The Application of Nanotechnology in the Codelivery of Active Constituents of Plants and Chemotherapeutics for Overcoming Physiological Barriers during Antitumor Treatment

Li, Qiushuang; Xiong, Yang; Ji, Conghua; Yan, Zhiqiang

doi:https://doi.org/10.1155/2019/9083068

BioMed Research International

On this page

Abstract Introduction Conflicts of Interest Acknowledgments References Copyright Related Articles

Special Issue

Plant-Derived Drugs as an Alternative Therapeutic Option for Cancer Treatment

View this Special Issue

Review Article | Open Access

Volume 2019 | Article ID 9083068 | https://doi.org/10.1155/2019/9083068

The Application of Nanotechnology in the Codelivery of Active Constituents of Plants and Chemotherapeutics for Overcoming Physiological Barriers during Antitumor Treatment

Qiushuang Li,¹Yang Xiong,²Conghua Ji,¹and Zhiqiang Yan³

Guest Editor: Md. Atiar Rahman

Received11 Oct 2019

Accepted27 Nov 2019

Published13 Dec 2019

Abstract

Antitumor therapy using a combination of drugs has shown increased clinical efficacy. Active constituents derived from plants can offer several advantages, such as high efficiacy, low toxicity, extensive effects, and multiple targets. At present, the combination of plants’ active constituents and chemotherapeutic drugs has attracted increased attention. Nanodrug delivery systems (NDDSs) have been widely used in tumor-targeted therapy because of their efficacy of delivering antitumor drugs. The in vivo process of tumor-targeted NDDSs has several steps. They include blood circulation, tumor accumulation and penetration, target cell internalization and uptake, and drug release and drug response. In each step, NDDSs encounter multiple barriers that prevent their effective delivery to target sites. Studies have been performed to find alternative strategies to overcome these barriers. We reviewed the recent progress of codelivery of active constituents of plants and chemotherapeutics using NDDSs. Progress into transversing the physiological barriers for more effective in vivo antitumor delivery will be discussed in this review.

1. Introduction

Cancer is one of the most deadly diseases that endangers human health. Chemotherapy is currently the major treatment strategy for treating cancers and preventing postsurgical recurrence. However, multidrug resistance (MDR) in tumor cells and serious adverse effects have hindered chemotherapy [1]. To address these issues, studies have been performed to investigate the effects of drug combinations for cancer treatment. The combination of active constituents of plants with first-line chemotherapy drugs has shown good efficacy in reversing tumor chemoresistance, enhancing curative effects, and reducing adverse reactions. Combination treatment of active constituents of plants with chemotherapy drugs for tumor therapy has recently become very popular [2–4]. However, direct administration of free drugs has several disadvantages, such as short duration in blood circulation and nonselectivity for tumor tissue and tumor cells. This reduces efficacy while increasing adverse reactions due to nonspecific targeting of healthy tissue. To solve this problem, several strategies have been developed. Nanodrug delivery systems (NDDSs) have demonstrated potential advantages for cancer therapy. The most common carriers of NDDSs include liposomes, nanoparticles, micelles, and polymers. They can effectively increase the duration of drugs in systemic circulation, improve pharmacokinetics, and promote drug tumor targeting and tumor accumulation. All these substantially increase the curative effects while reducing toxicity [5, 6]. Intravenous administration of NDDSs results in a series of complex in vivo delivery processes, which includes blood circulation, tumor targeting, tumor accumulation, tumor tissue penetration, tumor cell internalization, and intracellular transport. Several specific drug delivery barriers exist, with each directly affecting efficacy. In order to improve drug efficacy and reduce adverse reactions of NDDSs, researchers have developed several exceptional delivery strategies to overcome these barriers. In this review, the physiological basis of designing tumor-targeted drug delivery systems to overcome these physiological barriers will be discussed.

2. Tumor Pathophysiology

The pathophysiological features of the tumor are the basis for designing tumor-targeting drug delivery systems [7]. One of the important physiological features of tumor tissues is their enhanced permeability and retention effect (EPR effect) to nanoparticles. Tumors that reach greater than 2 mm³ are highly dependent on nutrients and oxygen that are supplied by tumor blood vessels. Tumor and lymph angiogenesis start to develop when tumor blood vessels are unable to meet the requirements of the rapidly growing tumor [8]. Blood vessels that have recently formed through neovascularization have enhanced permeability, lack a smooth muscle layer, and has dysfunctional angiotensin receptors. In addition, lymph vessels in the center of tumor tissues are usually dysfunctional, which results in lymphatic obstruction and retention of macromolecular substances like lipid particles. The high selective permeability and retention in tumor tissues are termed the EPR effect [9]. The EPR effect is the basis for designing passive tumor targeting NDDSs [10].

Additionally, unlike normal cells, tumor cells grow in an uncontrolled and invasive manner. In order to infinitely proliferate, tumor cells have increased expression of certain receptors. These include the folate receptor (FR) [11], integrin receptor, transferrin receptor (TfR), somatostatin receptor, vasoactive intestinal peptide receptor, and cholecystokinin receptor. In addition, several specific receptors are expressed on the surface of tumor blood vessels, such as vascular endothelial growth factor (VEGF) receptor [12], integrin αvβ3 [13], and E-Selectin [14]. Many of these receptors that are overexpressed are common in tumor tissue and tumor blood vessels. The active targeting mechanism of NDDS relies on these specific receptors to bind specifically to tumors. However, long-term administration of antitumor drugs induces P-glycoprotein (P-gp) overexpression in tumor cells. P-gp functions to expel antitumor drugs from tumor cells, thus reducing the intracellular drug concentration, which in-turn reduces antitumor efficacy and makes tumor cells resistant to chemotherapy. This process is termed MDR [15]. MDR has been identified in almost all human tumor cells.

Cancer stem cells (CSCs) in tumor tissues [16] have the ability to self-renew, multiply, and differentiate. They can also stimulate the growth of new tumors [17]. Even though they exist in limited numbers, CSCs play a significant role in the development, progression, metastasis, and recurrence of tumors. Conventional chemotherapy or radiotherapy induces tumor cell death to reduce tumor cell numbers and prevent the rapid growth of tumors [18]. However, CSCs are not sensitive to conventional chemotherapy or radiotherapy and are not completely eliminated [19, 20]. CSCs are one of the main reasons for tumor recurrence.

Tumor cells have a very high metabolic rate and produce high levels of acid leading to an acidic environment in tumor tissues. The extracellular pH in tumor tissues is approximately 6.0–6.5. In addition, the reduced blood supply to the central area of the tumor leads to local hypoxia to increase the acidic environment [21]. Tumor tissues also have several physiological features that include high interstitial fluid pressure, specific enzymes, and oxidative stress [22].

3. Types of Tumor-Targeted NDDSs for Plant Chemotherapeutic Drugs

Currently, the most commonly used NDDSs include liposomes, nanoparticles, polymeric micelle, and products of polymer-drug conjugates. The major structural features and drug-carrying mechanisms of these NDDSs are listed in Table 1.

3.1. Liposome

Liposomes are lipid nanovesicles formed by lipid bilayers [23–25]. The diameter of a liposome is approximately 90–200 nm. The center of the liposome consists of a hydrophilic internal aqueous phase. The internal aqueous phase and lipid bilayer of the liposome could be used to carry a variety of cargos. For instance, hydrophilic drugs could be packed into the internal aqueous phase, while hydrophobic drugs could be packed into the lipid membrane. Additionally, amphiprotic drugs could be packed in the aqueous phase and phospholipid membrane. Furthermore, antibodies and polypeptides could be used to modify the surface of liposomes to make them to target various organs or tumors [23]. Liposomes continuously release their loaded drugs slowly and hence have the ability to change the distribution and pharmacokinetic properties of the drugs, thereby reducing their toxic effects [24]. Long circulating liposomes will add significant benefit for long-term drug delivery but needs to be further optimized.

In general, the surface of liposomes is modified by hydrophilic macromolecules, such as polyethylene glycol (PEG), to reduce their recognition by opsonin in the blood and to reduce phagocytosis by the reticuloendothelial system (RES) which then increases the drug duration in blood circulation [25, 26]. There is a difference in water solubility between antitumor active constituents of plants and chemotherapeutic agents. This makes liposomes the preferred carrier for in vivo delivery of such drugs. To date, numerous studies have used liposomes as nanocarriers for combined antitumor drug therapy using active constituents of plants and chemotherapeutic agents. Hu et al. [27] developed a liposome using distearoylsn-glycero-3-phosphoethanolamine-N-(methoxy(polyethylene glycol)-2000) (DSPE-PEG 2000), which cocarried temozolomide (TMZ) and quercetin (QUE) for the treatment of drug-resistant U87 glioma cells. Transmission electron microscopy demonstrated that nanoliposomes loaded with TMZ and QUE had reduced diameters. In vitro studies demonstrated that this liposome could favor cellular uptake of drugs and thus effectively reduce the drug dose without reducing efficacy.

3.2. Nanoparticles

Nanoparticles are colloidal particles made from natural or synthetic high molecular polymers as carriers. The drugs are attached to the carrier material by physical entrapment, absorption, or chemical covalent binding. The natural high molecular polymers mainly include heparin [28], chitosan [29], gelatin [30], and albumin [31], while synthetic high molecular polymers are mainly polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), and polycaprolactone (PCL). Nanoparticles can be easily modified to increase their targeting capability. Compared with liposomes, nanoparticles have several advantages, such as better physical stability and higher drug-loading capability. In addition, they are easy to prepare, have certain degrees of sustained release function, and are suitable for packing insoluble drugs. Currently, nanoparticles have been used as carriers for targeting and controlled drug release and are administered by intravenous injection or topical administration. Xu et al. [32] developed a PLGA nanoparticle for the codelivery of docetaxel and gambogic acid. They identified the best ratio of docetaxel with gambogic acid, which was then packed into PLGA nanoparticles. Cell apoptosis and immunoblotting demonstrated that this codelivery nanoparticle could downregulate the expression of P-gp to increase cell apoptosis and thus effectively inhibit MDR of tumor cells.

3.3. Polymeric Micelles

Polymeric micelles are flexible spherical particles that are synthesized from the self-assembly of two amphiphilic block copolymers at the appropriate temperature and concentration. Polymers could be AB-type diblock copolymers or ABA-type triblock copolymers. Micelles formed using the triblock copolymer are more stable. Polymeric micelles have a hydrophobic core that is used to pack drugs that have poor water solubility or hydrophobic drugs. This increases the stability of the packed drugs and prevents their rapid degradation [33]. The hydrophilic outer shell forms a protective barrier to prevent the binding of micelles with plasma proteins. This prevents phagocytosis of the micelle by RES and thereby increases the half-life of the drug [34].

Yao et al. [35] designed a micelle that could codeliver paclitaxel (PTX) and curcumin (CUR) and demonstrated that it had a superior drug-loading capacity of up to 35% (w/w) and was able to synergistically induce anticancer effects. Sarisozen et al. [36] developed a mixed micelle using TF-polyethylene glycol polyethylene (TF-PEG-PE) that actively targeted TF to improve tumor targeting. Fang et al. [37] developed a magnetic micelle for the codelivery of doxorubicin and CUR. This codelivery system targeted lactoferrin and prolonged retention of the drugs at the tumor sites to efficiently suppress cancer growth compared with delivery of either drug alone.

3.4. Polymer-Drug Conjugates

In contrast to other drug-delivery systems, polymer-drug conjugates are drugs conjugated to a polymer via covalent bonding. This drug-delivery system has several advantages: (1) it increases the water solubility of hydrophobic drugs; (2) the covalent bonds could be modified (such as having a pH-sensitive linker, enzyme sensitive linker, or light sensitive linker). This enables the release of drugs to different sites [38]; (3) conjugation of drugs with polymers could increase their half-life; and (4) the increase in molecular weight could prevent EPR effect, thus favoring drug accumulation in solid tumors. Hence, these conjugates could overcome the differences in water solubility, selectivity, and stability between the antitumor active constituents of plants and chemotherapeutic drugs. The most commonly used polymers include polysaccharides, PEG, poly amino acids (PAA), and polypeptides [39].

Xue et al. [40] constructed a self-assembled prodrug nanoparticle that was conjugated to cabazitaxel and citronellol via a disulfide bond. This nanoparticle was redox-sensitive to high concentrations of glutathione (GSH) within tumor cells. Zhang et al. [41] designed a PEG-doxorubicin (DOX)-CUR prodrug nanoparticle for codelivery of DOX and CUR. Schiff-base reaction was used to conjugate DOX to PEG and then was conjugated to CUR in the nanoparticle to obtain PEG-DOX-CUR nanoparticles (NPs). The nanoparticle was acid-sensitive and hence could release DOX and CUR when it reached the tumor.

4. Strategies to Overcome the Physiological Barriers of NDDSs

To effectively deliver drugs to target tissues and sites, NDDSs need to overcome a number of physiological and physical barriers. These include the blood, tissue, and cellular and intracellular transportation barriers. Each barrier could directly affect the final efficacy of the antitumor drugs. In order to overcome these barriers, researchers have developed a series of strategies and methods (see Figure 1 and Table 2).

4.1. Blood Circulation

After intravenous injection, NDDSs enter the blood circulation and encounter a number of obstacles: (1) degradation of the nanoparticles or drugs by the various enzymes in the plasma [95]; (2) opsonization of the nanoparticles and subsequent phagocytosis and clearing by RES [96, 97]; and (3) absorption of the nanoparticles by plasma proteins leading to the aggregation and subsequent hematotoxicity, retention in the pulmonary capillaries, or phagocytosis by RES [98]. To overcome these barriers, NDDS needs to avoid interactions with charged proteins in the blood or avoid phagocytosis. To overcome the limitations of NDDS in blood circulation, numerous studies have focused on modifying the surface of these nanoparticles. PEG coated to the surface of nanoparticles increases the half-life of nanoparticles [99]. It works by inhibiting the formation of the hydrophilic shells around NDDSs [100], which prevents plasma proteins from interacting with the nanoparticle and hence prevents RES. Yu et al. [42] developed a PEG-modified long-circulating liposome that concurrently packed QUE (p-gp inhibitor) and Adriamycin (AMD/DOX). This increased the blood concentration of AMD and half-life of AMD in the plasma. PEG-modified nanoparticles, PEG-modified grafted polymers, PEG-modified polymeric micelles, and PEG-modified dendrimers all have been shown to increase the half-life of drugs in blood circulation [43–47, 101].

However, several studies also observed that continuous injection of PEG-modified nanoparticles could induce immune responses and thus lead to accelerated blood clearance (ABC) [102, 103]. Hence, the design of drug-delivery systems with biological characteristics to evade the immune system has garnered increased attention [104]. Several studies have demonstrated that nanoparticles coated with endogenous substances like red blood cell membranes (RBC-NP) could avoid phagocytosis by macrophages via immunomodulatory proteins (such as CD47) on their surface and hence extend their half-lives [105].

4.2. Tumor Accumulation and Penetration

The low efficiency of drug accumulation in tumor tissues is one of the hurdles in antitumor NDDS therapy. NDDS accumulation in tumors is mainly via EPR. However, the dense extracellular matrix and the extremely high interstitial fluid pressure in tumors significantly prevent drugs from entering the deep tissues of the tumor. Because of this, the majority of the NDDS are distributed in blood vessels around the tumors. This results in lower drug distribution into the actual tumor, reduced efficacy, and hence an incomplete elimination and subsequent recurrence [27, 106]. Several studies have demonstrated that nanodrugs with smaller diameters have increased efficacy because they can penetrate easier and deeper into tumor tissues [33, 51].

Numerous studies have demonstrated that several specific receptors are expressed on the surface of tumor blood vessels compared with normal blood vessels. These include endothelial cell surface-specific receptors integrinαv β3 [107] and nucleolin [108]. NDDSs that are modified on the surface to express ligands to these receptors could target both tumor blood vessels and tumor cells. Targeting of tumor blood vessels could increase the retention of the NDDSs near the tumor, which eventually increases the distribution in tumor tissues [93]. For example, RGD peptide is a short peptide containing arginine, glycine, and aspartic acid (Arg-Gly-Asp) and is the ligand for integrin αvβ3. Jiang et al. [48] developed an RGD-modified PTX and CUR coloaded liposomes and demonstrated better antitumor efficacy compared with unmodified liposomes. As a P-gp inhibitor, CUR could inhibit multidrug resistance, while the combined application of CUR and PTX had a synergistic effect. These RGD-modified nanoparticles have shown high aggregation and deep permeability at tumor sites [48–50]. Hence, targeting common receptors on tumor blood vessels and tumor cells is an effective strategy to improve the accumulation and penetration of nanoparticles into tumor tissues [52, 62, 109].

4.3. Target Cell Internalization and Uptake

After penetrating deep into tumor tissue, NDDS must be internalized by the tumor cells to exert into antitumor effects. Codelivery of active constituents of plants and chemotherapy drugs could promote NDDSs internalization by receptor-mediated endocytosis. In addition, P-gp inhibitors could be used to overcome the drug resistance in tumor cells [110–113].

Specific receptors that are highly expressed in tumors and on the surface of tumor endothelial cells include transferrin receptor, folate (FA) receptor, integrin receptor, somatostatin receptor, lectin receptor, and epidermal growth factor receptor (EGFR). NDDSs modified with different ligands or antibodies which is so-called active targeting NDDSs have shown better tumor-targeting and drug-delivery capability both in vivo and in vitro. TF and FA are very commonly used malignant tumor-targeting ligands, as most tumor cells express high levels of TfR or FR on their surface, while the expression of TfR and FR in normal tissues are much lower [114–116]. Cui et al. [55] used transferrin-modified nanoparticles for the codelivery of DOX and CUR. They first synthesized a pH-sensitive Tf-PEG-CUR prodrug and then packed DOX into the Tf-PEG-CUR NPs to obtain the Tf-PEG-CUR/DOX nanoparticle. This nanoparticle had active tumor-targeting features and could release their payload into tumor sites specifically because of its pH sensitivity in tumor tissue. Singh et al. [56] conjugated planetary ball-milled (PBM) nanoparticles and loaded it with resveratrol and DTXto FA for the treatment of prostate cancer. They found that Fa-modified DTX nanoparticles had increased cytotoxicity and hence could reduce the concentration of free drug by 28 folds. In addition, when DTX-resistant prostate cancer (PCa) cells were treated using this nanoparticle, there was a reversal of multidrug resistance in these cancer cells [57]. In addition, anti-GLUT1 antibody (GLUT1) has been used to modify polymeric micelles coloaded with CUR and doxorubicin and have shown increased efficacy in human colorectal cancer cell HCT-166 both in vitro and in vivo [58].

P-gp is a highly expressed multidrug transporter that could lead to MDR and chemotherapy failure in a number of cancers [15]. Numerous studies have demonstrated that the active constituents of plants, such as CUR, QUE, and triptolide, could inhibit the expression of P-gp gene and protein [117–121]. Thus, codelivery of such drugs with chemotherapeutic drugs could reverse MDR, increase chemotherapy sensitivity, and decrease adverse effects [53, 54]. Compared with chitosan-conjugated PLGA nanoparticles [122, 123], chitosan and anti-P-gp antibody-conjugated PLGA nanoparticles have demonstrated enhanced cell internalization. Hence, NDDS-targeting P-gp has provided an effective method to overcome drug resistance and increase drug internalization.

4.4. Drug Release

Drug release is the last step in drug delivery. Only released drugs from these nanoparticles can exert antitumor effects. Studies have taken advantage of the differences between the tumor microenvironment and the normal environment to figure out ways to release drugs from these nanoparticles. This has mainly been via dissociation of chemical bonds or structures that are sensitive to the tumor microenvironment [124, 125]. There are three common strategies for designing NDDS to promote drug release, i.e., pH-sensitive NDDSs, enzyme-sensitive NDDSs, and temperature-sensitive NDDSs.

The pH in the extracellular tumor tissues (∼pH 6.5) and endosomes/lysosomes (pH 4.5–6.0) are lower compared with normal tissues and blood (pH 7.4). This difference in pH could be used to design pH-responsive nanocarriers [126]. Acetal, hydrazine, imine, and esters are unstable at low pH and could be used to construct pH-responsive NDDSs. Xie et al. [59] utilized Schiff-base reaction to link methotrexate(MTX) with (DSPE-PEG2000) using a pH-sensitive imine linkage to obtain a pH-sensitive prodrug, i.e., DSPE-PEG-Imine-MTX. This prodrug could self-assemble to micellar nanoparticles (MTX-Imine-M) in aqueous solutions and could pack CUR into its core via hydrophobic interaction to form MTX-Imine-M-CUR nanoparticles. The active form of MTX is released more efficiently when the pH is 5.0 compared with 7.4. These nanoparticles are more efficacious and have lower toxicity profiles. In addition, pH-sensitive inorganic substances and polymers have been used to create nanoparticles to release drugs into tumor cells. pH-responsive nanocarriers, such as liposomes, nanoparticles, nanogels, polymer-drug conjugates, and micelle, have been designed and reported to have good efficacy and function [127]. Inorganic substances like calcium phosphate, chitosan, closed mesoporous silica nanoparticle pores (MSNPs), and poly(styrene-co-N,N′-dimethylaminoethyl methacrylate nanoparticles (P(St-co-DMAEMA))complexes and mPEG-b-PMaIPG (methoxy-polyethylene glycols (PEG)-b-poly (d-galactopyranose)) nanoparticles have been demonstrated to be sensitive to relatively small pH changes and have good drug release and relatively high antitumor activity [44, 49, 60, 62, 63]. Yang et al. [61] synthesized the pH-sensitive polymer (poly(ethylene glycol)-benzoic imine-poly(gamma-benzyl-l-aspartate)-b-poly(1-vinylimidazole) block copolymer (PPBV) and developed a multistage pH-responsive micelle system for the codelivery of PTX and CUR for the treatment of breast cancer CSCs. This multistage pH-responsive micelle system could intelligently convert the charges on the surface from neutralities to cations, reduce its diameter size to favor long-term blood circulation into tumor blood vessels, and promote tumor cell uptake and tumor permeability. All this enhanced the treatment efficacy of the nanoparticle for combination therapy using PTX and CUR.

Enzyme-responsive NDDS utilizes the overexpression of various enzymes in tumors to develop NDDS that contain substrates that could be specifically degraded by such enzymes [128]. Various proteases, such as matrix metalloproteases (MMPs) [129, 130] in tumor tissues and cathepsin in lysosomes of tumor cells [131, 132], are overexpressed in tumors. Li et al. [64] developed a protein NDDS that could intelligently respond in the tumor microenvironment. Based on the microenvironment, i.e., enzymes on the tumor surface (MMPs), pH, and high tumor GSH concentrations, the nanoparticle can respond and efficiently target tumors and also reduce metastatic rates.

Temperature-sensitive NDDS regulates drug release based on changes in temperature. Due to severe inflammatory reactions, the internal temperature of most solid tumors is generally higher compared with surrounding normal tissues. Temperature-sensitive drug-delivery systems could enhance the release of drugs in tumors, i.e., after adding the active tumor targeting feature, the temperature-sensitive targeting NDDS could be constructed [133]. Nguyen et al. [65] synthesized a heat-responsive Hep-F127 polymer for the codelivery of cisplatin (CDDP) and nano curcumin complex/pack to form a dual drug-delivery system. This nanoparticle had antiproliferative effects and tumor inhibition on MCF-7 cells and xenograft transplantation models. Zhang et al. [66] developed a near-infrared-responsive gold nanocagesusing biotin PEG thiol (biotin-PEG-SH) to codeliver doxorubicin and QUE for the treatment of breast cancer. This system had the feature of rapid drug release upon radiation of near-infrared rays and high cytotoxicity for MCF-7/ADR cells.

4.5. Drug Response

4.5.1. Synergistic Antitumor Effects

Using a single chemotherapeutic drug for antitumor treatment has several limitations, such as inducing drug resistance, high toxicity, and low therapeutic index [75, 134]. Drug combinations for the treatment of cancers have become more favorable. Active constituents of plants have multiantitumor effects. They can synergistically inhibit tumor-cell proliferation by enhancing tumor-cell apoptosis, induce cell autophagy, enhance oxidative stress, improve the sensitivity, and increase cell cycle arrest when used in conjunction with chemotherapy drugs [69, 134–138]. Investigators have developed novel combinatory approaches using cationic PEGylatedniosome-encapsulated nanoparticles. These have demonstrated synergistic effects in gastric, prostate, and breast cancer cells [81]. Delivering nanoparticles (functional polymeric micelles, polyamidoamine dendritic polymers, and copolymers) that carry active constituents of plants and chemotherapeutic drugs is more efficacious compared with monotherapy [33, 35, 69–80, 82, 106].

4.5.2. CSC-Targeting System

Although CSCs account for only a small portion of tumor cells, they have the capacity to self-renew, differentiate, and maintain tumor growth [139, 140]. CSCs can induce recurrence, metastasis, and resistance to antitumor drugs [141], which subsequently leads to chemotherapy failure. As the “drug pumps,” ABCG2 is highly expressed in CSCs. They pump drugs out of cells to prevent tumor killing. CSCs are considered the key to eradicating tumors. Signaling pathways and specific markers in CSCs could be the ideal targets for CSC-targeting NDDSs [142]. The active constituents of plants, such as CUR, can inhibit several signaling pathways, such as the Wnt/β-catenin, Notch, and Hedgehog pathways [143] and thus effectively inhibit the self-renewal of CSCs. Combining CSC-targeting therapy with conventional chemotherapy drugs could result in synergistic antitumor activity [61, 68]. For instance, pH-sensitive nanoparticles coloaded with CUR and DOX (CURDOX-NPs) prepared using monomethoxy (polyethylene glycol)-b-P (D, L-lactic-co-glycolic acid)-b-P (L-glutamic acid) polymer (mPEG-PLGA-PGlu) have shown better breast cancer-inhibitory effects compared with monotherapy [67].

4.5.3. Multifunctional Targeting Drug Delivery Systems

To further increase the targeting of NDDS to tumor tissues, several multifunctional targeting drug delivery systems using different modifications to overcome multiple barriers simultaneously have been developed [86, 87]. Nanoplatform for combinational therapy using PEG, PCEC (poly(“-caprolactone)-b-poly(ethylene glycol)-b-poly(”-caprolactone)) and CRGDK (cell-penetrating peptide (Cys-Arg-Gly-Asp-Lys, CRGDK)) has been developed. These can coload DOX/CUR, target the tumor, and respond to intracellular acidic environments. The synergistic antitumor effects of these nanoparticles have the following four aspects: (1) increased stability in blood circulation; (2) passive targeting due to EPR; (3) active targeting by recognition of CRGDK to neuropilin-1 receptor; and (4) high stability and low drug leakage under physiological pH, while the acidic environment dissociates the prodrugs to release DOX and CUR into the cells [83]. Based on the expression of Rf in the blood-brain barrier and glioma cells, human TfR ligand T7 (sequence: HAIYPRH)-modified magnetic PLGA nanoparticle (MNP/T7PLGA NPs) target tumors and release PTX and CUR. This system provides a dual-targeting strategy, i.e., ligand-mediated targeting and magnetic-guided targeting [37, 84]. Saha et al. [85] used the high-temperature solvothermal technique to manufacture Eu : Gd₂O₃ triangular nanoplates. Using this method, nanoparticles are conjugated on its surface to FA, which is the targeting ligand and is then loaded with daunorubicin and CUR via ester bonds. The acidity in tumor tissues induces esterolysis to release the chemotherapeutic drugs into the tumor.

To enhance the antitumor effects of NDDSs, combination drug administration, CSCs-targeting drug delivery system, and multifunctional targeting drug delivery systems have been widely used to achieve additive or synergistic antitumor effects. This approach is a new promising method for efficient tumor targeting.

4.6. Multidrug Resistance

MDR occurs when tumor cells are resistant to one or a series of chemotherapeutic drugs with different structures and mechanisms. MDR is an important reason for chemotherapy failure in clinical practice [144, 145]. The mechanisms of MDR are very complex and include inherent cellular or changes in tumor microenvironments. The complexity of the mechanisms involving MDR brings about challenges to overcome tumor drug resistance [146, 147]. One of the advantages of using nanocarriers to codeliver chemotherapy drugs and active constituents of plants is their capability to reverse MDR [32, 91, 148](seen Figure 2). Rejinold et al. [88] investigated using CUR as the nanocarrier to load PEG-doxorubicin hydrochloride for HCT-8/DOX-resistant cells to increase the in vivo and in vitro antitumor efficacy. In vitro anti-MDR experiments have shown that PEG CRC/DOX NPs had a higher antimetastatic and antiproliferative effect on MDR cancer cells while normal fibroblasts were unaffected. In addition, PEG CRC/DOX NPs have longer blood circulation times compared with CRC NPs. Previous studies have used NDDS coloaded with PTX and active constituents of plants (such as baicalin and borneol) for anti-MDR. These in vitro experiments have shown that such combinations enhanced the concentration of PTX in MCF-7/Tax and A2780/PTX cells, as well as increased cellular drug and cytotoxic effects [89, 90].

4.7. Immunomodulation

The body’s immune system has a significant influence on tumor development and progression. The tumor can modulate the immunocompetence of the body to recognize and kill tumor cells [149]. Quagliariello et al. [92] demonstrated that coadministration of rapamycin and QUE could reduce the levels of IL-8, IL-6, and IL-19, suggesting that such combinations could modulate the body’s immune system and thus enhance the tumor-killing capability. In addition, such combinations could downregulate VEGF, MMP2, and MMP9 levels, suggesting they could inhibit tumor metastasis. Sesarman et al. [93] developed a long term circulating liposome that could pack CUR and PTX (LCL-CURC-DOX). This liposome could significantly increase the cytokine rations of IL-12/IL-4, IL12/IL-1α, IL-12/IL-1β, IFN-γ/IL-6, IFN-γ/IL-1α, and IFN-γ/IL-1β by 1.18–3.14-fold, (), thus favoring the balance of Th1 and Th2 cells to stimulate antitumor effects in the tumor microenvironment.

4.8. Antagonizing/Supressing Toxic Side Effects

Chemotherapy drugs damage normal tissues and cells in the body. Using plants (crude drugs) in combination with chemotherapy drugs could affect tumor tissues via multiple targets and pathways thereby reducing the dose of chemotherapy drugs and hence decrease drug toxicity. In addition, some plants (crude drugs) could also suppress the toxic side effects of chemotherapy. Hence, the combined application of such plants could increase the safety of chemotherapy. Guo et al. [150] combined andrographolide, the active constituent of the plant Andrographis panicula, with bleomycin and found that it not only enhanced the antitumor effects but also reduced the toxic effects of bleomycin on the body. In addition, the combined application of andrographolide and bleomycin effectively reduced pulmonary fibrosis induced by bleomycin, which was manifested by the activation of superoxide dismutase, and inhibition of malondialdehyde and hydroxyproline. Such combinations also suppressed cytokine expression. Zhang et al. [94] developed a complex polymeric micelle system that copacked Adriamycin and CUR (CPMDC) and investigated their protective effects on Adriamycin-induced cardiac toxicity. Pharmacokinetics and tissue distribution showed that CPMDC increased DOX accumulation in tumors but decreased the levels of the toxic metabolite doxorubicin in heart tissue compared with DOX alone.

5. Future Prospects

With the continuous advancements in the understanding of the mechanisms of tumor development and progression, strategies using combination drug therapy have demonstrated significant advantages for cancer treatment. The development of nanotechnology further provides broad application prospects. In this review, we summarized novel strategies and methods in developing NDDSs for codelivery of active constituents of plants and chemotherapy drugs to overcome barriers to drug delivery. NDDSs must circumvent all these barriers before successful and effective antitumor activity is observed. Any problems in these delivery systems could lead to tumor treatment failure. Hence, NDDSs should be appropriately designed based on the physiological process in the body to overcome these barriers. However, the preparation of multifunctional and intelligent tumor-targeted NDDSs is very complex, and hence reduces the drugability of NDDSs. Currently, NDDSs for codelivery still faces a lot of challenges regarding its formulation, design, synthesis, and assessment. More studies are needed to further investigate the pathological features of tumors. This could help in developing multifunctional NDDSs that response to the pathological features of the body. The combination of pharmaceuticals, medicine, chemistry, and materials science will help in the development of NDDSs.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

The current review article work was supported by the National Natural Science Foundation of China (nos. 81774011, 81872812, and 81470861) and Chinese Medicine Research Program of Zhejiang Province (no. 2020ZB095). The authors wish to express their sincere thanks to Prof. Hai-Feng Pan for his technical assistance.

References

S. Shen, M. Liu, T. Li, S. Lin, and R. Mo, “Recent progress in nanomedicine-based combination cancer therapy using a site-specific co-delivery strategy,” Biomaterials Science, vol. 5, no. 8, pp. 1367–1381, 2017.
View at: Publisher Site | Google Scholar
C.-q. Ling, X.-q. Yue, and C. Ling, “Three advantages of using traditional Chinese medicine to prevent and treat tumor,” Journal of Integrative Medicine, vol. 12, no. 4, pp. 331–335, 2014.
View at: Publisher Site | Google Scholar
M.-Y. Huang, L.-L. Zhang, J. Ding, and J.-J. Lu, “Anticancer drug discovery from Chinese medicinal herbs,” Chinese Medicine, vol. 13, no. 1, p. 35, 2018.
View at: Publisher Site | Google Scholar
X. Wang, Y. Feng, N. Wang et al., “Chinese medicines induce cell death: the molecular and cellular mechanisms for cancer therapy,” Biomed Research International, vol. 2014, Article ID 530342, 14 pages, 2014.
View at: Publisher Site | Google Scholar
F. Dilnawaz and S. K. Sahoo, “Enhanced accumulation of curcumin and temozolomide loaded magnetic nanoparticles executes profound cytotoxic effect in glioblastoma spheroid model,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 85, no. 3, pp. 452–462, 2013.
View at: Publisher Site | Google Scholar
W.-M. Li, C.-S. Chiang, W.-C. Huang et al., “Amifostine-conjugated pH-sensitive calcium phosphate-covered magnetic-amphiphilic gelatin nanoparticles for controlled intracellular dual drug release for dual-targeting in HER-2-overexpressing breast cancer,” Journal of Controlled Release, vol. 220, pp. 107–118, 2015.
View at: Publisher Site | Google Scholar
H.-J. Li, J.-Z. Du, X.-J. Du et al., “Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy,” Proceedings of the National Academy of Sciences, vol. 113, no. 15, pp. 4164–4169, 2016.
View at: Publisher Site | Google Scholar
J. Folkman, “Transplacental carcinogenesis by stilbestrol,” New England Journal of Medicine, vol. 285, no. 7, pp. 404-405, 1971.
View at: Publisher Site | Google Scholar
H. Maeda, G. Y. Bharate, and J. Daruwalla, “Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 71, no. 3, pp. 409–419, 2009.
View at: Publisher Site | Google Scholar
H. Maeda, “Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity,” Advanced Drug Delivery Reviews, vol. 91, pp. 3–6, 2015.
View at: Publisher Site | Google Scholar
S. J. T. Rezaei, M. R. Nabida, H. Niknejad, and A. A. Entezami, “Folate-decorated thermoresponsive micelles based on star-shaped amphiphilic block copolymers for efficient intracellular release of anticancer drugs,” International Journal of Pharmaceutics, vol. 437, no. 1-2, pp. 70–79, 2012.
View at: Publisher Site | Google Scholar
D. Liu, F. Liu, Z. Liu, L. Wang, and N. Zhang, “Tumor specific delivery and therapy by double-targeted nanostructured lipid carriers with anti-VEGFR-2 antibody,” Molecular Pharmaceutics, vol. 8, no. 6, pp. 2291–2301, 2011.
View at: Publisher Site | Google Scholar
P. Mcquade, L. C. Knight, and M. J. Welch, “Evaluation of 64Cu- and125I-radiolabeled bitistatin as potential agents for targeting αvβ3Integrins in tumor angiogenesis,” Bioconjugate Chemistry, vol. 15, no. 5, pp. 988–996, 2004.
View at: Publisher Site | Google Scholar
E. Jubeli, L. Moine, V. Nicolas, and G. Barratt, “Preparation of E-selectin-targeting nanoparticles and preliminary in vitro evaluation,” International Journal of Pharmaceutics, vol. 426, no. 1-2, pp. 291–301, 2012.
View at: Publisher Site | Google Scholar
R. N. Montesinos, A. Béduneau, Y. Pellequer, and A. Lamprecht, “Delivery of P-glycoprotein substrates using chemosensitizers and nanotechnology for selective and efficient therapeutic outcomes,” Journal of Controlled Release, vol. 161, no. 1, pp. 50–61, 2012.
View at: Publisher Site | Google Scholar
C. E. Meacham and S. J. Morrison, “Tumour heterogeneity and cancer cell plasticity,” Nature, vol. 501, no. 7467, pp. 328–337, 2013.
View at: Publisher Site | Google Scholar
L. V. Nguyen, R. Vanner, P. Dirks, and C. J. Eaves, “Cancer stem cells: an evolving concept,” Nature Reviews Cancer, vol. 12, no. 2, pp. 133–143, 2012.
View at: Publisher Site | Google Scholar
H. Clevers, “The cancer stem cell: premises, promises and challenges,” Nature Medicine, vol. 17, no. 3, pp. 313–319, 2011.
View at: Publisher Site | Google Scholar
L. Brandolini, L. Cristiano, A. Fidoamore et al., “Targeting CXCR1 on breast cancer stem cells: signaling pathways and clinical application modelling,” Oncotarget, vol. 6, no. 41, pp. 43375–43394, 2015.
View at: Publisher Site | Google Scholar
V. Angeloni, P. Tiberio, V. Appierto, and M. G. Daidone, “Implications of stemness-related signaling pathways in breast cancer response to therapy,” Seminars in Cancer Biology, vol. 31, pp. 43–51, 2015.
View at: Publisher Site | Google Scholar
E. Markovsky, H. Baabur-Cohen, A. Eldar-Boock et al., “Administration, distribution, metabolism and elimination of polymer therapeutics,” Journal of Controlled Release, vol. 161, no. 2, pp. 446–460, 2012.
View at: Publisher Site | Google Scholar
F. Danhier, O. Feron, and V. Préat, “To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery,” Journal of Controlled Release, vol. 148, no. 2, pp. 135–146, 2010.
View at: Publisher Site | Google Scholar
S. Abdus, Y. Sultana, and M. Aqil, “Liposomal drug delivery systems: an update review,” Current Drug Delivery, vol. 4, no. 4, pp. 297–305, 2007.
View at: Publisher Site | Google Scholar
D. R. Khan, E. M. Rezler, L.-F. Janelle, and G. B. Fields, “Effects of drug hydrophobicity on liposomal stability,” Chemical Biology & Drug Design, vol. 71, no. 1, pp. 3–7, 2007.
View at: Publisher Site | Google Scholar
M. M. Frank, “The reticuloendothelial system and bloodstream clearance,” Journal of Laboratory & Clinical Medicine, vol. 122, no. 5, pp. 487-488, 1993.
View at: Google Scholar
Y. Krishnamachari, S. M. Geary, C. D. Lemke, and A. K. Salem, “Nanoparticle delivery systems in cancer vaccines,” Pharmaceutical Research, vol. 28, no. 2, pp. 215–236, 2011.
View at: Publisher Site | Google Scholar
J. Hu, J. Wang, G. Wang, Z. Yao, and X. Dang, “Pharmacokinetics and antitumor efficacy of DSPE-PEG2000 polymeric liposomes loaded with quercetin and temozolomide: analysis of their effectiveness in enhancing the chemosensitization of drug-resistant glioma cells,” International Journal of Molecular Medicine, vol. 37, no. 3, pp. 690–702, 2016.
View at: Publisher Site | Google Scholar
A. M. Thomas, A. J. Gomez, J. L. Palma, W. T. Yap, and L. D. Shea, “Heparin-chitosan nanoparticle functionalization of porous poly(ethylene glycol) hydrogels for localized lentivirus delivery of angiogenic factors,” Biomaterials, vol. 35, no. 30, pp. 8687–8693, 2014.
View at: Publisher Site | Google Scholar
N. Poth, V. Seiffart, G. Gross, H. Menzel, and W. Dempwolf, “Biodegradable chitosan nanoparticle coatings on titanium for the delivery of BMP-2,” Biomolecules, vol. 5, no. 1, pp. 3–19, 2015.
View at: Publisher Site | Google Scholar
W.-M. Li, C.-W. Su, Y.-W. Chen, and S.-Y. Chen, “In situ DOX-calcium phosphate mineralized CPT-amphiphilic gelatin nanoparticle for intracellular controlled sequential release of multiple drugs,” Acta Biomaterialia, vol. 15, pp. 191–199, 2015.
View at: Publisher Site | Google Scholar
J. Zhou, X. Zhang, M. Li et al., “Novel lipid hybrid albumin nanoparticle greatly lowered toxicity of pirarubicin,” Molecular Pharmaceutics, vol. 10, no. 10, pp. 3832–3841, 2013.
View at: Publisher Site | Google Scholar
Y. Xu, C. Wang, Y. Ding et al., “Nanoparticles with optimal ratiometric co-delivery of docetaxel with gambogic acid for treatment of multidrug-resistant breast cancer,” Journal of Biomedical Nanotechnology, vol. 12, no. 9, pp. 1774–1781, 2016.
View at: Publisher Site | Google Scholar
C. Li, X. Ge, and L. Wang, “Construction and comparison of different nanocarriers for co-delivery of cisplatin and curcumin: a synergistic combination nanotherapy for cervical cancer,” Biomedicine & Pharmacotherapy, vol. 86, pp. 628–636, 2017.
View at: Publisher Site | Google Scholar
G. S. Kwon and K. Kataoka, “Block copolymer micelles as long-circulating drug vehicles,” Advanced Drug Delivery Reviews, vol. 64, no. 2-3, pp. 237–245, 2012.
View at: Publisher Site | Google Scholar
Q. Yao, D. C. Gutierrez, N. H. Hoang et al., “Efficient codelivery of paclitaxel and curcumin by novel bottlebrush copolymer-based micelles,” Molecular Pharmaceutics, vol. 14, no. 7, pp. 2378–2389, 2017.
View at: Publisher Site | Google Scholar
C. Sarisozen, A. H. Abouzeid, and V. P. Torchilin, “The effect of co-delivery of paclitaxel and curcumin by transferrin-targeted PEG-PE-based mixed micelles on resistant ovarian cancer in 3-D spheroids and in vivo tumors,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 88, no. 2, pp. 539–550, 2014.
View at: Publisher Site | Google Scholar
J.-H. Fang, Y.-H. Lai, T.-L. Chiu, Y.-Y. Chen, S.-H. Hu, and S.-Y. Chen, “Magnetic core-shell nanocapsules with dual-targeting capabilities and co-delivery of multiple drugs to treat brain gliomas,” Advanced Healthcare Materials, vol. 3, no. 8, pp. 1250–1260, 2014.
View at: Publisher Site | Google Scholar
V. Delplace, P. Couvreur, and J. Nicolas, “Recent trends in the design of anticancer polymer prodrug nanocarriers,” Polymer Chemistry, vol. 5, no. 5, pp. 1529–1544, 2014.
View at: Publisher Site | Google Scholar
X. Pang, H.-L. Du, H.-Q. Zhang, Y.-J. Zhai, and G.-X. Zhai, “Polymer-drug conjugates: present state of play and future perspectives,” Drug Discovery Today, vol. 18, no. 23-24, pp. 1316–1322, 2013.
View at: Publisher Site | Google Scholar
P. Xue, D. Liu, J. Wang et al., “Redox-Sensitive citronellol-cabazitaxel conjugate: maintained in vitro cytotoxicity and self-assembled as multifunctional nanomedicine,” Bioconjugate Chemistry, vol. 27, no. 5, pp. 1360–1372, 2016.
View at: Publisher Site | Google Scholar
Y. Zhang, C. Yang, W. Wang et al., “Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer,” Scientific Reports, vol. 6, no. 1, p. 21225, 2016.
View at: Publisher Site | Google Scholar
J. Yu, H. Chen, L. Jiang, J. Wang, J. Dai, and J. Wang, “Co-delivery of adriamycin and P-gp inhibitor quercetin using PEGylated liposomes to overcome cancer resistance,” Journal of Pharmaceutical Sciences, vol. 108, no. 5, pp. 1788–1799, 2019.
View at: Publisher Site | Google Scholar
H. Danafar, K. Rostamizadeh, S. Davaran, and M. Hamidi, “Co-delivery of hydrophilic and hydrophobic drugs by micelles: a new approach using drug conjugated PEG-PCLNanoparticles,” Drug Development and Industrial Pharmacy, vol. 43, no. 11, pp. 1908–1918, 2017.
View at: Publisher Site | Google Scholar
C. Xu, R.-j. Song, P. Lu et al., “pH-triggered charge-reversal and redox-sensitive drug release polymer micelles co-deliver doxorubicin and triptolide for prostate tumor therapy,” International Journal of Nanomedicine, vol. 13, pp. 7229–7249, 2018.
View at: Publisher Site | Google Scholar
J. Lin, Q. Cai, Y. Tang et al., “PEGylated lipid bilayer coated mesoporous silica nanoparticles for co-delivery of paclitaxel and curcumin: design, characterization and its cytotoxic effect,” International Journal of Pharmaceutics, vol. 536, no. 1, pp. 272–282, 2018.
View at: Publisher Site | Google Scholar
L. Wang, W. Wang, Z. Rui, and D. Zhou, “The effective combination therapy against human osteosarcoma: doxorubicin plus curcumin co-encapsulated lipid-coated polymeric nanoparticulate drug delivery system,” Drug Delivery, vol. 23, no. 9, pp. 3200–3208, 2016.
View at: Publisher Site | Google Scholar
R. Rastegar, H. A. Javar, M. Khoobi et al., “Evaluation of a novel biocompatible magnetic nanomedicine based on beta-cyclodextrin, loaded doxorubicin-curcumin for overcoming chemoresistance in breast cancer,” Artificial Cells, Nanomedicine, and Biotechnology, vol. 46, no. 2, pp. 207–216, 2018.
View at: Publisher Site | Google Scholar
K. Jiang, M. Shen, and W. Xu, “Arginine, glycine, aspartic acid peptide-modified paclitaxel and curcumin co-loaded liposome for the treatment of lung cancer: in vitro/vivo evaluation,” International Journal of Nanomedicine, vol. 13, pp. 2561–2569, 2018.
View at: Publisher Site | Google Scholar
C. Murugan, K. Rayappan, R. Thangam et al., “Combinatorial nanocarrier based drug delivery approach for amalgamation of anti-tumor agents in breast cancer cells: an improved nanomedicine strategy,” Scientific Reports, vol. 6, no. 1, p. 34053, 2016.
View at: Publisher Site | Google Scholar
C. Wang, L. Su, C. Wu, J. Wu, C. Zhu, and G. Yuan, “RGD peptide targeted lipid-coated nanoparticles for combinatorial delivery of sorafenib and quercetin against hepatocellular carcinoma,” Drug Development and Industrial Pharmacy, vol. 42, no. 12, pp. 1938–1944, 2016.
View at: Publisher Site | Google Scholar
T. K. Dash and V. B. Konkimalla, “Formulation and optimization of doxorubicin and biochanin a combinational liposomes for reversal of chemoresistance,” AAPS PharmSciTech, vol. 18, no. 4, pp. 1116–1124, 2017.
View at: Publisher Site | Google Scholar
H. Cao, Y. Wang, X. He et al., “Codelivery of sorafenib and curcumin by directed self-assembled nanoparticles enhances therapeutic effect on hepatocellular carcinoma,” Molecular Pharmaceutics, vol. 12, no. 3, pp. 922–931, 2015.
View at: Publisher Site | Google Scholar
L. Lv, K. Qiu, X. Yu et al., “Amphiphilic copolymeric micelles for doxorubicin and curcumin co-delivery to reverse multidrug resistance in breast cancer,” Journal of Biomedical Nanotechnology, vol. 12, no. 5, pp. 973–985, 2016.
View at: Publisher Site | Google Scholar
J. Zhang, L. Wang, H. F. Chan et al., “Co-delivery of paclitaxel and tetrandrine via iRGD peptide conjugated lipid-polymer hybrid nanoparticles overcome multidrug resistance in cancer cells,” Scientific Reports, vol. 7, no. 1, p. 46057, 2017.
View at: Publisher Site | Google Scholar
T. Cui, S. Zhang, and H. Sun, “Co-delivery of doxorubicin and pH-sensitive curcumin prodrug by transferrin-targeted nanoparticles for breast cancer treatment,” Oncology Reports, vol. 37, no. 2, pp. 1253–1260, 2017.
View at: Publisher Site | Google Scholar
S. K. Singh, J. W. Lillard Jr., and R. Singh, “Reversal of drug resistance by planetary ball milled (PBM) nanoparticle loaded with resveratrol and docetaxel in prostate cancer,” Cancer Letters, vol. 427, pp. 49–62, 2018.
View at: Publisher Site | Google Scholar
J. S. Baek and C.-W. Cho, “A multifunctional lipid nanoparticle for co-delivery of paclitaxel and curcumin for targeted delivery and enhanced cytotoxicity in multidrug resistant breast cancer cells,” Oncotarget, vol. 8, no. 18, pp. 30369–30382, 2017.
View at: Publisher Site | Google Scholar
A. H. Abouzeid, N. R. Patel, I. M. Rachman, S. Senn, and V. P. Torchilin, “Anti-cancer activity of anti-GLUT1 antibody-targeted polymeric micelles co-loaded with curcumin and doxorubicin,” Journal of Drug Targeting, vol. 21, no. 10, pp. 994–1000, 2013.
View at: Publisher Site | Google Scholar
J. Xie, Z. Fan, Y. Li et al., “Design of pH-sensitive methotrexate prodrug-targeted curcumin nanoparticles for efficient dual-drug delivery and combination cancer therapy,” International Journal of Nanomedicine, vol. 13, pp. 1381–1398, 2018.
View at: Publisher Site | Google Scholar
J. Peng, S. Fumoto, H. Miyamoto, Y. Chen, N. Kuroda, and K. Nishida, “One-step formation of lipid-polyacrylic acid-calcium carbonate nanoparticles for co-delivery of doxorubicin and curcumin,” Journal of Drug Targeting, vol. 25, no. 8, pp. 704–714, 2017.
View at: Publisher Site | Google Scholar
Z. Yang, N. Sun, R. Cheng et al., “pH multistage responsive micellar system with charge-switch and PEG layer detachment for co-delivery of paclitaxel and curcumin to synergistically eliminate breast cancer stem cells,” Biomaterials, vol. 147, pp. 53–67, 2017.
View at: Publisher Site | Google Scholar
J. Zhang, J. Li, Z. Shi et al., “pH-sensitive polymeric nanoparticles for co-delivery of doxorubicin and curcumin to treat cancer via enhanced pro-apoptotic and anti-angiogenic activities,” Acta Biomaterialia, vol. 58, pp. 349–364, 2017.
View at: Publisher Site | Google Scholar
Z. K. Ghaleseiedi, A. D. Tehrani, and M. Parsamanesh, “Starch-based dual amphiphilic graft copolymer as a new pH-sensitive maltidrug co-delivery system,” International Journal of Biological Macromolecules, vol. 118, pp. 913–920, 2018.
View at: Publisher Site | Google Scholar
Y. Li, W. Li, W. Bao et al., “Bioinspired peptosomes with programmed stimuli-responses for sequential drug release and high-performance anticancer therapy,” Nanoscale, vol. 9, no. 27, pp. 9317–9324, 2017.
View at: Publisher Site | Google Scholar
N. T. Nguyen, N. N. T. Nguyen, N. T. N. Tran et al., “Synergic activity against MCF-7 breast cancer cell growth of nanocurcumin-encapsulated and cisplatin-complexed nanogels,” Molecules, vol. 23, no. 12, 2018.
View at: Publisher Site | Google Scholar
Z. Zhang, S. Xu, Y. Wang et al., “Near-infrared triggered co-delivery of doxorubicin and quercetin by using gold nanocages with tetradecanol to maximize anti-tumor effects on MCF-7/ADR cells,” Journal of Colloid and Interface Science, vol. 509, pp. 47–57, 2018.
View at: Publisher Site | Google Scholar
J. D. Yuan, D. L. ZhuGe, M. Q. Tong et al., “pH-sensitive polymeric nanoparticles of mPEG-PLGA-PGlu with hybrid core for simultaneous encapsulation of curcumin and doxorubicin to kill the heterogeneous tumour cells in breast cancer,” Artificial Cells, Nanomedicine, and Biotechnology, vol. 46, no. 1, pp. 302–313, 2018.
View at: Publisher Site | Google Scholar
H.-L. Xu, Z.-L. Fan, D.-L. ZhuGe et al., “Ratiometric delivery of two therapeutic candidates with inherently dissimilar physicochemical property through pH-sensitive core-shell nanoparticles targeting the heterogeneous tumor cells of glioma,” Drug Delivery, vol. 25, no. 1, pp. 1302–1318, 2018.
View at: Publisher Site | Google Scholar
Y. Cheng, P. Zhao, S. Wu et al., “Cisplatin and curcumin co-loaded nano-liposomes for the treatment of hepatocellular carcinoma,” International Journal of Pharmaceutics, vol. 545, no. 1-2, pp. 261–273, 2018.
View at: Publisher Site | Google Scholar
A. Minaei, M. Sabzichi, F. Ramezani, H. Hamishehkar, and N. Samadi, “Co-delivery with nano-quercetin enhances doxorubicin-mediated cytotoxicity against MCF-7 cells,” Molecular Biology Reports, vol. 43, no. 2, pp. 99–105, 2016.
View at: Publisher Site | Google Scholar
X. Zhao, Q. Chen, Y. Li, H. Tang, W. Liu, and X. Yang, “Doxorubicin and curcumin co-delivery by lipid nanoparticles for enhanced treatment of diethylnitrosamine-induced hepatocellular carcinoma in mice,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 93, pp. 27–36, 2015.
View at: Publisher Site | Google Scholar
W. Scarano, P. de Souza, and M. H. Stenzel, “Dual-drug delivery of curcumin and platinum drugs in polymeric micelles enhances the synergistic effects: a double act for the treatment of multidrug-resistant cancer,” Biomaterials Science, vol. 3, no. 1, pp. 163–174, 2015.
View at: Publisher Site | Google Scholar
H. Xu, F. Jia, P. Singh, S. Ruan, H. Zhang, and X. Li, “Synergistic anti-glioma effect of a coloaded nano-drug delivery system,” International Journal of Nanomedicine, vol. 12, pp. 29–40, 2016.
View at: Publisher Site | Google Scholar
M.-Y. Wong and G. N. C. Chiu, “Simultaneous liposomal delivery of quercetin and vincristine for enhanced estrogen-receptor-negative breast cancer treatment,” Anti-Cancer Drugs, vol. 21, no. 4, pp. 401–410, 2010.
View at: Publisher Site | Google Scholar
J. Wang, W. Ma, and P. Tu, “Synergistically improved anti-tumor efficacy by co-delivery doxorubicin and curcumin polymeric micelles,” Macromolecular Bioscience, vol. 15, no. 9, pp. 1252–1261, 2015.
View at: Publisher Site | Google Scholar
H. Jiang, D. Geng, H. Liu, Z. Li, and J. Cao, “Co-delivery of etoposide and curcumin by lipid nanoparticulate drug delivery system for the treatment of gastric tumors,” Drug Delivery, vol. 23, no. 9, pp. 3665–3673, 2016.
View at: Publisher Site | Google Scholar
J. Liu, H. Cheng, L. Han et al., “Synergistic combination therapy of lung cancer using paclitaxel- and triptolide-coloaded lipid–polymer hybrid nanoparticles,” Drug Design, Development and Therapy, vol. 12, pp. 3199–3209, 2018.
View at: Publisher Site | Google Scholar
A. Mohan, S. Narayanan, G. Balasubramanian, S. Sethuraman, and U. M. Krishnan, “Dual drug loaded nanoliposomal chemotherapy: a promising strategy for treatment of head and neck squamous cell carcinoma,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 99, pp. 73–83, 2016.
View at: Publisher Site | Google Scholar
R. Pangeni, V. K. Panthi, I.-S. Yoon, and J. W. Park, “Preparation, characterization, and in vivo evaluation of an oral multiple nanoemulsive System for co-delivery of pemetrexed and quercetin,” Pharmaceutics, vol. 10, no. 3, 2018.
View at: Publisher Site | Google Scholar
B. Zhu, L. Yu, and Q. Yue, “Co-delivery of vincristine and quercetin by nanocarriers for lymphoma combination chemotherapy,” Biomedicine & Pharmacotherapy, vol. 91, pp. 287–294, 2017.
View at: Publisher Site | Google Scholar
M. Hemati, F. Haghiralsadat, F. Yazdian, F. Jafari, A. Moradi, and Z. Malekpour-Dehkordi, “Development and characterization of a novel cationic PEGylated niosome-encapsulated forms of doxorubicin, quercetin and siRNA for the treatment of cancer by using combination therapy,” Artificial Cells, Nanomedicine, and Biotechnology, vol. 47, no. 1, pp. 1295–1311, 2019.
View at: Publisher Site | Google Scholar
H. B. Ruttala and Y. T. Ko, “Liposomal co-delivery of curcumin and albumin/paclitaxel nanoparticle for enhanced synergistic antitumor efficacy,” Colloids and Surfaces B: Biointerfaces, vol. 128, pp. 419–426, 2015.
View at: Publisher Site | Google Scholar
M. Yang, L. Yu, R. Guo, A. Dong, C. Lin, and J. Zhang, “A modular coassembly approach to all-in-one multifunctional nanoplatform for synergistic codelivery of doxorubicin and curcumin,” Nanomaterials (Basel), vol. 8, no. 3, p. 167, 2018.
View at: Publisher Site | Google Scholar
Y. Cui, M. Zhang, F. Zeng, H. Jin, Q. Xu, and Y. Huang, “Dual-targeting magnetic PLGA nanoparticles for codelivery of paclitaxel and curcumin for brain tumor therapy,” ACS Applied Materials & Interfaces, vol. 8, no. 47, pp. 32159–32169, 2016.
View at: Publisher Site | Google Scholar
A. Saha, S. C. Mohanta, K. Deka, P. Deb, and P. S. Devi, “Surface-engineered multifunctional Eu:Gd₂O₃ nanoplates for targeted and pH-responsive drug delivery and Imaging applications,” ACS Applied Materials & Interfaces, vol. 9, no. 4, pp. 4126–4141, 2017.
View at: Publisher Site | Google Scholar
J. Yan, Y. Wang, Y. Jia et al., “Co-delivery of docetaxel and curcumin prodrug via dual-targeted nanoparticles with synergistic antitumor activity against prostate cancer,” Biomedicine & Pharmacotherapy, vol. 88, pp. 374–383, 2017.
View at: Publisher Site | Google Scholar
J. Wang, F. Wang, F. Li et al., “A multifunctional poly(curcumin) nanomedicine for dual-modal targeted delivery, intracellular responsive release, dual-drug treatment and imaging of multidrug resistant cancer cells,” Journal of Materials Chemistry B, vol. 4, no. 17, pp. 2954–2962, 2016.
View at: Publisher Site | Google Scholar
N. S. Rejinold, J. Yoo, S. Jon, and Y.-C. Kim, “Curcumin as a novel nanocarrier system for doxorubicin delivery to MDR cancer cells: in vitro and in vivo evaluation,” ACS Applied Materials & Interfaces, vol. 10, no. 34, pp. 28458–28470, 2018.
View at: Publisher Site | Google Scholar
L. Zou, D. Wang, Y. Hu et al., “Drug resistance reversal in ovarian cancer cells of paclitaxel and borneol combination therapy mediated by PEG-PAMAM nanoparticles,” Oncotarget, vol. 8, no. 36, pp. 60453–60468, 2017.
View at: Publisher Site | Google Scholar
L. Meng, X. Xia, Y. Yang et al., “Co-encapsulation of paclitaxel and baicalein in nanoemulsions to overcome multidrug resistance via oxidative stress augmentation and P-glycoprotein inhibition,” International Journal of Pharmaceutics, vol. 513, no. 1-2, pp. 8–16, 2016.
View at: Publisher Site | Google Scholar
Y. Zhao, M.-l. Huan, M. Liu et al., “Doxorubicin and resveratrol co-delivery nanoparticle to overcome doxorubicin resistance,” Scientific Reports, vol. 6, no. 1, p. 35267, 2016.
View at: Publisher Site | Google Scholar
V. Quagliariello, R. V. Iaffaioli, E. Armenia et al., “Hyaluronic acid nanohydrogel loaded with quercetin alone or in combination to a macrolide derivative of rapamycin RAD001 (everolimus) as a new treatment for hormone-responsive human breast cancer,” Journal of Cellular Physiology, vol. 232, no. 8, pp. 2063–2074, 2017.
View at: Publisher Site | Google Scholar
A. Sesarman, L. Tefas, B. Sylvester et al., “Co-delivery of curcumin and doxorubicin in PEGylated liposomes favored the antineoplastic C26 murine colon carcinoma microenvironment,” Drug Delivery and Translational Research, vol. 9, no. 1, pp. 260–272, 2019.
View at: Publisher Site | Google Scholar
D. Zhang, Q. Xu, N. Wang et al., “A complex micellar system co-delivering curcumin with doxorubicin against cardiotoxicity and tumor growth,” International Journal of Nanomedicine, vol. 13, pp. 4549–4561, 2018.
View at: Publisher Site | Google Scholar
J.-K. Kim, M. D. Howard, T. D. Dziubla, J. J. Rinehart, M. Jay, and X. Lu, “Uniformity of drug payload and its effect on stability of solid lipid nanoparticles containing an ester prodrug,” ACS Nano, vol. 5, no. 1, pp. 209–216, 2011.
View at: Publisher Site | Google Scholar
C. Sun, K. Du, C. Fang et al., “PEG-mediated synthesis of highly dispersive multifunctional superparamagnetic nanoparticles: their physicochemical properties and function in vivo,” ACS Nano, vol. 4, no. 4, pp. 2402–2410, 2010.
View at: Publisher Site | Google Scholar
L. Sandiford, A. Phinikaridou, A. Protti et al., “Bisphosphonate-anchored PEGylation and radiolabeling of superparamagnetic iron oxide: long-circulating nanoparticles forin vivomultimodal (T1 MRI-SPECT) Imaging,” ACS Nano, vol. 7, no. 1, pp. 500–512, 2013.
View at: Publisher Site | Google Scholar
J. Han, Q. Wang, Z. Zhang, T. Gong, and X. Sun, “Cationic bovine serum albumin based self-assembled nanoparticles as siRNA delivery vector for treating lung metastatic cancer,” Small, vol. 10, no. 3, pp. 524–535, 2014.
View at: Publisher Site | Google Scholar
C. Allen, N. D. Santos, R. Gallagher et al., “Controlling the physical behavior and biological performance of liposome formulations through use of surface grafted poly(ethylene glycol),” Bioscience Reports, vol. 22, no. 2, pp. 225–250, 2002.
View at: Publisher Site | Google Scholar
Y. Liu, Y. Hu, and L. Huang, “Influence of polyethylene glycol density and surface lipid on pharmacokinetics and biodistribution of lipid-calcium-phosphate nanoparticles,” Biomaterials, vol. 35, no. 9, pp. 3027–3034, 2014.
View at: Publisher Site | Google Scholar
P. Li, X. Zhou, D. Qu et al., “Preliminary study on fabrication, characterization and synergistic anti-lung cancer effects of self-assembled micelles of covalently conjugated celastrol-polyethylene glycol-ginsenoside Rh2,” Drug Delivery, vol. 24, no. 1, pp. 834–845, 2017.
View at: Publisher Site | Google Scholar
A. S. A. Lila, H. Kiwada, and T. Ishida, “The accelerated blood clearance (ABC) phenomenon: clinical challenge and approaches to manage,” Journal of Controlled Release, vol. 172, no. 1, pp. 38–47, 2013.
View at: Publisher Site | Google Scholar
K. Shiraishi, M. Hamano, H. Ma et al., “Hydrophobic blocks of PEG-conjugates play a significant role in the accelerated blood clearance (ABC) phenomenon,” Journal of Controlled Release, vol. 165, no. 3, pp. 183–190, 2013.
View at: Publisher Site | Google Scholar
J.-W. Yoo, D. J. Irvine, D. E. Discher, and M. Samir, “Bio-inspired, bioengineered and biomimetic drug delivery carriers,” Nature Reviews Drug Discovery, vol. 10, no. 7, pp. 521–535, 2011.
View at: Publisher Site | Google Scholar
W. Gao, R. H. Fang, S. Thamphiwatana et al., “Modulating antibacterial immunity via bacterial membrane-coated nanoparticles,” Nano Letters, vol. 15, no. 2, pp. 1403–1409, 2015.
View at: Publisher Site | Google Scholar
Q. Guo, X. Li, Y. Yang et al., “Enhanced 4T1 breast carcinoma anticancer activity by co-delivery of doxorubicin and curcumin with core-shell drug-carrier based on heparin modified poly(L-lactide) grafted polyethylenimine cationic nanoparticles,” Journal of Biomedical Nanotechnology, vol. 10, no. 2, pp. 227–237, 2014.
View at: Publisher Site | Google Scholar
C. Zhan, B. Gu, C. Xie, J. Li, Y. Liu, and W. Lu, “Cyclic RGD conjugated poly(ethylene glycol)-co-poly(lactic acid) micelle enhances paclitaxel anti-glioblastoma effect,” Journal of Controlled Release, vol. 143, no. 1, pp. 136–142, 2010.
View at: Publisher Site | Google Scholar
Y. Zhang, M. Yang, J.-H. Park et al., “A surface-charge study on cellular-uptake behavior of F3-peptide-conjugated iron oxide nanoparticles,” Small, vol. 5, no. 17, pp. 1990–1996, 2009.
View at: Publisher Site | Google Scholar
F. Tian, F. Z. Dahmani, J. Qiao et al., “A targeted nanoplatform co-delivering chemotherapeutic and antiangiogenic drugs as a tool to reverse multidrug resistance in breast cancer,” Acta Biomaterialia, vol. 75, pp. 398–412, 2018.
View at: Publisher Site | Google Scholar
R. C. Mustata, A. Grigorescu, and S. M. Petrescu, “Encapsulated cargo internalized by fusogenic liposomes partially overlaps the endoplasmic reticulum,” Journal of Cellular and Molecular Medicine, vol. 13, no. 9b, pp. 3110–3121, 2009.
View at: Publisher Site | Google Scholar
S. Somani, D. R. Blatchford, O. Millington, M. L. Stevenson, and C. Dufès, “Transferrin-bearing polypropylenimine dendrimer for targeted gene delivery to the brain,” Journal of Controlled Release, vol. 188, pp. 78–86, 2014.
View at: Publisher Site | Google Scholar
A.-t. Wang, D.-s. Liang, Y.-j. Liu, and X.-r. Qi, “Roles of ligand and TPGS of micelles in regulating internalization, penetration and accumulation against sensitive or resistant tumor and therapy for multidrug resistant tumors,” Biomaterials, vol. 53, pp. 160–172, 2015.
View at: Publisher Site | Google Scholar
L. Mei, L. Fu, K. Shi et al., “Increased tumor targeted delivery using a multistage liposome system functionalized with RGD, TAT and cleavable PEG,” International Journal of Pharmaceutics, vol. 468, no. 1-2, pp. 26–38, 2014.
View at: Publisher Site | Google Scholar
R. S. Mulik, J. Monkkonen, R. O. Juvonen, K. R. Mahadik, and A. R. Paradkar, “Transferrin mediated solid lipid nanoparticles containing curcumin: enhanced in vitro anticancer activity by induction of apoptosis,” International Journal of Pharmaceutics, vol. 398, no. 1-2, pp. 190–203, 2010.
View at: Publisher Site | Google Scholar
Z. M. Qian, H. Li, H. Sun, and K. Ho, “Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway,” Pharmacological Reviews, vol. 54, no. 4, pp. 561–587, 2002.
View at: Publisher Site | Google Scholar
A. Widera, F. Norouziyan, and W.-C. Shen, “Mechanisms of TfR-mediated transcytosis and sorting in epithelial cells and applications toward drug delivery,” Advanced Drug Delivery Reviews, vol. 55, no. 11, pp. 1439–1466, 2003.
View at: Publisher Site | Google Scholar
X.-L. Hou, K. Takahashi, K. Tanaka et al., “Curcuma drugs and curcumin regulate the expression and function of P-gp in Caco-2 cells in completely opposite ways,” International Journal of Pharmaceutics, vol. 358, no. 1-2, pp. 224–229, 2008.
View at: Publisher Site | Google Scholar
J.-S. Choi, Y.-J. Piao, and K. W. Kang, “Effects of quercetin on the bioavailability of doxorubicin in rats: role of CYP3A4 and P-gp inhibition by quercetin,” Archives of Pharmacal Research, vol. 34, no. 4, pp. 607–613, 2011.
View at: Publisher Site | Google Scholar
C. Li, B.-Q. Sun, and X.-D. Gai, “Compounds from Chinese herbal medicines as reversal agents for P-glycoprotein-mediated multidrug resistance in tumours,” Clinical and Translational Oncology, vol. 16, no. 7, pp. 593–598, 2014.
View at: Publisher Site | Google Scholar
X. Ma, M. Hu, H. Wang, and J. Li, “Discovery of traditional Chinese medicine monomers and their synthetic intermediates, analogs or derivatives for battling P-gp-mediated multi-drug resistance,” European Journal of Medicinal Chemistry, vol. 159, pp. 381–392, 2018.
View at: Publisher Site | Google Scholar
W. Zhang, Y. Han, S. L. Lim, and L. Y. Lim, “Dietary regulation of P-gp function and expression,” Expert Opinion on Drug Metabolism & Toxicology, vol. 5, no. 7, pp. 789–801, 2009.
View at: Publisher Site | Google Scholar
G. Miao, W. Ying, R. Wenting, D. Liying, and Y. Shuqin, “Chitosan-modified PLGA nanoparticles as drug delivery carrier for modulating P-glycoprotein of enterocytes,” Journal of Controlled Release, vol. 172, no. 1, pp. e112–e113, 2013.
View at: Publisher Site | Google Scholar
P. Iangcharoen, W. Punfa, S. Yodkeeree et al., “Anti-P-glycoprotein conjugated nanoparticles for targeting drug delivery in cancer treatment,” Archives of Pharmacal Research, vol. 34, no. 10, pp. 1679–1689, 2011.
View at: Publisher Site | Google Scholar
A. P. Blum, J. K. Kammeyer, A. M. Rush, C. E. Callmann, M. E. Hahn, and N. C. Gianneschi, “Stimuli-responsive nanomaterials for biomedical applications,” Journal of the American Chemical Society, vol. 137, no. 6, pp. 2140–2154, 2015.
View at: Publisher Site | Google Scholar
Y. Qiao, J. Wan, L. Zhou et al., “Stimuli-responsive nanotherapeutics for precision drug delivery and cancer therapy,” Wiley Interdisciplinary Reviews-Nanomedicine and Nanobiotechnology, vol. 11, no. 1, p. e1527, 2019.
View at: Publisher Site | Google Scholar
E. S. Lee, Z. Gao, and Y. H. Bae, “Recent progress in tumor pH targeting nanotechnology,” Journal of Controlled Release, vol. 132, no. 3, pp. 164–170, 2008.
View at: Publisher Site | Google Scholar
A. E. Felber, M.-H. Dufresne, and J.-C. Leroux, “pH-sensitive vesicles, polymeric micelles, and nanospheres prepared with polycarboxylates,” Advanced Drug Delivery Reviews, vol. 64, no. 11, pp. 979–992, 2012.
View at: Publisher Site | Google Scholar
F. Klemm and J. A. Joyce, “Microenvironmental regulation of therapeutic response in cancer,” Trends in Cell Biology, vol. 25, no. 4, pp. 198–213, 2015.
View at: Publisher Site | Google Scholar
M. W. Roomi, J. C. Monterrey, T. Kalinovsky, M. Rath, and A. Niedzwiecki, “Patterns of MMP-2 and MMP-9 expression in human cancer cell lines,” Oncology Reports, vol. 21, no. 5, pp. 1323–1333, 2009.
View at: Publisher Site | Google Scholar
K. Kessenbrock, V. Plaks, and Z. Werb, “Matrix metalloproteinases: regulators of the tumor microenvironment,” Cell, vol. 141, no. 1, pp. 52–67, 2010.
View at: Publisher Site | Google Scholar
L. Liang, S.-W. Lin, W. Dai et al., “Novel cathepsin B-sensitive paclitaxel conjugate: higher water solubility, better efficacy and lower toxicity,” Journal of Controlled Release, vol. 160, no. 3, pp. 618–629, 2012.
View at: Publisher Site | Google Scholar
X. Zhang, K. Tang, H. Wang et al., “Design, synthesis, and biological evaluation of new cathepsin B-Sensitive camptothecin nanoparticles equipped with a novel multifuctional linker,” Bioconjugate Chemistry, vol. 27, no. 5, pp. 1267–1275, 2016.
View at: Publisher Site | Google Scholar
Y. Li, S. Pan, W. Zhang, and Z. Du, “Novel thermo-sensitive core-shell nanoparticles for targeted paclitaxel delivery,” Nanotechnology, vol. 20, no. 6, p. 065104, 2009.
View at: Publisher Site | Google Scholar
H. Wang, Y. Zhao, Y. Wu et al., “Enhanced anti-tumor efficacy by co-delivery of doxorubicin and paclitaxel with amphiphilic methoxy PEG-PLGA copolymer nanoparticles,” Biomaterials, vol. 32, no. 32, pp. 8281–8290, 2011.
View at: Publisher Site | Google Scholar
G. Meng, W. Wang, K. Chai, S. Yang, F. Li, and K. Jiang, “Combination treatment with triptolide and hydroxycamptothecin synergistically enhances apoptosis in A549 lung adenocarcinoma cells through PP2A-regulated ERK, p38 MAPKs and Akt signaling pathways,” International Journal of Oncology, vol. 46, no. 3, pp. 1007–1017, 2015.
View at: Publisher Site | Google Scholar
Y. Zhang, L. Wang, Y. Zi, L. Zhang, Y. Guo, and Y. Huang, “Oridonin effectively reverses the drug resistance of cisplatin involving induction of cell apoptosis and inhibition of MMP expression in human acute myeloid leukemia cells,” Saudi Journal of Biological Sciences, vol. 24, no. 3, pp. 678–686, 2017.
View at: Publisher Site | Google Scholar
W. Zhang, H. Zhou, Y. Yu et al., “Combination of gambogic acid with cisplatin enhances the antitumor effects on cisplatin-resistant lung cancer cells by downregulating MRP2 and LRP expression,” OncoTargets and Therapy, vol. 9, no. 1, p. 3359, 2016.
View at: Publisher Site | Google Scholar
D. d. Plessisstoman, J. G. H. d. Preez, and M. v. d. Venter, “Combination treatment with oxyplatlin and mangiferin causes increased apoptosis and downregulation of NFKB in cancer cell lines,” African Journal of Traditional Complementary & Alternative Medicines Ajtcam, vol. 8, no. 2, p. 177, 2011.
View at: Publisher Site | Google Scholar
P. Gener, D. F. d. S. Rafael, Y. Fernández et al., “Cancer stem cells and personalized cancer nanomedicine,” Nanomedicine, vol. 11, no. 3, pp. 307–320, 2016.
View at: Publisher Site | Google Scholar
J. E. Visvader and G. J. Lindeman, “Cancer stem cells in solid tumours: accumulating evidence and unresolved questions,” Nature Reviews Cancer, vol. 8, no. 10, pp. 755–768, 2008.
View at: Publisher Site | Google Scholar
S. Krishnamurthy, V. W. L. Ng, S. Gao, M.-H. Tan, and Y. Y. Yang, “Phenformin-loaded polymeric micelles for targeting both cancer cells and cancer stem cells in vitro and in vivo,” Biomaterials, vol. 35, no. 33, pp. 9177–9186, 2014.
View at: Publisher Site | Google Scholar
T. Klonisch, E. Wiechec, S. Hombach-Klonisch et al., “Cancer stem cell markers in common cancers—therapeutic implications,” Trends in Molecular Medicine, vol. 14, no. 10, pp. 450–460, 2008.
View at: Publisher Site | Google Scholar
J.-Y. Zhu, X. Yang, Y. Chen et al., “Curcumin suppresses lung cancer stem cells via Inhibiting wnt/β-catenin and sonic Hedgehog pathways,” Phytotherapy Research, vol. 31, no. 4, pp. 680–688, 2017.
View at: Publisher Site | Google Scholar
H. Lage, “An overview of cancer multidrug resistance: a still unsolved problem,” Cellular and Molecular Life Sciences, vol. 65, no. 20, pp. 3145–3167, 2008.
View at: Publisher Site | Google Scholar
S. Kunjachan, B. Rychlik, G. Storm, F. Kiessling, and T. Lammers, “Multidrug resistance: physiological principles and nanomedical solutions,” Advanced Drug Delivery Reviews, vol. 65, no. 13-14, pp. 1852–1865, 2013.
View at: Publisher Site | Google Scholar
N. R. Patel, B. S. Pattni, A. H. Abouzeid, and V. P. Torchilin, “Nanopreparations to overcome multidrug resistance in cancer,” Advanced Drug Delivery Reviews, vol. 65, no. 13-14, pp. 1748–1762, 2013.
View at: Publisher Site | Google Scholar
Q. Wu, Z. Yang, Y. Nie, Y. Shi, and D. Fan, “Multi-drug resistance in cancer chemotherapeutics: mechanisms and lab approaches,” Cancer Letters, vol. 347, no. 2, pp. 159–166, 2014.
View at: Publisher Site | Google Scholar
R. Misra and S. K. Sahoo, “Coformulation of doxorubicin and curcumin in poly(D,L-lactide-co-glycolide) nanoparticles suppresses the development of multidrug resistance in K562 cells,” Molecular Pharmaceutics, vol. 8, no. 3, pp. 852–866, 2011.
View at: Publisher Site | Google Scholar
G. Baronzio, G. Parmar, I. Shubina et al., “Update on the challenges and recent advances in cancer immunotherapy,” Immunotargets & Therapy, vol. 2, no. 1, pp. 39–49, 2013.
View at: Publisher Site | Google Scholar
H. Guo, Z. Zhang, Z. Su et al., “Enhanced anti-tumor activity and reduced toxicity by combination andrographolide and bleomycin in ascitic tumor-bearing mice,” European Journal of Pharmacology, vol. 776, no. 21, pp. 52–63, 2016.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2019 Qiushuang Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

1458

Downloads

1522

Citations