercially available agent (Naoxinqing tablets). They indicated that this developed formula shows better stability, solubility and sustained release than the commercial drug, as well as it is a promising drug delivery system for increasing the oral bioavailability following oral administration in fasting beagle dogs.¹⁸⁰ Recently, several novel herbal loaded SNEDDSs with desirable properties have been reported and are presented in Table 1.^181–185

Self Microemulsifying Drug Delivery System (SMEDDS)

SMEDDS is a lipid-based nanoparticle that is composed of oil, surfactant (Cremophor RH40, Cremophor EL, or Polysorbate 80) and co-surfactant (Figure 12). The role of surfactant in SMEDDS is to improve intestinal permeability by lowering surface tension and hence facilitating touch with gastrointestinal mucosa and additionally inhibiting drug efflux by P-glycoprotein.^186,187

Figure 12 A schematic illustration of SMEDDS. Notes: Adapted from Quan G, Niu B, Singh V, et al. Supersaturable solid self-microemulsifying drug delivery system: precipitation inhibition and bioavailability enhancement. Int J Nanomed. 2017;12:8801-8811³³⁰

Among the most preferred property of SMEDDS is bioavailability improvement due to its small particles and wide surface area, which ameliorate absorption, solubilization, and releasing capacity. Additionally, SMEDDS decreases the first-pass metabolism by facilitating drug absorption via the lymphatic system of the intestine, and thus it provides a promising way to raise bioavailability for poorly hydrophilic products. Moreover, SMEDDS is very stable, easy to administer, and easy to construct at industrial scale especially solid SMEDDS.¹⁸⁸

SMEDDS can produce microemulsions, nanoemulsions, or emulsions followed by injection into aqueous media with mild agitation that may develop drug precipitation. In order to overcome this phenomenon, a super-saturable self-micro emulsifying drug delivery system (S-SMEDDS) is developed that contains precipitation inhibitor with good crystallization-inhibiting capacity such as Polyvinylpyrrolidone (PVP) K17.¹⁸⁹ Instantly, ligand-modified SMEDDS was reported with targeted delivery of active compounds to specific absorption sites such as targeting of folate receptor overexpression in colorectal carcinoma by producing folate-modified SMEDDS.¹⁹⁰

In this connection, resveratrol, a poorly hydrophilic component isolated from some commonly desired fruits loaded SMEDDS is generated for oral delivery. This novel SMEDDS is also characterized by maintaining high drug solubilization for long period to improve drug absorption, improved bioavailability and provided more stability due to its small particle size (approximately 50 nm) and high zeta potential in a neutral environment. The antioxidant capacity and cytotoxicity of the formulation were also detected using DCFH-DA and CCK-8 assays. The formulation exhibited a greater antioxidant capacity with less toxicity than a free compound.¹⁹¹ More examples of herbal loaded NE are presented in Table 1.^192–196

Nanofiber

It is composed of solid polymer fibers with diameters of 10–1000 nm that have a large surface area with a small pore size (Figure 13) and is prepared by the electrospinning method.¹² This novel nanocarrier has a limited role in delivering active components but with potential improvements in the therapeutic treatments and support the using of active compounds in several biomedical areas such as tissue regeneration.^197,198

Figure 13 A schematic illustration of dexamethasone loaded nanofibers (Dex-NS). Notes: Adapted from Lee JW, Lee HY, Park SH, et al. Preparation and evaluation of dexamethasone-loaded electrospun nanofiber sheets as a sustained drug delivery system. Materials. 2016;9(3):175-186³³¹

Figure 14 A schematic illustration of polymerosome. Notes: Adapted from Prabhu RH, Patravale VB, Joshi MD. Polymeric nanoparticles for targeted treatment in oncology: current insights. Int J Nanomed. 2015;10:1001-1018⁸⁴

Figure 15 Transmission electron micrographs of 20(S)-protopanaxadiol cubosome with (A) and without (B) Pierine. Notes: Reproduced from Jin X, Zhang ZH, Sun E, et al. Enhanced oral absorption of 20 (S)-protopanaxadiol by self-assembled liquid crystalline nanoparticles containing piperine: in vitro and in vivo studies. Int J Nanomed. 2013;8:641-652³³²

Figure 16 A schematic illustration of chitosan nanoparticle.Notes: Reproduced from Tan Q, Liu W, Guo C, Zhai G. Preparation and evaluation of quercetin-loaded lecithin-chitosan nanoparticles for topical delivery. Int J Nanomed. 2011;6:16211630.²³³

The nanofibers are most likely carbon-based as they are extracted from various plants and thus they can be generated from different polymers and hence have different physical properties and application potentials.¹⁹⁹ Among the potential benefits of the nanofibers is to modify wound healing and preventing infection. Also, it is suggested that nanofibers have very strong adhesive features such as that is found with a gecko that allows it to easily climb surfaces using bundles of nanofibers on the surface of its feet. Moreover, the scaffolding of nanofibers to initiate the repair of damaged tissue is among the pronounced features.²⁰⁰

Regarding the anticancer potential of nanofiber, curcumin-loaded self-assembling peptide nanofiber as a novel tumor-targeting carrier was developed that showed high cellular uptake in αvβ3 integrin-positive HepG2 liver carcinoma cells, thereby leading to significantly higher cytotoxicity than nonloaded one. Additionally, ex vivo studies further demonstrated that curcumin could accumulate markedly in mouse tumors after administration via the tail vein.^201,202 More examples of herbal loaded nanofibers are displayed in Table 1.^203–207

Polymersome (PS)

Polymersome is a self-assembled polymeric nanosphere vesicle that may have relatively thick membranes (up to 40 nm), which are formed by synthetic amphiphilic block copolymers (Figure 14).²⁰⁸ They are able of incorporating hydrophilic and nonhydrophilic drugs, proteins, peptides, DNA and RNA fragments in their membrane which acts as a barrier to protect them from the biological environment. Additionally, the membrane flexibility of PS makes them applicable in targeting and control release.²⁰⁹ Polymersomes have some similarities to liposomes especially in the structure but are more stable and less permeable than liposomes. The PS is capable to bind with biologically active ligands, antibodies and biotinylated conjugation to their surface which enhances targeted therapy and imaging strategy.²¹⁰

It was documented that PS was used as anti-tumor agents for several drugs due to its controlled release, high permeation, retention and loading capacity of drugs into PS than liposome membrane.^211,212 In this respect, biotin functionalized leuko-polymersome to proctor and treat inflammation, cancer, and cardiovascular disease and Tat-loaded PS as a fantabulous agent for cellular tracking were also investigated as a promising tumor-fighting agent.²¹³ More examples of herbal loaded PS are found in Table 1.^{208,214–217}

Cubosome

It is a viscous isotropic vesicle that made mainly of unsaturated monoglycerides (monoolein-water) binary system with thermodynamically steric stable bi-continuous cubic liquid crystalline phase (poloxamers) (Figure 15).^218,219

Features such as high internal surface area per unit volume (approximately 400 m²/g) and a 3D structure with hydrophilic and hydrophobic domains make them entrap water-soluble and nonsoluble and amphiphilic materials successfully. Its large interfacial area can provide a complex diffusion pathway for sustained release of entrapped drug molecules, whereas lipid constituents are biocompatible, bio-adhesive, and digestible.²²⁰ They are usually constructed via dispersion or fragmentation of the cubic phases of gels in a liquid condition.²²¹ Previous works on somatostatin, insulin, indomethacin, and rifampicin drug encapsulation within cubosomes have been done intensively. Additionally, various pharmaceutical applications of cubosomes have also been investigated such as peptides, enzymes, antimuscarinic drugs, antibiotics, and analgesic delivery.^221,222

Cubosomes easily evacuate their contents to the epidermis as they have an almost same structure to that of the stratum corneum, as well as the properties of adhesion and penetration enhancement of cubosomes suggest their potential utility in skin cancer (melanoma) treatment.²²³ On the highlight of this, very recently, a report of biocompatible polymer-free cubosomes for potential application in both photodynamic therapy and bioimaging of skin malignant melanoma has been published with very low cytotoxicity to the cutaneous formulation.²²⁴ More examples of herbal loaded cubosome are shown in Table 1.^225–229

Biopolymer-Based Nanocarrier (BBN)

They have derived from proteins (such as gelatin, albumin, and milk proteins), polysaccharides (such as chitosan, hyaluronan, dextran, cyclodextrins, pectin, guar gum, cellulose, sodium alginate, and starch), and/or their modified versions, derivatives or their combinations. The most interesting features of these materials that render them to be used for BBN production are a biological realization, bioactivity, biodegradability, less toxicity, easy modification, and simplicity of producing gels from them.²³⁰ This type of nanocarrier is well established to have plausive water solubility, stability, degradation, and biocompatibility for a wide range of utilization that earned from their variable charges, molecular weights, and compositions.^9,12 Various approaches for fabrication of BBN delivery systems are well addressed which including coacervation, spray drying, electrospinning, electrospray, supercritical fluid, emulsion–diffusion, reverse micelle, emulsion-droplet coalescence, emulsification/solvent evaporation, salting-out, ultrasonication and high-pressure homogenization.²³¹

Pure Biopolymer Nanoparticles (PBN)

Chitosan, a cationic biocompatible and biodegradable linear polysaccharide, containing d-glucosamine and N-acetyl glucosamine units, which is extracted from the exoskeleton of crustacean arthropods such as insects, crabs, lobster and shrimps²³² reported to be the best example of natural pure biopolymer to deliver plant components such as curcumin, quercetin,²³³ and trans-resveratrol with better mucoadhesion, solubility, dissolution rate, and specific targeting.^234,235 Additionally, chitosan has been utilized for various biomedical applications such as in tissue engineering in the form of scaffolds, drug delivery carriers, fabricating surgical thread, bone healing, and as a wound dressing substance. On the other hand, modified chitosan molecules such as dextran sulfate-conjugated chitosan, biotinylated and galactosylated chitosan are well developed with advanced properties such as altering the surface charge, providing pH-sensitive swelling, more stability, enhancing bioactivity by modifying targeting to the specific site of action (Figure 16).²³⁶ More examples on this nanoparticle are available in Table 1.^237–241

Biopolymer-based Hydrogels (BBH)

Hydrogels are cross-linked polymeric networks with hydrophilic functionalities that supply spaces for homing aqueous biological fluids (Figure 17) and have is known as a promising bio-compatible material in numerous therapeutic applications.^12,242 This formula is characterized by adorable biocompatibility, high porosity, hydrophilicity that results in controlled drug release. Naturally available biopolymers such as chitosan, alginate, hyaluronic acid (HA), collagen, and gelatin are used to construct inherently biodegradable BBH that frequently pre-functionalized to integrin binding sites permitting for adherence and integrated cellular responses.⁹ However, the application of these substances is somewhat restricted because significant batch-to-batch variability and potential immunogenicity within foreign models are obtained.²⁴³

Figure 17 A schematic illustration of biopolymeric hydrogel. Notes: Reproduced with permission from MDPI. Zhao F, Yao D, Guo R, Deng L, Dong A, Zhang J. Composites of 2075 polymer hydrogels and nanoparticulate systems for biomedical and pharmaceutical applications. Nanomaterials. 2015;5(4):2054–2130.²⁴²

Figure 18 A schematic illustration of biopolymeric drug conjugate. Notes: Reproduced from Safer AM, Leporatti S, Jose J, Soliman MS. Conjugation Of EGCG And Chitosan NPs As A Novel Nano-Drug Delivery System. Int J Nanomed. 2019;14:8033-8046.³³³

Figure 19 A schematic illustration of gold nanoparticle.Notes: Reproduced with permission from Luna Nanotech.²⁶⁰

Figure 20 A schematic illustration of silica nanoparticle. Notes: Reproduced from ud Din F, Aman W, Ullah I, et al. Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. Int J Nanomed. 2017;12:7291-7309.⁸

Figure 21 A schematic illustration of magnetic nanoparticle.Notes: Adapted with permission from Frontier in Microbiology. Souza AC, Amaral AC. Antifungal therapy for systemic mycosis and the nanobiotechnology era: improving efficacy, biodistribution and toxicity. Front Microbiol. 2017;8(336):1–13. ²⁸⁰

Figure 22 A schematic illustration of veteran cockle shell-derived calcium carbonate nanoparticles. Notes: Reproduced from Muhammad Mailafiya M, Abubakar K, Danmaigoro A, et al. Cockle Shell-Derived Calcium Carbonate (Aragonite) Nanoparticles: A Dynamite to Nanomedicine. Appl Sci. 2019 ;9(14):2897-2922.³³⁴

Figure 23 A schematic illustration of halloysite clay nanotubes. Notes: Reproduced with permission from Kamal N, Kochkodan V, Zekri A, Ahzi S. Polysulfone Membranes Embedded with Halloysites Nanotubes: Preparation and Properties. Membranes. 2020;10(1):2-29.³³⁵

Figure 24 A schematic illustration of single walled carbon nanotube (A) and double walled carbon nanotube (B). Notes: Reproduced from ud Din F, Aman W, Ullah I, et al. Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. Int J Nanomed. 2017;12:7291-7309.⁸

Figure 25 Types and structures of hybrid nanocarrier. Notes: Adapted from Prabhu RH, Patravale VB, Joshi MD. Polymeric nanoparticles for targeted treatment in oncology: current insights. Int J Nanomed. 2015;10:1001-1018.⁸⁴

Figure 26 A schematic illustration of biological nanocarrier. Notes: Reproduced from ud Din F, Aman W, Ullah I, et al. Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. Int J Nanomed. 2017;12:7291-7309.⁸

In this connection, biopolymer-based pH-sensitive hydrogels were prepared using chitosan with PEG of different molecular weights in the presence of silane crosslinker. The incorporated components remain undissolved in different swelling media as they are connected by siloxane linkage which was confirmed by FTIR spectroscopy. The swelling in water was enhanced by the addition of higher molecular weight PEG. The swelling behavior of the hydrogels against pH showed high swelling in acidic and basic pH, whereas, the low swelling was examined at pH 6 and 7. This characteristic pH-responsive behavior at neutral pH made them suitable for injectable controlled drug delivery.²⁴⁴ More examples on this nanoparticle are available in Table 1.^245–249

Biopolymer Drug Conjugate (BDC)

Thermally sensitive biopolymer with the potential ability to quickly form insoluble viscous co-acervate at body temperature can be used for this purpose (Figure 18).^250,251 Although some of the biomedical polymer–drug conjugates are approved for clinical trials, they lack photothermal properties and multi-imaging capabilities, impeding them from imaging-guided precision cancer therapy and total cancer arrested development.²⁵² Thus, researchers introduced a novel all-in-one biopolymer–drug conjugate nanotheranostics, such as that of intracellular pH-sensitive polydopamine–doxorubicin conjugate nanoparticles under a mild situation that are characterized by excellent photothermal attribute, dual stimuli-triggered drug release activity, and about elongated blood circulation time than nonconjugated doxorubicin.²⁵³ More examples on this nanoparticle are available in Table 1.^254–259

Inorganic Nanocarrier

Recently, different kinds of inorganic nanocarriers have been developed and investigated for their potential delivery of plant active ingredients.

Metal Nanoparticle (MN)

These are nanoparticles such as silver nanoparticles (AgNPs), gold nanoparticles (AuNPs) (Figure 19),²⁶⁰ copper nanoparticles (CuNPs), zinc oxide (ZnONPs) nanoparticles, quantum dots, cerium oxide (CeO₂) nanoparticles, iron oxide nanoparticles (Fe₃O₄), yttrium oxide (Y₂O₃) nanoparticles and titanium dioxide nanoparticles (TiO₂) possess special benefits in biomedical application due to their contents of essential mineral elements that have strong activity for human body.²⁶¹ These nanoparticles gained their noncovalent interaction or covalent conjugation drug-loading capacity due to their surface plasmon resonance (SPR) ability, structural diversity, poor toxicity, and high biocompatibility. Thus, they can be utilized for achieving intracellular drug delivery and controlled release through a photothermal route.²⁶²

Moreover, a novel metal nanoparticle with multi-functional groups is also investigated by developing much active component-loaded complex metal nanoparticle integrated multifunctional liposomes to improve intracellular drug delivery, overwhelm multi-drug resistant (MDR), fasten anti-tumor activity, and lower side effects.²⁶³ Very recently, it has proven that biopolymers complexed with bioactive nanoparticles endowing antimicrobial and anti-inflammatory properties have a fantastic effect in wound care to prompt the healing mechanism of wound infections caused by hyperglycemia.

In this regard, a combination of antibacterial nanoparticles such as silver, gold, or copper nanoparticles with polymeric matrix could potentially suppress bacterial propagation and similarly fastens the healing process of a wound and mitigate the diabetes mellitus-based foot ulcer.²⁶⁴ More examples on this nanoparticle are available in Table 1.^265–269

Mesoporous Silica Nanoparticle (MSN)

MSN is the most recent promising carrier for drug storage and delivery that has large surface area with high loading capacity for therapeutic agents, high pore volume and porosity (honeycomb-like architecture), adjustable pore diameter, modifiable surface potential, selective surface functionality, morphology control, adorable biocompatibility and controlled release properties (Figure 20).^270,271

Moreover, MSN has been applied in pharmaceutics to improve drug bioavailability, reduce drug toxicity, and deliver with cellular targetability. Particularly, the exciting progress in the development of MSN-based effective delivery systems for poorly soluble drugs, anticancer agents, and therapeutic genes.²⁷²

In general, MSNs are synthesized by using a silica precursor (tetraethylorthosilicate or sodium silicate) in an alcoholic solution under basic conditions and incorporating a surfactant. On the other hand, the synthesis of mesoporous silica particles in the nonalcoholic medium was conducted but the formation of spherical particles is limited by the amount of the surfactant.²⁷³

The developed formula in this area is silybin from the seed of the milk thistle (Silybum marianum)-meglumine encapsulated MSN with high drug-loading capability, in vitro, sustained release, and in vivo high absorption ability.²⁷⁴ More examples on this nanoparticle are available in Table 1.^275–279

Magnetic Nanoparticle (MNP)

Attributing with the use of developed magnetic nanoparticle (especially iron oxide) owing to receive the highest target positioning and best trigger drug release, biocompatibility, and nontoxicity in a magnetic field (Figure 21).²⁸⁰ Magnetic nanoparticles with appropriate surface coatings are used clinically for various biomedical applications, such as magnetic resonance imaging, hyperthermia, drug delivery, tissue repair, cell, and tissue targeting and transfection.²⁸¹ Other benefits of using magnetic nanocarriers are referred to be more rapid and effective for curing diseases even if a small amount of drug is consumed; thus, it can reduce the concentration of the drug in healthy tissues, and consequently diminished side effects. Moreover, MNP small size renders them to gain more bioaccessibility to deserted tissues and bio interact with them at molecular and cellular levels, also binding to particular tumor-suppressor antibodies and conveying these adsorbed anti-tumor materials to the site of the tumor.²⁸² In this respect, gambogic acid (from the brownish or orange resin from Garcinia hanburyi)-loaded magnetic iron oxide (Fe₃O₄) nanoparticles were produced and investigated for its improvement in the water solubility of gambogic acid and halting the proliferation and migration of Panc-1 pancreatic cells by inactivating transcription factor ETS1 in vitro using MTT and scratch assays, respectively.²⁸³ More examples on this nanoparticle are available in Table 1.^284–288

Calcium Carbonate (CaCO₃) Nanoparticle

Aragonite CaCO₃ nanoparticle is less stress to achieve, environmentally pleasant, and less costly process that involved a simply automated stirring of cockle shell powder in the occurrence of BS-12 as a biomineralization catalyst (Figure 22).^289,290 CaCO₃ is utilized as therapeutic agents with outstanding efficacy due to its biocompatibility, nontoxicity, changeable surface chemistry, excellent physicochemical property, simple preparatory methods in a bulk scale, controlling release, slow biodegradability, pH-sensitivity, and porous nature.²⁹¹

CaCO₃ potential to be functionalized with targeting agents gives it the distinctive property that can be used in targeted delivery systems for anticancer drugs, in addition to slow CaCO₃ matrix degradation, constant and organized discharge property, controlled release, at the targeted location.²⁹²

The best example in this area is doxorubicin-loaded CaCO₃-NPs for cancer therapy. Generally, the physiological pH of blood and the extracellular spaces around tumors is about 6.8–7.2, while the pH of endolysosomes of cancer cells is highly acidic (pH <6). Then, CaCO₃ nanoparticles holding DOX are swiftly unprotected to the acidic environments of endosomes, loss its stability, and is believed to discharge drugs at lesser pH, which results in a rise in the cellular uptakes of drugs.²⁹³ Unfortunately, until this moment plant metabolite loaded CaCO₃ nanoparticles are not available in the research area.

Nanotube

Halloysite Clay Nanotubes (HNT)

They are aluminosilicate clay that constructed from 2 different dimensional structures (tetrahedral and octahedral) through surface weathering of aluminosilicate and composed of aluminum, silicon, oxygen, and hydrogen (Figure 23).²⁹⁴ These hollow tubes with several nanocavities are best known for having the high surface area, biocompatibility and loading capacity.²⁹⁵ Halloysite nanotubes are natural green cylindrical clays that are not costly, not difficult to collect, and possessing chemical composition similar to that of kaolin. Features such as proper lumens, high aspect length–diameter ratio and low hydroxyl density on their surface make them be more adjustable to be used for many projects.²⁹⁶ Continuing in this area, resveratrol (from berry family)-loaded halloysite nanotube coated layer-by-layer with polyelectrolytes in order to control its drug release ability and to reduce its toxicity is developed successfully. Additionally, the system showed enhanced resveratrol cytotoxicity to MCF-7, breast cancer cells and produced pronounced apoptosis.²⁹⁷ More examples on this nanoparticle are available in Table 1.^298–302

Carbon Nanotubes (CNT)

CNTs are allotropes of carbon with a cylindrical nanostructure that have unusual properties, which are valuable for nanotechnology, electronics, and optics with some remarkable properties such as excellent thermal conductivity, mechanical strength, and electrical conductivity (Figure 24).^303,304

One of the most recently developed nanodevices for biomarker detection is CNT in which a single-walled CNT as a high-resolution atomic force microscopy (AFM) for the selective detection of specific sequences of kilobase-size DNA from single-base mismatch sequences was used.³⁰⁵ The principle of this technique is hybridizing of targeted DNA fragments with labeled oligonucleotides to be easily detected by AFM. This method enabled the straight detection of genetic disorders causing cancers that encoded by specific haplotypes. Additionally, this model can be utilized as nanoscale carriers for bioimaging, drug delivery and used for photothermal destruction of cancer cells.³⁰⁶

In this connection, freshly prepared Ocimum tenuiflorum (tulsi extract) mediated photosynthesized AgNP loaded into emulsified multiwalled carbon nanotube (MWCNT) was developed that characterized by a spherical shape, 5–40 nm size and surface plasmonic resonance at 430 nm. Their targetability to the intracellular part of the sperm cell (without disrupting the sperm cell membrane) for its further application in biosensing-based infertility diagnosis was also investigated in detail and confirmed that AgNP-MWCNT composite is suitable in fertility diagnosis and reproductive health care.³⁰⁷

Hybrid Nanocarrier (HNC)

This type of nanocarrier is composed either from the combination of 2 different organic materials or a combination of an organic with an inorganic material to emerge improved drug delivery performance. Many HNC possesses a core-shell structure that composed of different types of biomaterials (Figure 25).^308,309 This composition endows the HNC with many desirable properties, such as high encapsulation and loading ability, the betterment of stability, sustained release, improvement of intracellular drug delivery, and the enhancement of conjugating with targeting ligands.²⁹⁵ On the other hand, specific functionalities of organic materials at the surface of inorganic materials can be promoted to improve the selectivity and efficiency of therapy especially those utilized as anticancer agents.³¹⁰ In this respect, hybrid nanocarrier conjugated folic acid for targeted letrozole (LTZ) delivery for breast cancer treatment was produced in which physicochemical properties, in vitro in vitro drug release, cytotoxicity and ex vivo work of the formula were studied intensively. As a result, the system could overwhelm the restrictions related to the LTZ as a potent nonsteroidal drug. Finally, it was concluded that both the entrapment and therapeutic efficiency of LTZ in the amphiphilic carrier were enhanced using the lipid nanoparticles and the surface modification, respectively.³¹¹ More example of this nanoparticle is available in Table 1.³¹²

Biological Nanocarriers (BNC)

These are naturally occurring highly diverse nanoparticles that are shared a common structure of a shell composed of capsid proteins surrounding the DNA or RNA viral genome. They have variable sizes (within the nanometer range) and morphologies from simple spheres to rods to icosahedrons (Figure 26).^313,314 In this respect, viruses have been dedicated to targeting the most pronounced organisms and tissues. Most applications use virus nanoparticle (VNP) and virus-like particles (VLP) are native viral capsid proteins without nucleic acid in order not to cause infection.²⁹⁹ VNP and VLP are nanosized (approximately 100 nm), self-assembled robust protein net that possessing uniform nanostructures and distinct geometry. Recently, this system is used for many purposes such as drug delivery and gene therapy in the form of nanoreactors, filamentous or spherical scaffolds.¹²

Modified VNP and VLP are also utilized in vivo for vaccination either to induce immunity against the parent virus or to modify other diseases. Additionally, VLP conjugated to appropriate epitopes have been used for anti-tumor vaccines and for vaccines against chronic diseases such as hypertension.³¹⁵ Regarding their use in bioimaging system, VLP has also been adapted for use as contrast agents in MRI and PET. Furthermore, the natural affinity of VLP for defined cell types allows targeted delivery, as well as the VLP, can be modified by conjugation to targeting molecules, such as folic acid, for cell-specific delivery.³¹⁶ More examples of herbal loaded BNC are presented in Table 1.^317–321

Conclusion

Poor solubility in water and bioavailability have limited the therapeutic efficacy of naturally available potential natural plant products. Currently, recent studies have attempted to address these problems using nanocarriers and studies have anticipated that nanomedicine as a plausible approach for diagnosis, imaging, and therapeutics for a variety of disease treatment and management including cancer, diabetes, hyperglycemia, hypertension, and anemia. Currently, several nanocarrier-encapsulated natural plant extract formulations are in clinical or preclinical development and some of them are already approved by the Food and Drug Administration (FDA) to be used safely in human especially those that are already confirmed that they do not have potential long-term toxicity, degradation, and incomplete metabolism after mitigated by the concept of modifications and piolet study that could be developed as an inexpensive, safe, tolerable, and an appropriate approach for disease control and management.

Acknowledgement

The authors appreciate a grant that has been funded by a Research University Grant Scheme (RUGS) (Project No. UPM/700-2/1/GPBI/2017/9554100) provided by Universiti Putra Malaysia (UPM), Malaysia.

Disclosure

The authors declared that there is no conflict of interest in this current review article.

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