<p>Traditional Chinese medicine-combination therapies utilizing nanotechnology-based targeted delivery systems: a new strategy for antitumor treatment</p>

Zhe Ma; Yuqi Fan; Yumei Wu; Dereje Kebebe; Bing Zhang; Peng Lu; Jiaxin Pi; Zhidong Liu

doi:10.2147/IJN.S197889

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Review

Traditional Chinese medicine-combination therapies utilizing nanotechnology-based targeted delivery systems: a new strategy for antitumor treatment

Authors Ma Z, Fan Y, Wu Y, Kebebe D , Zhang B, Lu P, Pi J , Liu Z

Received 12 December 2018

Accepted for publication 12 February 2019

Published 22 March 2019 Volume 2019:14 Pages 2029—2053

DOI https://doi.org/10.2147/IJN.S197889

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Mian Wang

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Zhe Ma,^1,2 Yuqi Fan,^2,3 Yumei Wu,^1,2 Dereje Kebebe,^1,2,4 Bing Zhang,^1,2 Peng Lu,^1,2 Jiaxin Pi,^1,2 Zhidong Liu^1,2

¹Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; ²Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; ³School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; ⁴School of Pharmacy, Institute of Health Sciences, Jimma University, Jimma, Ethiopia

Abstract: Cancer is a major public health problem, and is now the world’s leading cause of death. Traditional Chinese medicine (TCM)-combination therapy is a new treatment approach and a vital therapeutic strategy for cancer, as it exhibits promising antitumor potential. Nanotargeted drug-delivery systems have remarkable advantages and allow the development of TCM-combination therapies by systematically controlling drug release and delivering drugs to solid tumors. In this review, the anticancer activity of TCM compounds is introduced. The combined use of TCM for antitumor treatment is analyzed and summarized. These combination therapies, using a single nanocarrier system, namely codelivery, are analyzed, issues that require attention are determined, and future perspectives are identified. We carried out a systematic review of >280 studies published in PubMed since 1985 (no patents involved), in order to provide a few basic considerations in terms of the design principles and management of targeted nanotechnology-based TCM-combination therapies.

Keywords: cancer, codelivery, combination therapy, nanotargeted drug-delivery system, tumor targeting, TCM

Introduction

Cancer is the leading cause of disease-associated death in China,¹ and is now the world’s leading cause of death.² According to the Global Cancer Report 2018 on the trend of 36 cancers in 185 countries worldwide by the WHO, the global burden of cancer is increasing at an alarming rate (one in eight deaths on average are due to cancer). The report also pointed out that the incidence and mortality rate of cancer continues to rise each year, with developing countries accounting for approximately 60% of the world’s new cases and 70% of annual deaths. In 2018, nearly half the world’s new cases of cancer occurred in Asia, most of which occurred in China.³ Bray et al² provided a status report on the global burden of cancers using GLOBOCAN 2018. It is estimated that there will be 18 million new cases of cancer and 9.6 million cancer deaths in 2018. Lung cancer and breast cancer are the most frequent cancers in men and women, respectively, and the two leading causes of cancer death. Due to the high incidence and mortality rate of cancer, the global health care burden is also increasing rapidly.

Surgical treatment, chemotherapy, and radiotherapy are the primary treatment methods for cancer.⁴ If cancer patients are diagnosed early and receive timely surgical treatment, the probability of surviving for 5 years after surgery is greatly improved. However, when cancers are diagnosed late, the vast majority of patients are already in the terminal stages, and thus may have lost the opportunity of surgical treatment. In addition, due to adverse reactions caused by radiotherapy, such as fatigue, gastrointestinal reactions, skin damage, bone-marrow suppression, and cardiotoxicity,⁵ chemotherapy is still the main method of cancer treatment.

Nevertheless, due to lack of specificity and poor targeting, chemotherapy drugs not only kill tumor cells but also act on normal tissue, causing a reduction in immunity, significant side effects, and low drug efficacy. In addition, cancer patients can develop resistance to a single chemotherapy drug in clinical practice, resulting in a decrease in the subsequent curative effect. Multidrug resistance (MDR) was once considered the leading cause of chemotherapy failure, and may also promote tumor metastasis and recurrence.⁶ Based on recent statistics from the American Cancer Society, >90% of cancer patients die from different levels of MDR.

Therefore, the treatment of cancer should be changed from an initial single medication to combination therapy. The combination of two or more active antitumor ingredients plays a crucial role in complementarity and synergy, and has become the preferred scheme in cancer treatment. Notably, the combination of traditional Chinese medicines (TCMs) with chemotherapeutic drugs and the combination of various TCMs, which involves multiple targets and multiple signaling pathways, have improved efficacy compared with drugs with a single molecular target and become a new strategy for tumor therapy in recent years.⁷ Due to a great deal of investment and rapid development, nanotechnology is already used in various fields of biomedical science.⁸ Novel nanoformulation-based drug-delivery systems, such as liposomes, nanoparticles (NPs), vesicles, mesoporous silica NPs (MSNs), and micelles, provide promise in overcoming current limitations, including poor targeting, insufficient absorption, poor pharmacokinetics and bioavailability, and limited biodistribution.^9–11

In this review, the anticancer activity of TCM compounds is introduced. The combined use of TCMs for antitumor therapy is analyzed and summarized. These combination therapies using a single nanocarrier system, namely codelivery, are analyzed to determine their potential in prolonging drug duration in vivo, targeting drug delivery, and reducing toxicity (Figure 1). Matters requiring attention and future perspectives in this field are also reviewed, in order to accelerate the clinical application of combination antitumor therapy using targeted nanotechnology.

Figure 1 Advantages of targeted nanotechnology-based TCM-combination therapy.
Notes: (A) Antitumor effects of TCM; (B) antitumor effects of TCM-combination therapy; (C) antitumor effects of targeted nanotechnology-based TCM-combination therapy.
Abbreviations: TCM, traditional Chinese medicine; MDR, multidrug resistance.

Antitumor effects of TCMs

Herbs, animals, and minerals are used widely as health foods and medicines to remedy various diseases in Asia, and have been collected and recorded as effective and traditional therapies in the TCM literature. For example, artemisinin was isolated by Youyou Tu at the China Academy of Traditional Chinese Medicine in Beijing, and is now an effective medicine in the treatment of malaria. As a result, Tu won the Nobel Prize in Physiology or Medicine in 2015. In most developing countries, 80% of the population continue to use traditional medicines for primary health care.¹² From 2016 to 2017, the total amount of TCM herbal medicines and other related products exported to the Belt and Road Initiative countries reached US$295 million. In addition, the WHO also recognized traditional medicine in its influential global medical compendium.¹³

Worldwide, including in Western countries, TCM has been increasingly used in the past few decades, and is well known for its vital role in cancer prevention and treatment. A number of studies have confirmed that the active ingredients in TCM (curcumin [Cur], gambogic acid, and baicalein [BA], among others) are able to effectively induce apoptosis, interfere with tumor progression, inhibit tumor development, inhibit angiogenesis, cause cell-cycle arrest, and block metastasis. A summary of the antitumor effects of drugs isolated from TCMs is shown in Table 1. Structures of TCM compounds are shown in Figure 2.

Table 1 Antitumor effects of traditional Chinese medicine

Figure 2 Chemical structures of the active components in traditional Chinese medicine.

Antitumor effects of TCM-combination therapy

Initially, cancer therapy consisted of a single drug, which could involve a single target. However, malignant disease is caused by many complicated factors, and treatment with a single drug is not adequate. Patients are usually susceptible to drug resistance after sequential cycles of therapy with these chemotherapy drugs,¹⁰⁰ and a single medication frequently causes serious side effects. For instance, although cisplatin is clinically effective, it lacks selectivity for tumor tissue, resulting in serious side effects, such as kidney-function damage,¹⁰¹ neurotoxicity,¹⁰² ototoxicity,¹⁰³ and the emergence of MDR, resulting in the failure of chemotherapy.¹⁰⁴ In addition, long-term or high-dose cisplatin treatment can also cause severe anemia.¹⁰⁵ Therefore, the clinical application of single drugs, such as cisplatin, has been greatly restricted.

Cancer therapy urgently requires a new therapeutic approach to overcome these shortcomings. Combination-drug therapy is a new mode of treatment, and has gradually gained the attention of researchers.¹⁰⁶ Combination therapy involves the simultaneous or sequential use of two or more medicines for therapeutic purposes, and gradually plays a meaningful role in a complementary way, has synergistic action, and alleviates adverse reactions. It can not only produce a better therapeutic effect by regulating multiple signaling pathways in abnormal cells and act on multiple targets simultaneously but also reduce the occurrence of MDR and reduce both the dosage and side effects. The combination of two or more active antitumor ingredients is now a vital treatment method for tumors, and has received US Food and Drug Administration (FDA) approval.¹⁰⁷

Based on classic TCM theory, the combination of antitumor TCMs exhibits promising potential in cancer treatment such as: 1) enhancing the therapeutic efficacy of chemotherapeutic drugs – due to the combined effects of Cur and cisplatin determined in vitro and in vivo, experimental results demonstrate that Cur can enhance the antitumor effect of cisplatin in A549 cells in vitro, the combination markedly inhibiting tumor growth and promoting apoptosis in the A549-xenograft mouse model;¹⁰⁸ 2) achieving synergistic therapeutic effects – resveratrol and Cur synergistically cause apoptosis in breast cancer cells by p2 (Waf/Cip1)-mediated inhibition of the Hedgehog–Gli cascade;¹⁰⁹ 3) reversing drug resistance – the combination of cryptotanshinone and cisplatin leads to cell death and apoptosis, and cryptotanshinone reverses cisplatin resistance in human lung carcinoma A549 cells by downregulating the Nrf2 pathway;¹¹⁰ 4) reducing the dose of drugs – combination therapy with triptolide and cisplatin completely suppresses tumor growth, suggesting that lower concentrations of cisplatin and triptolide may produce a synergistic anticancer effect;¹¹¹ and 5) prolonging survival – As₂O₃ combined with ginsenoside Rg₃ can significantly inhibit the proliferation of NCIH1299 cells and prolong survival of tumor-bearing nude mice, with a significant effect on lung cancer treatment.¹¹² In addition, TCM-combination therapy results in good prognosis, has fewer adverse reactions, has long-lasting curative effects, regulates the expression of intracellular marker proteins, and reduces the side effects of drugs.^112–115 Further superior effects are shown in Table 2. The anti–lung cancer and anti–breast cancer mechanisms of TCM-combination therapy are shown in Figures 3 and 4. TCM-combination therapy achieves the effects that single chemotherapeutic drugs fail to achieve, and has become the main direction in clinical and experimental research on antitumor therapy.¹¹⁶

Table 2 Antitumor effects of TCM-combination therapy
Abbreviations: SCID, severe combined immunodeficiency; MDR, multidrug resistance; CDDP, cis-diamminedichloroplatinum; EMT, epithelial–mesenchymal transition.

Figure 3 Anti–lung cancer mechanism of TCM-combination therapy.
Abbreviations: Cur, curcumin; Rsv, resveratrol; Tmp, tetramethylpyrazine; Cts, cryptotanshinone; Qct, quercetin; Bbr, berberine; Dhb, dihydroberberine; GA, gambogic acid.

Figure 4 Anti–breast cancer mechanism of TCM-combination therapy.
Abbreviations: Cur, curcumin; Rsv, resveratrol; Bbr, berberine; Hcpt, hydroxycamptothecin; Qct, quercetin; GNA, gambogenic acid; BA, baicalein.

Nevertheless, there are three possible interactions in drug combinations: antagonistic, additive, and synergistic effects. Therefore, if we do not understand interactions among drugs, blindly combining drugs will not only fail to achieve the desired response but also lead to reduced efficacy and increased toxicity, and even produce drug-borne diseases. For instance, the combination of paclitaxel (Ptx) and BA shows antagonism in breast cancer MCF7 cells,¹¹⁷ and Liu et al¹¹⁸ suggested that the combination of gambogic acid and bortezomib should be avoided in patients. In addition, attention should be paid to the proportion and sequence of the two drugs in combination.

Applications of targeted nanotechnology in TCM-combination therapy

During the early 20th century, Paul Ehrlich proposed the concept of targeted drugs, which consisted of three components: the drug, targeting moiety, and drug carrier. The main aim was to deliver the drug to the specific target organ under the specific guiding mechanism.¹⁶⁸ Targeted preparations are characterized by increasing the intensity of pharmacological action in target tissue, controlling drug release, and decreasing systemic adverse reactions. Targeted drug-delivery systems have become one of the important high-profile topics in modern pharmacy. Nanotargeted drug-delivery systems have remarkable advantages in improving the bioavailability of drugs, enhancing the targeting ability of drugs, improving the distribution and pharmacokinetic properties of antitumor drugs in vivo and in vitro, increasing the stability of drugs, solubilizing poorly soluble drugs, protecting drugs from degradation in vivo, intelligently regulating the release of components, enhancing efficacy, and reducing toxicity.^169–172 Moreover, metastasis of neoplastic cells is the major cause of death in cancer patients,^173,174 and nanosize drug-delivery systems also provide an encouraging strategy for lymphatic metastases.¹⁷⁵ In 2004, the National Cancer Institute (NCI) launched the NCI Cancer Nanotechnology Alliance, which aims to use nanotechnology to combat cancer.¹⁷⁶

In recent years, many types of nanopreparations of TCMs, which involve the combination of nanotargeted drug-delivery systems and the advantages of TCM components in the treatment of tumors, have been reported.^177–179 Simultaneously, nanotargeted drug-delivery systems are also promising multidrug carriers and allow the development of drug combinations by systematically controlling drug release and delivering drug to solid tumors.¹⁸⁰ Codelivery of multiple antitumor agents in a single well-designed nanocarrier has significant advantages over monotherapy.^181,182 Generally, drug targeting can be classified into three categories: passive targeted preparations, active targeted preparations, and other physicochemical targeted drug-delivery systems.

Passive targeted drug-delivery systems

In a passive targeted drug-delivery system, lipids, adipoids, proteins, and biodegradable high-molecular-weight polymers are mainly used as carriers, and the drug is encapsulated or embedded into various colloidal systems, forming stable structures, such as polymeric NPs (PNPs), micelles, nanovesicles, and liposomes, to increase drug concentration in tumor cells, decrease drug distribution in blood and other organs, and prevent toxicity and adverse reactions. This spontaneous accumulation, or “passive” targeting, is particularly effective against tumors, due to leaky angiogenic vessels and poor lymphatic drainage of the tumor, which is currently referred to as the enhanced permeability and retention (EPR) effect. That is to say, the high permeability of tumor blood vessels allows nanosystems to enter the interstitial spaces of the tumor, while impaired lymphatic filtration allows these nanosystems to remain there. This phenomenon does not exist in normal tissue. Currently, EPR-mediated drug delivery is considered effective in delivering drugs into tumors, especially nanocarriers (Figure 5). The size of the particles is also closely related to their distribution.¹⁸³ The different sizes of these nanosystems decide the in vivo distribution behavior. Nanopreparations of <100 nm can be slowly accumulated in bone marrow; nanocarriers of 100–200 nm are apt to become enriched in the solid-tumor site; nanosystems of 0.2–3 μm are taken by macrophagocytes in the liver and spleen and particles of >7 μm are often intercepted by pulmonary capillary beds and enter the pulmonary tissues or alveoli.¹⁸⁴

Figure 5 Passive (A) and active (B) targeting of tumors.
Abbreviation: EPR, enhanced permeability and retention.

Liposomes

Liposomes are microvesicles with one or more aqueous cavities formed by the encapsulation of one or two amphiphilic molecular double-layer membranes, and the drug is encapsulated or embedded into the liposomes to form the liposome drug. Due to the similarity between the structure and the biological membrane, the encapsulation of water-soluble and fat-soluble drugs can reduce the drug dose, lower drug toxicity, delay release, lower in vivo elimination speed, change in vivo distribution of the drug, and achieve targeted release. Due to these advantages, liposome drugs have attracted considerable attention, and many studies have been carried out on them.¹⁸⁵

Plumbagin is a quinonoid isolated from the roots of Plumbago zeylanica (bai hua dan in Chinese).¹⁸⁶ It has high antiproliferative activity against a variety of tumor cell lines,^187,188 and its anticancer properties have also been demonstrated in vivo.¹⁸⁶ Celecoxib and plumbagin are two antitumor drugs that synergistically kill melanoma cells instead of normal cells. The combined use of these two agents in traditional approaches was not possible, due to their poor bioavailability and toxicity concerns. In order to circumvent these challenges, Raghavendra et al¹⁸² developed a nanoliposome containing celecoxib and plumbagin, named CelePlum 777, which has good stability and can release these two drugs at optimal proportion to achieve the maximum synergistic killing effect. Compared to nanoliposomes containing individual drugs, CelePlum 777 can enhance the inhibition of melanoma-cell proliferation in vitro and reduce the growth of melanoma tumors, with negligible systemic toxicity in nude mice. The goal of loading different individual drugs into a nanoliposome that releases the drugs at synergizing ratios was realized.

Previous studies have shown that Cur can reduce side effects caused by cisplatin (cis-diamminedichloroplatinum [CDDP]), including ototoxicity,¹⁸⁹ nephrotoxicity,¹⁹⁰ and neurotoxicity.¹⁹¹ In addition, Cur can also overcome resistance to CDDP and improve the sensitivity of hepatocellular carcinoma cells to CDDP.¹⁹² However, due to poor water-solubility and the different pharmacokinetics of CDDP and Cur,¹⁹³ the cocktail of both drugs controlling the drug proportions and dose regimen at target cancer cells would be challenging. Based on a previous approach and advantages of the liposome, Cheng et al¹⁹⁴ developed a liposomal delivery system using a reverse-microemulsion and film-dispersion method, which coencapsulated CDDP and Cur and transplanted them into hepatocellular carcinoma cells. The antitumor activity of CDDP-Cur liposomes against HepG2 cells was higher than that of free drug or encapsulated-monodrug therapy, and retention was prolonged (t_½=2.38 hours). Therefore, coloaded liposomes can be used as an effective treatment for tumors, with great clinical application potential.

Polymeric nanoparticles

NPs are solid colloid particles 10–100 nm in size formed by drug dissolution, encapsulation, or adsorption on macromolecular materials. NPs within the particle-size range of 10–100 nm can hide the physicochemical characteristics of the drug, and the in vivo process of the drugs depends on the physicochemical characteristics of the carriers.¹⁹⁵ NPs are characterized by a relatively simple preparation process, a significant solubilization effect on active components, significantly improved drug targeting to tumors, and proneness to surface modification. They can improve drug stability, reduce digestive tract stimulation, achieve sustained release or controlled release,¹⁹⁶ effectively overcome multiple physiological barriers encountered in vivo, and achieve accurate, safe, efficient, and targeted therapeutic effects. Coating the surface of NPs with polyethylene glycol (PEG), or “PEGylation”, is a commonly used approach to improve the efficiency of drug delivery to target cells and tissue. PEGylation is capable of achieving prolonged blood circulation of nanocarriers, and can improve colloidal stability by providing steric surface hindrance. In addition, it has the ability to improve particle dispersion and decrease hemolysis.^197,198 Polylactic-co-glycolic acid (PLGA), a biodegradable polymer, is atoxic to final degradation products and has been approved by the FDA.^181,199 The antitumor effects of codelivered PNPs in TCM combinations are shown in Table 3.

Table 3 Polymeric nanoparticles (NPs) for codelivery of antitumor agents
Abbreviation: PEG, polyethylene glycol.

Lipid–polymer hybrid nanoparticles

As indicated, it has been demonstrated by the increasing numbers of research reports that biodegradable PNPs and liposomes have become the two main types of active TCM nanocarriers. Lipid–polymer hybrid NPs (LPNs) are nuclear-shell NPs formed by polymer core–lipid/lipid–PEG shells^206,207 that have the advantages of biodegradable PNPs and bionic liposomes.

Li et al²⁰⁸ prepared LPNs and PNPs loaded with cisplatin and Cur. Results indicated that LPNs had higher anticancer efficacy than PNPs and free drugs. Cytotoxicity was highest in vitro and antitumor effect best in vivo. Therefore, LPNs can be used as a targeted and synergistic nanodrug codelivery system for tumor chemotherapy. In a similar study, Zhu et al²⁰⁹ developed vincristine–quercetin (Qct) dual-loaded LPNs. The experimental results proved that the LPNs loaded with both drugs exhibited better antitumor efficacy in vitro and in vivo.

Ruttala et al²¹⁰ developed nanocarriers loaded with Ptx and Cur using a method different from the previously mentioned studies. Ptx-loaded albumin NPs were prepared and encapsulated in PEGylated hybrid liposomes containing Cur by a thin-film hydration method. This combination guaranteed the release of Ptx and Cur in a sustained and sequential manner. Compared with a cocktail combination, the dual-drug-loaded nanocarrier had a better cytotoxic effect at a lower dose. Therefore, such coloading drug-delivery systems can be used as a promising treatment method to improve clinical efficacy in various malignant tumors. NPs containing genistein and Ptx have also showed similar experimental results.²¹¹

Nanostructured lipid carriers

Nanostructured lipid carriers (NLCs) are novel lipid NPs and mixtures of solid and liquid lipids, which have the advantages of excellent drug-loading capacity and sustained-release properties. Jiang et al²¹² prepared etoposide (Etp)- and Cur-loaded NLCs by the solvent-injection technique. Etp-Cur NLCs had the highest cytotoxicity in vitro and higher accumulation in tumor tissues in vivo compared with other preparations, including Etp NLCs, Etp + Cur solution, Etp solution, and NLCs. In addition, Etp-Cur NLCs displayed low cytotoxicity in normal tissue in vivo, suggesting that NLCs could serve as a promising therapeutic strategy in the treatment of tumors.

Mesoporous silica nanoparticles

MSNs have attracted much attention due to their potential biomedical applications. MSNs possess many attractive features for application in the delivery of TCMs, such as the size of tuning particles/pores, large surface, large pore volume, high loading capacity, mass producibility, biocompatibility, and chemical inertia.^213,214 TCMs can be dissolved in surfactant micelles, simultaneously hydrolyzed, and concentrated with silica to form NPs.

Jia et al²¹⁵ prepared NPs using the self-assembly in situ drug-loading approach, in order to deliver the anticancer drug Ptx and the MDR-reversal agent tetrandrine (Tet) to increase the intracellular concentration of Ptx, enhance its antitumor effect, and minimize the exposure of normal cells to Ptx and Tet. The study demonstrated that Tet significantly increased the accumulation of NPs in cells. Furthermore, Ptx-Tet–cetyltrimethylammonium bromide MSNs suppressed tumor-cell growth more efficiently than the delivery of Ptx (Ptx–cetyltrimethylammonium bromide MSNs) or free Ptx alone. The prepared NPs released the drugs easily in the acidic environment of tumors, and thus, side effects and toxicity in normal tissue and organs were reduced. This nanocarrier may have important potential in clinical applications to avoid MDR by codelivering multiple TCMs. Solid self-nanoemulsifying drug-delivery systems containing tamoxifen and Qct have also shown similar experimental results.²¹⁶

PEGylated lipid bilayer–supported mesoporous silica nanoparticles

The anticancer drug axitinib (Axt) is a small-molecule tyrosine kinase–receptor inhibitor of VEGFR1, -2, and -3.^217,218 Another anticancer drug, celastrol (Cst), can induce the suppression of angiogenesis²¹⁹ and enhance the antitumor activity of standard chemotherapeutic drugs.²²⁰ Choi et al²²¹ loaded Cst into an MSN carrier and subsequently coated it with a lipid bilayer containing Axt, denoted by “ACML”, to increase the synergistic efficacy of the two agents. The difference in drug loading resulted in a sequential-release pattern where Axt was released first to exert its anticancer effect, and then Cst was released to further induce a synergistic effect. The experimental results showed that the synergistic apoptotic effect of ACML against cancer cells was stronger than the Axt-Cst cocktail. Moreover, ACML had a greater tumor-inhibitory effect than either drug administered alone in a tumor-xenograft mouse model. It has been proved that PEGylated lipid bilayer–supported MSNs have the potential to be used as an effective therapeutic strategy for malignant tumors.

Micellar systems

Self-assembled polymeric micelles have been studied widely, due to their excellent role in cancer treatment. Polymeric micelles have a core–shell structure, where hydrophobic drugs are soluble and remain stable in the hydrophobic core of the micelles, and the hydrophilic shell can prolong internal circulation and improve spatial stability by reducing opsonization during blood circulation. Furthermore, polymeric micelles can selectively and effectively accumulate in tumor tissues due to the EPR effect, thus enhancing the therapeutic effects of the loaded chemotherapeutic drugs. As such, codelivery micellar systems have attracted considerable attention.^222,223

Doxorubicin (Dox) has extensive antitumor activity against various solid tumors, including lung cancers, melanoma, neurological cancers, sarcoma, leukemia, lymphoma, gastrointestinal cancers, genitourinary cancers, breast cancers, and ovarian cancers.¹⁴ Due to the rapid elimination of drugs in vivo, the cocktail combination of free Dox and Cur often fails to provide enough antitumor efficacy or low systemic toxicity. Furthermore, the combination of Dox and Cur has not been realized clinically. In recent years, a few studies have proposed that codelivering Dox and Cur may result in less toxicity, good drug-release profiles, and improved drug distribution in tumor tissue.^224–226 Zhang et al²²³ prepared dual-loaded micelles with coencapsulated Dox and Cur. The experimental results showed that Dox delivered by this method prolonged systemic circulation and increased its accumulation in the tumor, resulting in a lower level of the toxic metabolite doxorubicinol in heart tissue than free Dox alone or the cocktail combination. In addition, Gu et al²²⁵ assembled micelles loaded with Dox and Cur. The micelles prolonged the circulation of Dox or Cur when compared with the individual administration of either, and exhibited strong inhibition of tumor growth and reduced Dox side effects.

Ptx has a broad spectrum of activity against various tumors. It has been used clinically for more than two decades. However, it is poorly soluble and has considerable limitations in clinical applications. In addition, Ptx extravasation of cancer cells caused by Pgp activity is also a main factor limiting its clinical efficacy.^227,228 Abouzeid et al²²⁹ prepared micelles loaded with Ptx and Cur using the thin-film hydration method. Cur–Ptx-loaded micelles released the entrapped drugs with a slow pattern, and resulted in a threefold inhibition of tumors in vitro. The combination of Cur and Ptx was shown to reverse MDR in a resistant human ovarian adenocarcinoma model. Therefore, these combinations of micelles have significant advantages in vitro and in vivo over individual drug treatment, especially in drug-resistant tumors.

Microemulsions

A microemulsion is a transparent or semitransparent oil–water system with low viscosity, isotropism, and thermodynamic stability, and is spontaneously formed by an oil phase, water phase, emulsifier, and coemulsifier. As an ideal drug carrier, it has the advantages of solubilizing components with different solubility properties, good dispersibility, excellent absorbability, and increased bioavailability.²³⁰

BA is one of the most commonly used traditional chemotherapeutic drugs for the treatment of various cancers, including HCT116 human colon cancer,³¹ pancreatic cancer stem cells,³² and bladder cancer.³³ It is known that BA has the ability to inhibit the function of Pgp.²³¹ Meng et al²³⁰ developed nanoemulsions (NEs) coencapsulating Ptx and BA using rotary evaporation. The research showed that compared with other Ptx preparations, Ptx-BA NEs had a better antitumor effect on MCF7/Tax cells. Studies on cellular uptake have shown that Ptx-BA NEs accumulate effectively in cancer cells. More importantly, Ptx-BA NEs have a higher antitumor effect than other Ptx formulations used in antitumor in vivo studies. The combined delivery of Ptx and BA by NEs may provide a potential combination-treatment strategy to overcome MDR.

Nanovesicles

Nanovesicles are microvesicles with a quasiliposome dual-layer structure formed by the self-assembly of synthesized or naturally modified amphiphilic polymers and cholesterol in hydrophilic media. In contrast to other micromolecular vesicles, the polymer vesicle is characterized by good molecular designability, high intensity of the vesicle, excellent stability, and strong permeability.^232,233 As a TCM carrier, it can improve histocompatibility and cell permeability and encapsulate hydrophilic drugs or lipophilic drugs.

Alemi et al²³⁴ loaded both Cur and Ptx into cationic PEGylated niosomal formulations using thin-film hydration method to enhance efficacy in MCF7 human breast adenocarcinoma cells. The combination of Ptx and Cur, particularly in the nanoniosome formulations, improved the effectiveness of cancer therapy. The novel cationic PEGylated niosome delivery of combined Ptx and Cur is an effective strategy in the treatment of breast cancer.

Schematic illustrations of these nanosystems for drugs are shown in Figure 6. In addition, graphene oxide,²³⁵ carbon nanotubes,^236,237 nanorods,²³⁸ nanosponges,²³⁹ solid lipid NPs,²⁴⁰ nanometal–organic frameworks,²⁴¹ metallosupramolecular nanogels,²⁴² and microspheres²⁴³ all provide new opportunities for the antitumor effects of TCM-combination therapy.

Figure 6 Schematic illustrations of several nanosystems for drugs.

Despite the EPR effect, most nanosystems fail to find their way toward tumor sites.²⁴⁴ Under most circumstances, 90% or more of the administered nanosystems end up in the liver or spleen, increasing adverse systemic reactions and causing low therapeutic efficacy.^245,246

Active targeted drug-delivery systems

An active targeting preparation is a drug-delivery system which can utilize the modified drug carrier as a “missile” and deliver the drug selectively to the target area to allow the drug to accumulate and exert its efficacy. The mechanism of active targeting is that after surface modification with the specific targeted antibody or ligand via covalent or noncovalent binding, the nanodelivery system can avoid recognition and phagocytosis by macrophages and change natural in vivo distribution, so as to deliver the drug to the targeted tumor site and exert its active tumor-targeting effects.²⁴⁷ For instance, due to the difference between tumor cells and normal cells in terms of receptor expression or other biological characteristics, the tumor-targeted drug-delivery system has been developed to ensure that the drug acts only on tumor cells²⁴⁸ and induces the off-target effect in normal tissue, which has become a high-profile topic in studies on drug-delivery systems.

Transferrin (Tf)-modified nanocarriers

The Tf receptor is commonly present in normal cells and tumor cells. However, expression of the Tf receptor is approximately four to five times that on the surface of tumor cells than on normal cells.²⁴⁹ Transferrin can bind with the Tf receptor and be internalized into the cells under mediation by the receptors to reach the targeted site.

Cui et al²⁵⁰ designed Tf-decorated NPs (Tf-PEG Cur–Dox NPs) to codeliver Cur and Dox for breast cancer therapy. Results showed that the combination of Tf-PEG-Cur and Dox NPs exerted higher cytotoxicity in MCF7 cells compared with Tf-PEG-Cur NPs alone. Higher accumulation of Tf-PEG Cur–Dox NPs was observed in tumors compared to the Cur-Dox injection. Therefore, Tf-PEG Cur–Dox NPs displayed higher efficiency in vitro and in vivo, and resulted in efficient tumor-targeted drug delivery, reduced cytotoxicity, and a stronger antitumor effect.

Folic acid–modified nanocarriers

Similarly to distribution of the Tf receptor on surfaces of tumor-cell membrane, folic acid receptors on tumor cells are overexpressed compared with normal cells, and their activity is also significantly higher than that on normal cells. In addition, folic acid is characterized by low immunogenicity, high modifiability, and high storability. Utilization of the difference in folic acid–receptor expression between tumor sites and normal tissue can achieve targeted delivery of a folic acid–modified drug to cancer cells.^251,252

Prodrugs of Ptx and baicalein containing dual-targeted ligands of folate and hyaluronic acid have been synthesized. NPs loaded with these prodrugs (Ptx–baicalein) have also been prepared and the synergistic antitumor effect evaluated in vitro and in vivo. The results showed that the Ptx–baicalein NP drug-delivery system delivered Ptx–baicalein prodrugs to drug-resistant human lung cancer cells, and the delivery was proven to be effective. In addition, Ptx–baicalein NPs exerted an enhanced synergistic anticancer effect, which also overcame MDR to Ptx.²⁵³

Low-density lipoprotein–modified nanocarriers

The low-density lipoprotein (LDL) receptor is widely present on the surface of various cells and tissue types, but is overexpressed in tumor cells. LDL is an endogenous NP with good biocompatibility, good biodegradability, and low immunogenicity, and can avoid being recognized and cleared by the in vivo endogenous reticuloendothelial system.^254,255 Therefore, LDL is an ideal potential ligand for tumor targeting.

A novel nanocarrier containing Ptx-loaded micelles and siRNA-loaded LDL has been developed. Results showed that the delivery system delivered siRNA and Ptx directly to cancer cells, enhancing the intracellular release of drugs and genes, increasing intracellular drug concentration, decreasing drug efflux, prolonging circulation, and reversing MDR.^256,257

Cell-penetrating/tumor-targeting peptide–modified nanocarriers

Nanocarriers using cell-penetrating and/or tumor-targeting peptides for functionalization are a promising strategy, and have attracted the attention of researchers. In our previous report, we reviewed the classification of polypeptide- and polypeptide-modified nanocarriers in detail.²⁵⁸ In this report, recent research progress is summarized in the following paragraphs.

Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, has been widely studied as a potential anticancer drug. Narayanan et al²⁵⁹ prepared targeted drug-loaded core–shell NPs using anti-EGFR and anti-HER2 antibodies, and entrapped a combination of Ptx and EGCG at different doses in the core and shell, respectively, using emulsion precipitation. Cellular uptake in MDA-MB231 cells was higher for targeted NPs than untargeted NPs at 24 hours. The sequential release of EGCG followed by Ptx from this core–shell nanocarrier sensitized Ptx-resistant MDA-MB231 cells to Ptx, induced their apoptosis, and inhibited NFκB activation. In addition, EGFR-peptide (GE11)-targeted, pH-sensitive docetaxel Dtx–Cur NPs²⁶⁰ and arginylglycylaspartic acid–modified lipid-coated PLGA NPs targeting delivery of both sorafenib and Qct²⁶¹ achieved significant inhibition of tumor growth in vitro and in vivo.

In addition, galactosamine can recognize and bind to the asialoglycoprotein receptor on the surface of hepatocellular carcinoma cells, and a galactosamine-mediated drug-delivery carrier was significant for targeted liver cancer therapy.^262,263 Glycyrrhizin, glycyrrhetinic acid, and mannose can serve as the guiding group in liver-targeted drug-delivery systems, with good potential.^264–270 As natural endogenous ligands, bile acids have good biocompatibility and are ideal routes for targeting hepatocellular cancer.²⁷¹ In addition, sialic acid,²⁷² human Nanog,²⁷³ and hyaluronic acid²⁷⁴ are excellent targets in cancer therapy. Vapreotide is a somatostatin analogue and can be also used as a ligand for targeted drug delivery based on its high affinity to somatostatin receptors, which are overexpressed in many tumor cells.²⁷⁵ Several studies have shown that double-modified nanocarriers have also attracted considerable attention in anticancer drug research.^276,277 Dual or multiple targeting also provides a new approach for antitumor therapy.

Physicochemical targeted drug-delivery systems

Physicochemical targeting refers to the binding of magnetic, pH-sensitive, temperature-sensitive, or electromagnetic wave–responsive materials onto the surface of drug-delivery systems (such as NPs and liposomes) to make them respond to various stimuli in vitro and in vivo (such as pH, temperature, applied magnetic fields, ultrasonic waves, infrared rays, and electromagnetic radiation) to ensure that the drug acts directly on the target area, increases drug concentration at the lesion site, and reduces adverse reactions. Most studies have used magnetic NPs, temperature-sensitive NPs, and pH-sensitive NPs.

NPs that are pH-sensitive have been designed to promote uptake in tumor cells²⁷⁸ and accelerate drug release at tumor sites, as the extracellular pH (6.5–7.2) of the tumor is different to that of normal tissue.²¹⁶ Zhang et al²⁷⁸ developed a codelivery system for Dox and Cur using pH-sensitive NPs. Enhanced release in the acidic environment of cancer cells and enhanced cellular internalization of the cargoes delivered from Dox–Cur NPs were observed in SMMC7721 cells and human umbilical vein endothelial cells compared to the free drugs. Therefore, pH-sensitive NPs can provide a promising strategy for the effective inhibition of cancer in a synergistic manner. Danafar et al²⁷⁹ achieved codelivery of Cur and sulforaphane (SF) with PEGylated gold-coated Fe₃O₄ magnetic NPs as an effective and promising antitumor agent. Results showed that SF–Cur coloaded Fe₃O₄@Au NPs caused a decrease in cell viability and induced apoptosis by increasing the Bax:Bcl2 ratio. Moreover, photosensitizer NPs,²⁸⁰ thermosensitive NPs,²⁸¹ and redox-sensitive NPs²⁸² also provide new opportunities for nanosystems with antitumor TCM combinations.

Conclusion

The significant challenge posed by cancers, as well as adverse reactions and drug resistance induced by long-term treatment of a single drug, compels us to change our focus from a single target to the regulation of networks in vivo. Many complex factors cause cancer; therefore, it is rational that treatment should involve multiple components, genes, systems, and target pathways. The combination of drugs has resulted in a new approach to cancer treatment. Rational combinations of drugs not only result in synergy but also reduce the occurrence of drug resistance and adverse reactions, which has resulted in combination therapy, thus becoming a significant antitumor treatment in the clinic and in research. As such, this significant research direction may allow medical researchers to identify a chemotherapeutic combination regimen with high efficacy and low toxicity.

The combination of TCMs for clinical therapy has increased. TCM combinations can exert improved synergistic antitumor effects by adjusting the multiple signaling pathways of tumor cells. Compared with single-drug therapy, combinations of TCMs can reduce the toxicity and side effects of chemotherapy drugs and increase the antitumor effect of drugs. Simultaneously, TCM combinations and chemical drugs can improve immunofunction, relieve clinical symptoms, improve patient survival and quality of life, and improve the efficacy of chemotherapy drugs.

It should be noted that there are usually three approaches in targeted nanotechnology-based TCM-combination-therapy: nanodrugs combined with conventional preparations, coloading of two or more anticancer drugs in a single nanocarrier system (recorded as codelivery), and combined administration of different nanosystems. The loading of two drugs into a single well-designed nanocarrier synchronizes the pharmacokinetic and biological distribution of different drugs to achieve a synergistic effect, which has distinct advantages. This method has been summarized in detail. An increasing number of studies have shown that dual nanosystems have distinct advantages in antitumor treatment and can provide drugs for different targets or sites of action, as they are administered flexibly using different dose/time schedules. Consequently, the remaining two methods urgently require further investigation. In addition, with further comparative analyses of these three research methods, the most suitable form of drug use for cancers can be identified to provide basic considerations in terms of design principles and management progress.

Acknowledgment

This study was financially supported by the National Natural Science Foundation of China (81673605).

Disclosure

The authors report no conflicts of interest in this work.

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