Rising horizon in circumventing multidrug resistance in chemotherapy with nanotechnology

Materials Science & Engineering C 101 (2019) 596–613

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Review

Rising horizon in circumventing multidrug resistance in chemotherapy with nanotechnology

T

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Hira Choudhurya,b, , Manisha Pandeya,b, Tan Hui Yinc, Taasjir Kaurc, Gan Wei Jiac, S.Q. Lawrence Tanc, How Weijiec, Eric Koh Sze Yangc, Chin Guan Keatc, Subrat Kumar Bhattamishrad, Prashant Kesharwanie, Shadab Mdf, Nagasekhara Molugulua,b, ⁎⁎ Mallikarjuna Rao Pichikab,g, Bapi Gorainh, a

Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Jalan Jalil Perkasa, Bukit Jalil, 57000, Kuala Lumpur, Malaysia Centre for Bioactive Molecules and Drug Delivery, Institute for Research, Development and Innovation, International Medical University, 57000, Kuala Lumpur, Malaysia Bachelor of Pharmacy student, School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia d Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia e Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India f Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia g Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia h School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Selangor 47500, Malaysia b c

A R T I C LE I N FO

A B S T R A C T

Keywords: Multidrug resistance Nano-delivery P-gp inhibition Effective chemotherapy, tumor-targeted delivery

Multidrug resistance (MDR) is one of the key barriers in chemotherapy, leading to the generation of insensitive cancer cells towards administered therapy. Genetic and epigenetic alterations of the cells are the consequences of MDR, resulted in drug resistivity, which reflects in impaired delivery of cytotoxic agents to the cancer site. Nanotechnology-based nanocarriers have shown immense shreds of evidence in overcoming these problems, where these promising tools handle desired dosage load of hydrophobic chemotherapeutics to facilitate designing of safe, controlled and effective delivery to specifically at tumor microenvironment. Therefore, encapsulating drugs within the nano-architecture have shown to enhance solubility, bioavailability, drug targeting, where co-administered P-gp inhibitors have additionally combat against developed MDR. Moreover, recent advancement in the stimuli-sensitive delivery of nanocarriers facilitates a tumor-targeted release of the chemotherapeutics to reduce the associated toxicities of chemotherapeutic agents in normal cells. The present article is focused on MDR development strategies in the cancer cell and different nanocarrier-based approaches in circumventing this hurdle to establish an effective therapy against deadliest cancer disease.

1. Introduction Cancer cells grow and divide uncontrollably, forming new abnormal cells rather than dying or entering into the process of apoptosis. Cancer can be divided into few categories, such as sarcoma, leukemia, lymphoma and myeloma, and brain and spinal cord cancers. Among these, few form solid tumors but some cancers involve circulating blood. Some tumors are benign, which don't grow uncontrollably and are not lifethreatening [1]. This disease has become one of the main causes of mortality globally, where the statistics from the World Health Organization (WHO) reported 12.4 million new cases of cancers along with 7.6

million deaths per year. For the treatment of cancer, chemotherapy was started back in the 1940s with the cytotoxic agent, nitrogen mustard. There was a development of chemotherapeutic from natural-origin in the 1960s, such as anthracyclines and vinca alkaloids, which are still in use for the treatment of cancers. Since then, about 50 types of chemotherapeutics agents are existing for treating around 200 types of cancers, however, the major drawbacks of such treatments include unavoidable side effects of myelosuppression, alopecia, loss of appetite, causing damage to other organs and chemotherapy -induced nausea and vomiting [2]. Apart from the severe toxicities, multidrug resistance (MDR) is

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Correspondence to: H. Choudhury, Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia. ⁎⁎ Correspondence to: B. Gorain, School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Selangor 47500, Malaysia. E-mail addresses: [email protected], [email protected] (H. Choudhury), [email protected], [email protected] (B. Gorain). https://doi.org/10.1016/j.msec.2019.04.005 Received 8 February 2019; Received in revised form 24 March 2019; Accepted 2 April 2019 Available online 06 April 2019 0928-4931/ © 2019 Elsevier B.V. All rights reserved.

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two transmembrane binding domains consist of 6–12 membrane-spanning alpha-helices, the main aspect to determine substrate specificity [15]. Expression of ABC transporters has been upregulated during cancer and thus, these transporters block the access of chemotherapeutic to their cellular targets by acting on the cellular compartments. The drugs are recognized by the transporters once the drug molecules internalized through the plasma membrane and expelled the drug molecules out of the cells using the energy derived from the hydrolysis of ATP as mentioned before and resulted in low bioavailability and resistance of the cancer cells towards the chemotherapeutics [2,13]. Besides, P-glycoprotein (P-gp) also takes part in cancer cells to remove anti-cancer drugs and develops simultaneous resistance to multiple chemotherapeutics. There are other drug pump proteins such as breast cancer resistance protein (BCRP) and MDR-associated proteins (MRPs) present within the human body, but they have different resistance profile and location in the body. LRP, also known as lung resistance-related protein mainly involved in intracellular transport processes including the delivery of anti-cancer drugs between the cytoplasm and nucleus. It alters the intracellular drug distribution and enhances drug efflux, which leads to MDR in cancer cells [2,16]. Alternatively, enzymes such as glutathione transferase (GST) have higher expression in solid tumors to deactivate and detoxify anti-cancer drugs. For example, platinum in cisplatin will be complexed with glutathione and removed from the cancer cells [2]. P-gp, being the main culprit of MDR that efflux the drugs out of the cells [14,17], is vital to have P-gp inhibitor to prevent the drug efflux out of the cells [18]. Thus, one of the strategies to overcome MDR would be co-delivery of chemotherapeutic along with P-gp inhibitor by nanoparticulate drug delivery approach, which has been represented in Fig. 1 [19]. A number of researches have been carried out with P-gp inhibitors (e.g., folate, curcumin, tetrandrine, etc.) to overcome the developed drug resistance in cancer cells [11,20,21]. Similarly, overexpression of the antiapoptotic protein involves Bcl-2 [22] also resulted in MDR, where modulating the expression of Bcl-2 family proteins could solve the intrinsic MDR problems [23]. Fig. 2 illustrates a few mechanisms of MDR in cancer cells such as the increased activity of ATP-dependent efflux pumps. Besides that, resistance can also occur when the influx of drug in the cell decreases and changes the drug accumulation, activation of detoxifying proteins like CYP450 and mixed-function oxidases. The third mechanism is when the apoptotic signaling pathway is disrupted which leads to cells becoming resistant to drug-induced cell death [24]. Consequently, many nanotechnological strategies have been developed encapsulating chemotherapeutics in nanocarrier to circumvent MDR and allows the anti-cancer drugs to cross the cell membrane to exhibit very low to zero off-target effects [2,13,25,26]. As discussed, inhibitors of protein efflux pumps can bind to the transporters and cause a conformational change to inhibit their exocytotic function. Alternatively, targeting the gene expression of MDR proteins [2,13], via small interfering RNAs (siRNAs), induce target mRNAs degradation in a sequence-specific manner [27]. Consequently, siRNA silences MDR genes and down-regulates MDR-related proteins, and thus allows the anti-cancer drugs to deliver successfully into the MDR cancer cells [2]. MDR may also result via production of oncogene epidermal growth factor receptor (EGFR) and desensitize of p53 gene [28,29]. The high expression of EGFR triggered DNA synthesis and cell proliferation [30–33], whereas mutation of p-53 lead to uncontrolled cell cycle and enhanced cell proliferation [34–36]. MDR might be due to ‘pre-target’, ‘on-target’ and ‘post-target’ resistance [37]. ‘Pre-target’ represent the ability of transporters such as Pgp to export drugs and decrease drug uptake [38,39]. ‘On-target’ refers to structurally or functionally alteration of the actual target of drugs. ‘Post-target’ means the alteration of key components or key regulators such as apoptosis-associated molecules ranging from Bax to Bcl-2 [40–42]. Besides, microRNAs (miRNAs) do play a role as gene expression regulators. Studies have reported that miRNAs could be able to reverse MDR and sensitize chemotherapy. The consequence of

another major drawback of chemotherapy. The cancer cells become insensitive or resistant towards administered therapy in MDR [3]. MDR towards chemotherapeutics occurs due to impaired delivery and epigenetic and genetic modifications of the drug sensitivity towards the cancer cell [4]. Poor absorption, increase in biotransformation or excretion of the administered chemotherapeutics leads to low concentration of drug in the blood, therefore the diffusion of drug to the cancer cells reduces. MDR has become the major barrier in achieving a successful clinical treatment in many cancer patients. Several genetic materials are over-expressed in cancer cells during chemotherapy, which protect the cancer cells and unfortunately leads to about 90% of treatment failure in cancer patients [2]. Progression of nanotechnologybased drug deliveries has brought a major breakthrough in cancer therapy. Unique physicochemical and biological characteristics make these nanocarriers a distinct category with decreased size range with increased surface area to cross different biological barriers with options to architect targeting ligand for specific cells [5]. Simultaneously, structural orientation of the tumor microenvironment, such as tortuous circulatory vessels, proliferating inner lining of endothelial cells, lack of perivascular cells, and abnormal basement membrane, allows enhanced permeation of the novel delivery tools, whereas poor lymphatic drainage in tumor area attributes enhanced retention of the therapeutics for a prolonged period [6]. Such enhanced penetration and retention (EPR) of the nanocarriers results in internalization of the carriers within the tumor microenvironment via pinocytosis, phagocytosis, endocytosis and micropinocytosis process [7]. Several studies over the worldwide scientists revealed that shape, size, and properties of nanocarriers determine their residual time in circulatory blood, to obtain passive targeting of the nanocarrier [8]. Alternatively, engineered nanocarriers with specific targeting ligand have been explored to achieve effective and safe treatment by targeting cancer cells or by targeting the cancerous endothelial cells [2,9–11]. Advantages of nanotechnology brought several multi-functional nanocarriers to combat against MDR with potential molecular mechanisms. Various experiments support hypotheses of nanocarrier to alter membrane transport-efflux protein, modulating apoptotic potential, improving DNA repair potential, altering pharmacokinetic and toxic properties of the chemotherapeutics against MDR [12]. In this current article, we have focused on several nanotechnological approaches to overcome the issues associated with MDR in cancer therapy. Before discussing on nanotechnological approaches against MDR, a brief discussion on the development of MDR has been represented in the connecting section. 2. Multidrug resistance in cancer cells Resistance to the chemotherapeutics can be developed against every effective chemotherapy. Possible mechanisms of such resistance development involve enhanced drug efflux from the cancer cells, reduced cellular uptake of the drug, activation of DNA repairmen, activation of drug detoxifying process, circumvention of drug-induced apoptosis, etc. Many factors can be contributed to MDR in cancer cells and one of the examples is due to ATP-binding cassette (ABC) transporters [13]. These transporters reduced the accumulation of chemotherapeutics in the intracellular cancer cells by blocking the access of anti-cancer drugs [2,14]. In addition, it will also use the ATP energy to efflux drugs out of the cancer cells and leads to low bioavailability and resistant to the drug [2,13]. ABC transporters are classified as those transporters of the cellular protein having a wide range of functions and can be found in both, prokaryotes and eukaryotes. Hydrolysis process of ATP to ADP provides the energy to these transporters for transporting a wide array of substrates across the membrane which is against the concentration gradient [15]. The human genome encodes 48 ABC transporter genes, which can further classify into seven subfamilies, ranging from A-subfamily of ABC transporters (ABCA) through G-subfamily of ABC transporters (ABCG) [13]. ABC transporter proteins consist of two transmembrane binding domains and two nucleotide-binding domains. The 597

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Fig. 1. Representation of conventional chemotherapy, where chemotherapeutic is efflux out of the cancer cell vs. the treatment condition with the approach to prevent efflux of chemotherapeutics' in the presence of P-gp inhibitor.

intracellular drug concentration while the expression of P-gp decreased [44,46]. Metal derivatives of a Schiff base viz. N-(2-hydroxy acetophenone) glycinate (NG) can deactivate c-Raf-1-kinase and ras signaling pathway to inhibit tumor growth in vivo and in vitro [47]. Besides, drug resistance can be overcome by modulating efflux pump or intracellular

downregulated miRNA expression, miR-508-5p, had been reported in different cancers [43]. Instantaneously, the increased expression of miR-508-5p shown a significant reduction in expression of ABCB1, Zinc ribbon domain-containing 1 (ZNRD1; regulator of Bcl-2) and P-gp [44,45]. Researchers have also investigated that increased expression of miR-508-5p leads to decrease in ZNRD1, which could increase in

Fig. 2. A representation of MDR in cancer cells. 598

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as compared to the formulation without FK506. A further test was performed on comparing PTX micelle (PTX/M) against PTX and FK506 co-loaded MPEG-PCL micelles (PTX-F/M) in sensitizing MDR cancer cell where, it was found that PTX-F/M triumph over PTX in terms of accumulation in A2780/T cells. Increased expression of Caspase-3, Caspase-8, and Caspase-9 was observed with PTX-F/M, which further lead to enhance tumor apoptosis. MPEG-PCL drugs delivery system have potential in fighting MDR cancer cells [76]. Alternatively, another group had developed gambogic acid(GA)-loaded mixed micelle system, which was made up of PEG-poly(L-histidine)-poly(D, L-lactide-co-glycolide) (PEG-pHis-PLGA) and D-α-tocopheryl polyethylene glycol 1000 (TPGS 1K). This micelle system was believed to be effective due to P-gp inhibition and down-regulation of anti-apoptotic proteins. The pattern of P-gp inhibitory effect as reflected by fluorescence emission in fluorometric MDR study were of, cells treated with GA/PEG-pHisPLGA/TPGS micelle (80.85) > cells treated with GA/PEG-PLGA/TPGS micelle (59.83) > control cells (24.49), which might be explained by the possible synergism of TPGS and GA, where further enhancement was observed in presence of histidine [79]. Although free DOX exhibited significant cell cytotoxicity against MCF-7 cells in a concentration-dependent manner, however, insignificant cell cytotoxicity was found against resistant MCF-7/ADR cells. Whereas, superior research outcomes of DOX-loaded TPGS 2000 micelles (DOX-TPGS-2K/M) in cell cytotoxicity against MCF-7 and MCF-7/ ADR cells compared to free DOX solution was due to the capability of DOX-TPGS-2K micelle in inhibiting P-gp mediated efflux of DOX out of MCF-7/ADR [80]. At the same time, Qiu and team had also reported DOX-loaded polymeric micelle composing hyaluronic acid-g-poly(Lhistidine) (HA-pHis) and TPGS 2K [DOX-HPHM/TPGS2K) mixed micelles. This micelle has a pH sensitive characteristics that could aid in increasing the cytotoxicity of DOX in MDR cancer cells. DOX-HPHM and DOX-HPHM/TPGS2K exhibited comparable DOX accumulation in a non-resistant cancer cell (MCF-7), which suggests that TPGS2K does not influence the recognition of CD44 receptors and pH-sensitive release. It was expected that DOX-HPHM would result in passive accumulation in tumor tissue and further internalization to the tumor cell through CD44 receptor-mediated endocytosis with the help of incorporation of HA, a CD44 ligand, and further incorporation of pHis enabled the endo-lysosomal escape through protonation of pHis moiety and lead to pH-sensitive DOX release to the cytosol (Fig. 3). TPGS2K incorporation would be expected to inhibit P-gp efflux and reversing the MDR effect (Fig. 3). P-gp is overexpressed in MCF-7/ADR compare to MCF-7 which can be reflected from 6.6 folds of DOX accumulation in MCF-7 cells with free DOX when compared to MCF-7/ADR. DOX-loaded HPHM/TPGS2K micelles has a 12.7 folds higher uptake into MCF-7/ADR resistant cells efficiency compared to free DOX and 1.8 fold greater than HPHM micelles. This shows that the combination concept of drug accumulation in the cancer cell as well as inhibition of P-gp efflux could serve to overcome the drawback of MDR cancer chemotherapy [75]. Interestingly, Genoxol-PM is a PEG-PLA polymeric micelle of PTX, developed by Samyang Company in Korea. PTX is encapsulated inside the hydrophobic core whereas the hydrophilic shell of the polymeric micelle prevent PTX from the reticuloendothelial system (RES) and increased circulation time. Increased maximum tolerated dose and the median lethal dose of PTX in mice with Genoxol-PM delivery was reported. However, Genoxol-PM is not effective against MDR cancer. Further, Fan and group developed PEG-PLA with TPGS mixed micelle containing PTX and reported to be biocompatible and capable of safely delivering PTX. The effectiveness of TPGS on reversing MDR A549 tumor cell was determined through conducting MTT assay of vinblastine-resistant subclone human oral epithelial cancer cell KBv and human oral epithelial cancer cell line KB, where they observed superior inhibitory effect of TPGS mixed micelle on growth of KBv cell compared to PEG-PLA micelles and free PTX whereas both the micelles exhibited strong cytotoxicity against the proliferation of KB cells. IC50 values were in order of 0.82 μg/mL (mixed micelle) < 7.08 μg/mL for PEG-PLA

glutathione (GSH) level [48]. Research by Majumder et al., proved that the copper complex of NG (CuNG) leads to doxorubicin (DOX) accumulation and retention in CEM/ADR5000 cells by inhibiting efflux pump. Besides, CuNG can also reduce the expression of P-gp to decrease efflux out of the drug from cells. CuNG does also downregulate the expression of GST-PI, GST-M1, and MRP1 which are thought to be responsible for DOX resistance [49,50]. Moreover, CuNG also depleted GSH in DOX-resistant Ehrlich ascites carcinoma (EAC/DOX) cells, which causes accumulation of DOX and induce apoptosis in EAC/DOX cells. Furthermore, downregulation of antioxidant capacity resulted in decreased reactive oxygen species (ROS) can confer resistance mechanism to chemotherapeutics due to toleration to exogenous stress and increased drug inactivation [51]. With this, CuNG could induce an intrinsic apoptotic pathway by the generation of ROS and lead to the reversal of MDR in DOX-resistant T-lymphoblastic leukemia cells, CEM/ ADR5000 [52]. One of the factors is hypoxia, which causes MDR through different pathways, such as p53-mediated apoptosis desensitization and increased P-gp expression [53]. Altered distribution of chemotherapeutics from the nucleus to cytoplasm is one of the factors too [54,55], whereas detoxification of chemotherapeutics by drug metabolizing enzymes is another factor of resistance development [56–58]. The chemotherapeutic agent is useless when the DNA damage repair efficiency is modified [59]. The topoisomerases changed the anticancer drug target to itself and cause MDR [60,61]. To overcome MDR, anticancer drugs which are not a P-gp substrate could be used, such as anthracyclinemodified drugs [62]. The use of MDR modulators reverse the MDR via chemosensitization and inhibiting MDR [63,64]. Nanocarriers could enhance the effect of drugs through tumor-targeting abilities [65]. Another approach is interfering the gene expression of the MDR gene by low-molecular-weight active moiety [66]. Combination of nanocarriers with anticancer and MDR modulators could sensitize the tumor and improve chemotherapy [67]. Moreover, the internal pH environment may also play a role in drug resistance. For instance, low pHe (extracellular pH) and pHi (intracellular pH) reduce the uptake of DOX which is a weakly basic drug [68–70]. Recent data shown that vacuolar-type (V-type) H+-ATPases which pump protons across plasma membrane can cause acidification and sensitize the tumor cells towards anticancer agents [71]. Therefore, the reduction in intracellular pH could promote cellular apoptosis [72,73]. Besides, several nanotechnological approaches have been made by the worldwide researchers to overcome MDR problem to obtain hassle-free chemotherapy. Connecting section of the article is focused to provide the available approaches by the researchers towards prevention of MDR in cancer therapy. 3. Nanotechnological approaches circumventing MDR in cancer therapy 3.1. Therapeutic implications of polymeric micelle in MDR Micelles are a globular structure consisting of hydrophobic fatty acyl chains facing into the core and polar head groups facing outwards. Micelles have attracted many cancer researcher's attention due to its unique properties such as the capability of encapsulating drug molecules and other co-polymer to form different micelle molecules [74]. These micelles have been extensively researched and many of the formulation scientists have reported an increase in cytotoxicity of the medication loaded. Formation of co-polymer micelles are even capable of fighting against MDR cancer cells [75]. Wang et al., formulated poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles of paclitaxel (PTX) and tacrolimus (FK506) by solid dispersion method [76]. FK506, an immunosuppressive agent, is a potent dose-dependent drug transporter inhibitor [77,78] which acts upon MRP-1, BCRP, and P-gp. MTT result represented an increase in cytotoxicity of PTX against A2780/T cells due to the presence of FK506 599

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Fig. 3. Schematic illustration of the approach to overcome MDR by DOX-loaded HA-PHis/TPGS2k mixed copolymer micelles (HPHM/TPGS2k) [75].

micelles < 25.00 μg/mL for free PTX against KBv. Mixed micelles were distributed more extensively and reached deeper in the A549 tumor spheroids than the PEG-PLA micelle [81]. Through analyzing the research outcomes of various authors on micelle delivery tool against MDR cancer cells revealed that micellar delivery approach along with the P-gp inhibitor can effectively be made for the treatment of MDR cancers for effective control of the cancer cell growth.

overloaded with RR are resistant to GEM [90,91]. Results showed that the level of RRM1 protein was significantly reduced when TC-1-GR treated with 4-(N)-GemC18-SLNs, which indicates that the 4-(N)GemC18-SLNs have the potential to downregulate the overexpression of RRM1 protein. This study also showed that the intracellular deoxycytidine triphosphate level was significantly reduced, which allows better incorporation of dFdCTP in the DNA as compared to the treatment with GEM HCl or 4-(N)-GemC18 alone in TC-1-GR cells [87]. [RR: ribonucleotide reductase, NDP: ribonucleoside diphosphates, hENT: human equilibrative nucleoside transporter, dNTP: deoxyribonucleotide triphosphate, dNDP: deoxyribonucleoside diphosphate, dFdCTP: gemcitabine trisphosphate, dFdCDP: gemcitabine diphosphate, dFdCMP: gemcitabine monophosphate, dCK: deoxycytidine kinase, CDA: (deoxy)cytidine deaminase]. In another study, the emulsification-sonication technique was used to load vorinostat (VOR) into SLN via hot homogenization. The final product, VOR-SLNs was tested against resistant human breast cancer cell (MDA-MB-231). During the in vitro cytotoxicity, VOR-SLNs were found to significantly inhibit cell growth in a time- and dose-dependent manner. The cytotoxicity level of VOR-SLNs was significantly higher than that of free VOR in resistant MDA-MB-231 and sensitive cells (MCF-7 and A-549) (Fig. 5). This distinct activity can clearly be explained by the fact that the improved cytotoxicity of VOR-SLNs may due to the lipophilic nature of the carrier, facilitating intracellular uptake [92]. Miao and team developed two novel SLNs by using solvent dispersion method with two anti-cancer drugs, PTX and DOX. It showed that PTX/SLN had lower IC50 value compared to Taxol when tested in the sensitive breast cancer cell MCF-7 as well in resistant MCF-7/ADR cell, the reversal power of PTX/SLN was 31.0 [93]. The cytotoxicity of PTX/ SLN was higher in MCF-7/ADR cell than MCF-7 cell which supports that SLN completely reverses MDR, might be via enhanced endocytosis and bypassed the drug efflux effect [93,94]. Besides, DOX/SLN also shown improvement about 6-fold compared to DOX solution in MCF-7/ADR and the reversal power of SLN was 4.3 fold, however, no much

3.2. Solid lipid nanoparticle in combating MDR It has been discussed earlier that overexpression of P-gp always lead to resistance to a variety of drugs and became one of the hallmarks of MDR cells [82,83]. In order to avoid drug efflux, nanotechnology approaches such as solid lipid nanoparticles (SLNs) have been successfully developed which are surfactant stabilized lipid matrix, solid at room and body temperature [84]. SLNs are widely used to deliver chemotherapeutic agents to MDR cancer cells to improve overall therapeutic effects [85]. Additionally, nanoparticles consist of lipid and solid matrix at room and body temperature are widely used to deliver chemotherapeutics to the MDR cancer cells with the advantage of physiological tolerability. In another study, gemcitabine (GEM, 2,2-difluorodeoxycytidine, dFdC) was incorporated in SLN to form 4-(N)-stearoyl gemcitabine SLN (4-(N)-GemC18-SLNs) and tested in GEM resistant mouse lung cancer (TC-1-GR). These cells lack human equilibrative nucleoside transporter1 (hENT1) or deoxycytidine kinase (dCK) which are essential to deliver anti-cancer drugs [86,87]. The function of hENT1 is to help to deliver GEM into cells whereas dCK helps to phosphorylate GEM to form GEM monophosphate (dFdCMP). dFdCMP forms the active metabolite, GEM diphosphate (dFdCDP) with the help of nucleotide kinase and slowly to the final active product, GEM triphosphate (dFdCTP) that inhibit the synthesis of DNA (Fig. 4) [88]. One of the functions of dFdCDP is to inhibit ribonucleotide reductase (RR), the enzyme involved in synthesis DNA components (Fig. 4) [89]. Hence, tumor cells that lack dCK or 600

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Fig. 4. A cartoon depicting how the uptake of gemcitabine, 4-(N)-GemC18 in solution, or 4-(N)-GemC18-SLNs influence their intracellular metabolism and activity against tumor cells [87].

effect of the SLN to the PTX, which evaded P-gp MDR effect and enhanced the intracellular drug efficacy and bioavailability [96,97]. Although Miao and team showed a complete reversal of MDR via SLN formulation, however, another group investigated that active targeting of SLN by attaching ligand can provide greater reversal effect of MDR. Bombesin (Bn)-modified, DOX-loaded SLN (Bn-DOX/SLNs) were formulated by another group [98]. It is important to mention that Bn is a 14-amino-acid peptide which can be found in amphibian tissues and

difference in cytotoxicity was observed with DOX/SLN and DOX solution against MCF-7 cell line. Although PTX/SLN and DOX/SLN did show positive results in SKOV3-TR30, the reversal power was not much appreciable, only 3.8 and 1.9 fold respectively [93]. Another study with PTX-SLN against human breast cancer cell line (MDA-MB-436), consists of multidrug resistance protein 1 (MDR1) gene that activates the effect of P-gp. PTX-SLN found to have lower IC50 value and higher internalization than free drug [95]. This can be explained by the shielding

Fig. 5. Cell viability following introduction of VOR-SLNs, blank SLNs, free VOR in MDA-MB-231, A549, and MCF-7 cells for a period of 24 or 48 h [92]. 601

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3.3. Potential role of nanoemulsion in MDR

Bn receptors have been found to be overexpressed in ovarian, breast, prostate, etc. [99,100]. Therefore, Bn was chosen as the ligand for DOX/ SLNs to obtain targeted delivery where the formulation was prepared by using the solvent-evaporation method and tested in DOX-resistant MCF-7/MDR cells [98,101]. The in vitro cytotoxicity level of DOX/SLNs was shown to have significantly higher than DOX solution (p < 0.05) whereas free DOX showed no significant effect on the cells due to the MDR effect of MCF-7/MDR cells. Further, Bn-DOX/SLNs exhibited better cell inhibition activity compared to DOX/SLN, which is due to active targeting of Bn. Simultaneously, in vivo antitumor study results in BALB/c mice bearing DOX-resistant MCF-7/MDR cells, revealed that the volume of tumor was significantly smaller in SLN group compared to without SLN group and smallest tumor volume was observed in BnDOX/SLNs group [98]. These indicate that SLN needs to have more modification in order to deliver anti-cancer drugs successfully into the MDR cancer cells. In summary, outcomes on various researchers with SLNs in treating MDR cancer cells, it is undeniable that SLNs have shown much improvement in terms of their effectiveness to deliver chemotherapeutic agents into the MDR cancer cells compared to free drugs, where active targeting additionally improves chemotherapy. The tabular representation of several SLN approached in the reversal of MDR in cancer therapy has been represented in Table 1.

Nanoemulsion (NE) is a combination of nanotechnology and emulsion. Nano means the droplets size is ranging from 20 nm to 200 nm [6,102,103]. NEs are the combination of pharmaceutical excipients, lipids(oils), surfactants and water, with key value with biocompatibility, biodegradable, reduced toxicity as well as easy to prepare and handle in pharmaceutical set up [104,105]. The main uses of NE are encapsulating the hydrophobic drugs to enhance its solubility, bioavailability, allows drug delivery targeting and most importantly, it has a vital role in chemotherapy [6,106,107]. NE is a potential tool because it is believed to have long circulation time and could accumulate in tumor cells by EPR effect and reduced unwanted tissue uptake [6,108]. Our previous reports on PTX NE system revealed this delivery system as a potential carrier to transport hydrophobic chemotherapeutics successfully to the cancerous cells without producing significant toxicities [107,109], however, those works were not focused on MDR. Different researchers targeted MDR via modified NE delivery. Baghbani and Moztarzadeh developed a new class of multifunctional ultrasound-responsive perfluorohexane NE, loaded with chemotherapeutic (DOX) and chemosensitizing agent (curcumin, CUR) [110]. CUR, the polyphenol constituent of turmeric, is reported to reverse MDR in cancerous cells because of its ability to suppress overexpression

Table 1 Solid lipid nanoparticular approaches of chemotherapeutics in the reversal of multidrug resistance in cancer therapy. Chemotherapeutic delivered

Type of cancer

Cell line

In vitro model

In vivo model

Outcome

Source

GEM

Mouse Lung cancer

TC-1-GR cell

GME resistant mouse lung cancer cell

Tumor induced mouse model with TC-1-GR

When TC-1-GR cells treated with SLN:

[87]

Human breast cancer

MDA-MB-231 cell

VOR resistant human breast cancer cell

N/A

Human Breast cancer

MCF-7/MDR cell

DOX-resistant human breast cancer cell

Tumor induced mouse model by MCF-7/MDR

VOR

DOX

PTX

PTX and DOX

Human Breast cancer

Human breast cancer and ovarian cancer

MDA-MB-436 cell

MCF-7/ADR cell and SKOV3-TR30 cell

effects increased • Cytotoxicity protein reduced • RR1 • Significantly inhibit tumor growth Drugs delivered by SLNs are more effective to treat MDR cancer cells. When MDA-MB-231 cell treated with SLN: suppression of cell proliferation • Significant in a dose- and time-dependent manner cytotoxicity • Increased Inhibitory effect was more prominent • SLNs enhanced the VOR bioavailability in

PTX-resistant human breast cancer cell that are resistant to

N/A

PTX and DOX-resistant human breast cancer cell PTX and DOX-resistant human ovarian cancer cell

N/A

treating MDR cancer cells. When MCF-7/MDR cell treated with SLN:

[98]

inhibition rate significantly increased • Cell Tumor volume decreased • Bn-DOX/SLNs reversed the resistance of drugs and may benefit on treating human breast MDR cancer. When MDA-MB-436 cell treated with SLN:

[95]

IC value • Lower Higher internalization rate • SLNs enhanced the drug bioavailability and 50

intracellular drug efficacy of MDR cancer cells. When MCR-7/ADR cell treated with SLN: IC value • Lower reversal power • Higher Higher cellular uptake percentage for PTX • SLNs improve the drug efficacy in treating 50

MCR-7/ADR cancer cells. When SKOV3-TR30 cell treated with SLN: power was not much appreciable • Reversal cellular uptake percentage for both • Lower drugs SLNs did not show much benefits in treating SKOV3-TR30 cancer cells.

602

[92]

[93]

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drastically decreased (270-fold) when treated with DTX-NE(folate) compared to DTX alone. This supports that FR mediated endocytosis does play a role in bypassing ABC transporter, however further studies are necessary to establish the concept behind it [119]. Similarly, Patel et al., has used a similar strategy to deliver platinum (Pt) [108]. The group incorporated di-fatty-acid platin to oil core of NE could possibly increase the loading efficiency of Pt in formulation and NE can increase the blood circulation time of Pt [108]. Surface functionalization with folate ligand (FA-PEG3400-DSPE) and further co-encapsulation of C6ceramide, a pro-apoptotic molecule in the NE significantly enhanced in vitro efficacy by inducing cell apoptosis [120]. Therefore, the potency is increased by 30 to 44-fold with modified NE of various aliphatic chain length compared to cisplatin in cisplatin resistance cancer cells (KBCR1000). This can be attributed due to surface functionalized NE delivery along with synergistic interaction of Pt and C6 ceramide to bypass the ABC transporter and alter the apoptotic potential of cells. Incorporation of di-fatty-acid platin, C6 ceramide and ligand for folate receptor in NE played a vital role in protecting drugs from premature inactivation and the nano size of NE could cause EPR [108]. Recent trend to deliver drugs directly to the brain via nose-to-brain route has attracted research attention, and our recent report has displayed the ability of intranasal teriflunomide microemulsion to circumvent rigid characteristics of blood-brain-barrier, where the nano-sized oil droplets of the incorporated drugs found to deliver directly via olfactory and trigeminal route [121]. Such formulations can be orchestrated to deliver efficiently to the cancer cells to fight against MDR. In general, NE is advantageous to bypass ABC transporter-mediated drug efflux by utilizing receptor-mediated endocytosis. Nanoemulsification approaches against MDR in cancer therapy has been represented in Table 2. Besides, the ability of NE to cause biphasic drug release of cancer chemotherapeutic may be advantageous for prolonged release and effectiveness. Additionally, NE does also play a role in inducing cell apoptosis. Last but not the least, surface functionalized NE could facilitate cellular uptake by increasing the drug circulation in blood.

of P-gp [111,112]. Multifunctional NE core exhibited higher entrapment of DOX in alginate shell may be due to adsorption of cation characteristics of DOX to anion characteristics of alginate molecules and the entrapment of CUR was increased due to the addition of SPAN 60 as a co-surfactant in NE [110]. Moreover, nanodroplets formulations are able to show a biphasic release mechanism in which rapid release of surface drug in the first 4 to 5 h followed by slow release of drug from the core up to 24 h. Low-frequency ultrasound caused higher drug release due to cavitation. In adriamycin resistant A2780 ovarian cancer cells, DOX-nanodroplets exhibited higher cytotoxicity compared to free DOX with a IC50 value of 6.5 ± 0.8 μg/mL and 44.3 ± 4.1 μg/mL respectively. The drastic lowered of IC50 value signifies nanodroplets of DOX bypassing the drug efflux mechanism to overcome MDR [110,113]. Furthermore, a significant reduction in the IC50 value of DOX-CUR-nanodroplets in drug sensitive and drug resistant cell line was also reported [110]. Furthermore, tumor cells inhibitory effects by DOX-CUR-nanodroplets in ultrasound treated group may be described by the mechanical effects of ultrasound for instance, cavitation, radiation forces and acoustic streaming which potentially trigger the release of drug by enhancing plasma membrane permeability and facilitate the entry of drug into the cells, thus, bypassing the efflux mechanism mediated by ABC transporter [110,114]. Another group co-encapsulated DOX and bromotetrandrine (W198) in lipid nanoemulsion to reverse MDR. W198 is known to be a potential P-gp inhibitor which possibly reverses MDR [18]. Along with internalization of NE via endocytosis, accumulation by EPR effect, NE also demonstrated a biphasic release profile of drugs. The drug release in a rapid manner in the first 12 h followed by prolonged release up to 120 h [18]. By incorporating W198 and DOX in lipid NE (DOX/W198-LNs), DOX was thought to be effectively delivered to targeted cells because DOX/W198-LNs was intracellularly released and inhibited P-gp on the cellular surface or nuclear membrane [115,116]. According to Cao et al, IC50 values were above 100 μg/mL in DOX resistance human breast cancer cells (MCF-7/ADR) for both DOX solution and DOX-LNs, where the value was dramatically decreased to 3.4 ± 0.12 and 1.2 ± 0.27 μg/mL with DOX + W198 solution and DOX/W198-LNs, respectively. Alternately, the drastic increase of intracellular DOX fluorescence intensity for DOX + W198 and DOX/W198-LNs signified an effective reversal of MDR by W198-LNs probably by inhibiting P-gp and facilitating the cellular uptake of DOX in MCF-7/ADR cells. Simultaneously, an increase in the rate of apoptosis of MCF-7/ADR cells treated with DOX + W198 solution is 20-fold while increased drastically by 30-fold for those treated with DOX/W198-LNs. The nuclear fragmentation and chromatin condensation signified the formation of apoptotic bodies in DOX + W198 and DOX/W198-LNs treated cells. In addition, the biodistribution of DOX in mice was obtained by ex vivo imaging, where, based on Fig. 6, DOX/W198-LNs displayed comparable higher DOX uptake by tumor tissue compared to DOX alone, DOX + W198 and DOX-LNs [18]. Reduced gastrointestinal injury and cardiac toxicity were observed in DOX/W198-LNs treated rats compared to DOX solution treated rats. Another research has been approached in MDR cells using NE delivery in addition of the role of folate receptors (FR). FR contains three isoforms namely alpha(α), beta(β) and gamma(γ), where FR- α mostly expressed in human ovarian, breast and lung cancers cells [117]. The distribution of FR- α on the cell surface allow them to have free interaction with folate-targeted NE [108,118]. Hence, folate-targeted NE [NE(folate)] was designed to utilize receptor-mediated endocytosis to deliver docetaxel (DTX) to bypass ABC transporter-mediated drug efflux because it is believed to be the main reason of drug-resistant. This NE (folate) was tested in taxane-resistant ovarian cancer cells (SKOV3/TR) and ovarian cancer cells (SKOV3), where IC50 of DTX against SKOV3 cells decreased by 3.33-fold when treated with DTX-NE(folate) compared to DTX alone, which may be due to general fusion of NE with cellular membrane and probably go through non-specific transport by phagocytosis. On the other hand, IC50 against SKOV3/TR was

3.4. Overcoming MDR with carbon nanotube Carbon nanotubes (CNTs) with unique cylindrical nanomaterial are one of the potential candidates for nanodrug delivery systems (NDDS). It consists of allotropes of carbon with hollow cylindrical nanostructure which are well-ordered, with a high aspect ratio, mechanical strength, surface area, ultralightweight, and excellent chemical and thermal stability [122]. Due to its rolled sheets of hexagonal arrangements, carbon atoms are valuable for nanocarrier, optics, electronics and other areas of material science and technology. Nanotubes can be categorized as single-walled nanotubes (SWCNTs) and multi-walled nanotubes (MWCNTs) [122,123]. Nevertheless, the size of CNTs (generally length) is equivalent to body cells diameter which makes them inappropriate for drug-delivery vehicles for cell endocytosis [124]. Hence, further investigation was performed on the effect of shortened CNTs on realtime reversal of MDR in the tumor. Their length was optimized by cutting and purifying them via ultrasonication and oxidative acid treatment. Then, the chemotherapeutic agent, DOX and P-gp inhibitor, verapamil (VER) were co-loaded on the shortened CNTs (VER/DOX/ shCNTs). With VER/DOX/shCNTs, VER was able to inhibit the transport activity of P-gp of MDR leukemia cells K562/A02, and also increased the intracellular concentration of DOX. Hence, it can be mentioned that the co-loaded reversal agent and chemotherapeutic drug with shortened CNTs can reverse the MDR in cancer cells which could be projected as a potential drug delivery tool [125]. Alternate approach on CNTs to overcome the problem of MDR in cancer, a CNTs-based radio-sensitive nanodrug delivery system had been designed to combat MDR in cancer, particularly against hepatocellular carcinoma. A potent ruthenium polypyridyl complex (RuPOP) was loaded in nanocarrier via π-π interaction and hydrogen bond. The cellular uptake of RuPOP in hepatic 603

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Fig. 6. Biodistribution of DOX in MCF-7/ADR-bearing mice, 6 h after the injection of control, DOX solution, DOX + W198 solution, DOX-LNs, and DOX/W198-LNs. (A) Whole body fluorescent images of MCF-7/ADR-bearing mice. (B, C) Representative fluorescent images of excised organs and tumors after termination of treatments [18].

novel MWCNTs system synergistically provides the chemotherapeutic agents as well as thermally active agents in order to overcome intrinsic MDR in chemotherapy [128]. Besides, a therapeutic semiconducting SWCNT (s-SWCNT) drug delivery system was developed to target CD44overexpressed MDR cancer cells. The targeted cells are drug-sensitive OVCAR8 and resistant OVCAR8/ADR cancer cells. In this study, the drug delivery system was developed using CD44 targeting cholanic acid-derivatized hyaluronic acid (CAHA) biopolymer that self-assembled onto s-SWCNTs and loaded with DOX (CAHA/s-SWCNT/DOX). Targeted CAHA/s-SWCNT/DOX killed OVCAR8/ADR cancer cell much more effectively compared to free DOX and phospholipid PEG-modified s-SWCNT loaded DOX (PL-PEG/s-SWCNT/DOX). Viscoelastic responses of the drug-resistant cells and further drug internalization are better with CAHA/s-SWCNT/DOX than free drug and non-targeted PL-PEG/sSWCNT/DOX. Intravenous administration of targeted CAHA/s-SWCNT/ DOX (equivalent 12 mg/kg DOX dose) along with photothermal therapy is resulted in complete eradication of subcutaneous OVCAR8/ADR MDR tumors in xenograft model while free DOX even failed to delay tumor growth [123]. Therefore, CNTs are developed and designed in order to overcome the problem in MDR due to its unique characteristics. These include its rolled sheets of hexagonal arrangements, which are well-ordered, having a high surface area and its ability to lo load chemotherapeutics drugs and acts as a sensitizer to enhance drug internalization. Different approaches of CNT based deliveries in overcoming the MDR barrier in cancer therapy has been presented in Table 3. Hence, CNT based drug delivery system can enhance therapeutic efficacy against drug-resistant cancer cells due to its ability to load chemotherapeutic drugs along with other possible modifications to improve delivery of chemotherapeutics.

cancer cells, especially drug-resistant R-HepG2 cells was enhanced through functionalized RuPOP/MWCNTs nano-system, via endocytosis. Intravenous administration of RuPOP/MWCNTs resulted in a significant increase in blood circulation time of RuPOP in experimental mice. Simultaneously, this nano-system improved the efficacy of the chemotherapeutic agents and decreased associated toxic side effects of chemotherapy and radiotherapy. As for radiotherapy, RuPOP/MWCNTs enhanced the sensitivity of R-HepG2 cells towards X-ray radiation. Therefore, the use of high dosages of radiation can be avoided, which usually damages the normal cell and lead to the secondary tumor [126]. Another study was conducted to investigate the ability of MWCNTs to suppress c-Myc, a proto-oncogene which is responsible in regulating ABC gene expression. This study was done using human colon adenocarcinoma Caco-2 cells which constitutively express ABC transporter. A parallel decrease in c-Myc expression and expression of ABCB1/P-gp and ABCC4/MRP4 was observed in the Caco-2 cell model, provide evidence on MWCNTs induced downregulation of c-Myc and ABC transporter expression, thus may MWCNTs delivery system increase the accumulation of chemotherapeutic drugs in cancer cells. Cell membrane and MWCNT interaction and oxidative damage of cell membrane were observed, however, antioxidants such as vitamin C, dimethylthiourea and β-mecaptoethanol were unable to antagonize the down-regulation of ABC transporters by MWCNTs which evidenced that MWCNTs may be acting through c-Myc, not through oxidative stress [127]. Furthermore, a nano-biosystem based on PEGylated MWCNTs (MWCNTs/PEG) e was developed to target mitochondrial membrane depolarization mechanism in order to cause immediate cellular apoptosis in pancreatic cancer cells (PANC-1). The photothermal effect of this MWCNTs/PEG on pancreatic cancer cell was studied by analyzing mitochondria potential and caspase activity laser irradiated cells. The result showed that administration of MWCNTs/PEG with laser irradiation can depolarize the mitochondrial membrane which activates free radicals flux within the cell and cellular damage mediated by the oxidative state via apoptotic pathways. The group concluded that the

3.5. Dendrimer in overcoming MDR in cancer Dendrimers are characterized by its hyper-branched, nano-sized, well-defined structure with a high degree of symmetry. There are many cavities inside the dendritic structure and the surface of the dendrimer 604

DOX and CUR

DTX

Platinum (Pt)

DOX

NE

Folate-targeted NE

FA-PEG3400-DSPE functionalized NE

NE with bromotetrandrine

Breast cancer

Ovarian

Ovarian Breast Lung

Ovarian cancer

Type of cancer

605 Leukemia

Colon adenocarcinoma Pancreatic cancer

VER and DOX

–

–

DOX

Shortened CNT

MWCNT

PEGylated MWCNT

CAHA/s-SWCNT

Ovarian cancer

Hepatocellular carcinoma

Anticancer ruthenium polypyridyl complex (RuPOP)

MWCNT

Type of cancer

Chemotherapeutics delivered

Delivery approach

Drug-sensitive OVCAR8 and resistant OVCAR8/ADR cancer cells

PANC-1

Caco-2 cell line

MDR leukemia cells K562/A02

MDR Hepatocellular Carcinoma cell lines (R-hepG2)

Cell line

Nude mice xenograft model

OVCAR8/ADR tumors in xenograft mice model

–

–

–

Mouse model with Hepatocellular Carcinoma

In vivo model

Resistant human breast cancer (MCF-7/ADR)

N/A

50

to protect drugs from premature inactivation and could cause • Vital EPR effect increase Pt circulation in blood cellular uptake • Enhanced was increased for DOX + W198 solution and DOX/ • Cytotoxicity W198-LNs compared to DOX solution and DOX-LNs. has shown a greater rate of apoptosis compared to • DOX/W198-LNs DOX alone and DOX-LNs in MCF-7/ADR cells

FA-PEG3400-DSPE functionalized NE co-loaded with di-fatty-acid platin and C6 ceramide:

50

50

exhibits higher cytotoxicity compare to free DOX against • DOX-NDs A2780 ADR cell Significant reduction in the IC value of DOX-CUR-nanodroplets in • drug sensitive and drug resistant cell line was observed cells inhibitory effects were also seen in DOX-CUR-NDs with • Tumor ultrasound treated group. against SKOV3 cells decreased by 3.33-fold when • ICtreatedof DTX with DTX-NE(folate) compared to DTX alone of DTX against SKOV3/TR decreased by 270-fold when treated • ICDTX-NE (folate) compared to DTX alone.

Outcome

model.

killed OVCAR8/ADR cancer cell • Effectively viscoelastic responses of the drug-resistant cells and further resulted • Affect in better drug internalization administration along with photothermal therapy resulted in complete • IVeradication of subcutaneous OVCAR8/ADR MDR tumors in xenograft mice

CAHA/s-SWCNT/DOX

mitochondrial membrane—activates free radicals flux—cellular • Depolarize damage mediated by the oxidative state via apoptotic pathways

MWCNT/PEG combined with laser irradiation

parallel decrease in c-Myc expression and expression of ABCB1/P-gp and • AABCC4/MRP4 were observed in the Caco-2 cell model

transport activity of P-gp of MDR cancer cells

blood circulation time of RuPOP significantly in experimental • Increased mice efficacy and reduced associate toxicity related to chemotherapy • Increased sensitivity of R-HepG2 cells towards X-ray radiation • Enhanced CNTs co-loaded with DOX and VER resulted in the increased • Shortened intracellular concentration of DOX whereas VER was able to inhibit the

Outcome

SKOV3 tumor-bearing mice

Taxane resistant ovarian cancer cells (SKOV3/TR) And ovarian cancer cell (SKOV3) Cisplatin-resistant KB cells (KBCR1000)

Ovarian cancer bearing mice models.

In vivo model

Adriamycin resistant ovarian cancer cells (A2780 ADR)

Cell line

Table 3 Carbon nanotube approaches circumventing multidrug resistance in cancer therapy.

Chemotherapeutic(s) delivered

Delivery approach

Table 2 Nanoemulsification approaches in chemotherapy in combating multidrug resistance cancer.

[123]

[128]

[127]

[125]

[126]

Source

[18]

[108]

[119]

[110]

Source

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siRNA loaded PAMAM complex (HSPCs) against normal cells was observed in MTT assay (cell viability > 90%) [140]. HSPCs released strong fluorescence signals in CSLM assay [140] due to the amino group on the surface of the PAMAM increased the proton-sponge effect which aided in releasing siRNA into the cytoplasm [141,142]. A test on P-gp (MDR1) silencing efficacy of HSPCs demonstrated the alteration of MDR1 mRNA levels. Around 99.4% knockdown in MDR1 expression in the MCF-7/ADR cells was achieved by HSPCs. The results were further supported by combining DOX with HSPCs, where, increased DOX accumulation in MCF-7/ADR was observed and a combination of PTX with HSPCs enhanced PTX effect, which is reflected by enhanced MCF7/ADR cells growth inhibition and induced greater apoptosis in MCF-7/ ADR cells [140]. In another study, amine-terminated G5 PAMAM dendrimer (G5.NH2) modified selenium nanoparticles (SE-NP) has been developed for dual delivery of a therapeutic small interfering RNA (siRNA) and chemotherapeutic agents, cisplatin (cis-diamminedichlorplatinum-(II), DDP) [Se-DDP-siRNA-NP]. The accumulation of siRNA from Se-NPDDP-siRNA was 80%, suggests Se-DDP-siRNA-NP released siRNA effectively and persisted good potential to inhibit MDR and also demonstrated good gene-silencing efficacy. High transfection efficiency was observed with Se-DDP-siRNA-NP, which might be due to high buffering capacity of primary, secondary and tertiary amine groups in nanocarrier. This dendrimer nanocarrier can be used as an effective gene carrier due to its high transfection efficacy. Along with high transfection efficiency, it was also observed that Se-DDP-siRNA-NP could also effectively distribute siRNA and DDP into cells [143]. The outcomes depicted that the cellular uptake of Se-NP-DDP-siRNA is higher and effective in escaping from endosomes [143,144]. G5-Se-NP appeared to be less toxic than G5.NH2 dendrimers in both normal cell (HEK293) as well as in cancer cells (A549 and A549/DDP cells). Attachment of Se-NP in G5.NH2 could decrease the toxicity of dendrimer. Whereas, both Se-NP-DDP with or without siRNA could produce greater apoptosis in A549/DDP, 23.9%, and 46.2%, respectively. This showed that the Se-DDP-siRNA-NP could increase the cytotoxicity in A549/ DDP. Se-DDP-siRNA-NP is also effective in downregulating the P-gp expression in A549/DDP cells, as a summary, the Se-DDP-siRNA-NP can effectively increase the accumulation of DDP and siRNA in the A549/ DDP via inhibiting P-gp. Furthermore, animal studies demonstrated a significant enhancement in the anti-tumor efficacy of Se-DDP-siRNA on tumor-bearing nude mice, with no appreciable abnormality in the major organs (Fig. 7) [143]. In contrast, one of the studies reported that the delivery of chemotherapeutics using dendrimer platform could not improve the efficacy of the anticancer drug. The authors used amine-terminated PAMAM dendrimers in this study against MCF-7 and MCF-7/ADR cell lines. PAMAM-NH2 exerted significant cytotoxicity effect against MCF7/ADR and MCF-7 cells in high concentration (100–1000 μg/mL), whereas at low concentration (10–50 μg/mL) it was low cytotoxic. Further, the cytotoxicity of PAMAM-NH2 in MCF-7/ADR was lower than MCF-7 cells, which may be due to lower uptake efficiency of PAMAM-NH2 in MCF-7/ADR and the higher excretion from the resistant cells [145,146]. The increase of uptake efficiency by PAMAMNH2 was proven by incubating PAMAM in MCF-7 and MCF-7/ADR with P-gp inhibitor and outcome was increased cellular efficacy but no change in uptake rate, which means the inhibitors had no effect on uptake rate of PAMAM. The exocytosis of PAMAM in MCF-7/ADR was found to be decreased. Therefore, the high exocytosis and low endocytosis of PAMAM in the MCF-7/ADR was due to P-gp and protein of MDR [146]. A different research on polypropylenimine (PPI) dendrimer with Pluronic-123 (P-123) conjugated to transport the pDNA-iMDRI-short hairpin (sh) RNA to the nucleus by reversing the MCF-7/ADR cell lines [147]. It has already been reported that the P123-PPI had low toxicity and greater gene transfection efficiency [148]. An anti-CD44 antibody was added into P-123-PPI to form anti-CD44-P123-PPI, which enhanced

contain large numbers of the functional group which can be modified for the improvement of the delivery system [129]. It is used to increase the solubility and bioavailability of poorly soluble drugs and protects the drug against premature elimination and through covalent conjugation or physical loading in the interior cavity, it possesses high loading efficiency for drugs. The dendrimers have advantages like small particle size, which make them easy to be transported into the cancer cells and enhance the accumulation of anticancer drugs in the cells. Besides, high encapsulation of drugs in the dendrimer, it is stable and will be released when reaching the target sides. The most commonly used dendrimer is polyamidoamine (PAMAM) which is a cationic dendrimer used to deliver chemotherapeutics as well as genetic materials [129–133]. A research on PTX, a chemotherapeutic and borneol (BRL), a natural P-gp inhibitor co-loaded PAMAM dendrimer modified with PEG (PTXBRL/PEG-PAMAM) to neutralize the positive charge of amine groups and enhance biocompatibility [134–136] demonstrated sustained-release profiles (60% released at 240 h). Enhanced intracellular concentration and improved cellular uptake of PTX in PTX resistant A2780 (A2780/PTX) cell lines were achieved for both PTX-BRL/PEG-PAMAM and PTX/PEG-PAMAM + BRL [136,137]. The use of dendrimer with PTX in presence BRL had shown to reverse the MDR in cancer cell via obstructing the function of mitochondria by inhibiting intracellular ATP production. Since P-gp required ATP to control the entry of the drugs, the reduction of ATP lead to the reversal of MDR. PEG-PAMAM plays an important role in inhibiting MDR, which is very clear from a higher reduction in ATP level in PTX and BRL dendrimer group and PTX dendrimer + free BRL compared to free PTX + BRL group. Resulting ATP inhibition partly because of BRL presence and PTX dendrimer delivery. The combined effect of PTX, BRL in PEG-PAMAM increased the rate of apoptosis when compared to PTX alone which indicated that the apoptotic effect had been reinforced due to boosted cell endocytosis. In vivo outcomes were in line with the results of tumorbearing nude mice towards the reduction of tumor growth [136]. Although, similar tumor accumulation was observed in both PTX + BRL dendrimer and PTX dendrimer + free BRL groups, however, significant reduction in tumor growth was observed in PTX + BRL dendrimer group in A2780/PTX tumor-bearing mice compared to PTX dendrimer + free BRL group, which represented the advantages of co-delivery of PTX and BRL PEG-PAMAM nanocarrier in MDR chemotherapy. In another study, PAMAM is modified by phospholipid (PL) and loaded with siRNA targeting MDR1 gene (PL-PAMAM/siMDR1) [138]. The PL aided by interacting with the cationic charged dendrimer to produce complex formation, while the lipid elements help to interact with the plasma membrane to stimulate endocytosis of the drug-complex and increase the gene silencing efficiency (small interfering RNA (siRNA) targeting MDR1) [139]. Evaluation of cellular uptake of siRNA through PL-PAMAM/siMDR1 delivery in MDR breast cancer cell line (MCF-7/ADR) by confocal laser scanning microscopy (CLSM) revealed that siRNA was protected from degradation of lysosomal enzymes and discharged into the cytoplasm. The outcome of Western-blot assay revealed reduced expression of P-gp to 95.6% when treated with PLPAMAM/siMDR1 whereas only 16.5% was observed with naked siMDR1, which further represented the contribution of PL-PAMAM dendrimer in reversing MDR by effectively hindering the p-gp expression. This PL-PAMAM dendrimer delivery system exhibited appreciable efficiency in gene delivery efficiency along with higher cellular uptake. Moreover, PL-PAMAM/siMDR1 system inhibit p-gp efflux function and impaired cell-migration behaviors. In concluding remark, the group mentioned that PL-PMAMA complex could be a potential vector for siRNA delivery in MDR human breast cancer [138]. Another research on PAMAM dendrimer loaded with nimotuzumab (IgG1 humanized epidermal growth factor receptor inhibitor monoclonal antibody) modified siRNA against MDR human breast cancer MCF-7/ADR cells provided an impressive result. Reduced cytotoxicity effect with improved biocompatibility of nimotuzumab (hR3) modified 606

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Fig. 7. Plan of PAMAM dendrimers modified selenium nanoparticles was designed for systemic dual-delivering mdr1 siRNA and DDP to reverse drug resistance [143].

were successfully delivered with a sustained release profile of the drugs. The efficacy of the liposomal composite on the drug-resistant tumor in mice was significant (p < 0.01) without causing any increase in the toxicity of the incorporated anti-tumor drugs [152]. In a recent study, there was a systemic administration of the PEG–HA-modified liposomal siRNA delivery system (PEG–HA–NP) with anti-γ-glutamylcyclotransferase (GGCT) siRNA for the drug-resistant MCF-7 breast cancer therapy. The transferring of the anti-GGCT siRNA with the PEG–HA–NP into the cells of naked or purified nucleic acid could downregulate the tumor-related protein, glutamylcyclotransferase (GGCT) and also associated to trigger the cell cytotoxicity against the resistant breast cancer cells (MCF-7/ADR cells). With the route of systemic administration, the PEG–HA–NP with siRNA can significantly suppress the growth of the tumor and subsequently provide the action of the destruction of the tumor cell at a dose of 0.35 mg/ kg. This superior activity is observed because PEG-HA-NP has high drug retention in the circulation and increases the cellular uptake efficiency of the drug. This administration did not show any unfavorable side effects to the normal cells, thus suggesting a novel pathway to solve the problem of the MDR of the cancer therapy [153]. Correspondingly, Xia and team reported that the co-delivery of the MDR1 siRNA with the anti-cancer drug can significantly inhibit the proliferation of MDR tumor. The polydiallydimethylammonium chloride (PDADMAC) coated liposome was synthesized to carry siMDR1 carrier (AL-PDAD-RNA) which had been applied for reversing the drug resistance of DOX in OVCAR8/ADR cells. The siRNA was reported to be loaded successfully by AL-PDAD-RNA and released effectively under physiological condition, which has provided the evidence of improved tumor inhibition. Therefore, this newly invented siRNA-liposomal carrier has a simple structure with high efficacy against MDR without producing any toxicity to the normal cells [154]. Similarly, an approach to entrap DTX and siRNA against the ABCG2 gene was used for the treatment of laryngeal cancer. The cancer cells of squamous morphology were targeted by the DTX/ABCG2-siRNA liposomal molecules via attachment of EGFR-targeting ligand, GE11 [154,155]. The quantities of the chemotherapeutic agent entered into the Hep-2 laryngeal cancer cells were enhanced due to the presence of the GE11 peptides on the structure of the liposomes.

the efficiency of transfection because of increased specific receptor binding. The result stated that anti-CD44-P123-PPI had the highest expression due to a polycation, which can condense pDNA to produce polycation/pDNA complexes that attached to the cell membrane to enable endocytosis by the positive charge of the surface. The Pluronic copolymer enhanced the endocytic processes in eukaryotic cells and elevate cellular uptake thereby increase the transfection of the complexes [147]. The cellular uptake of the P123-PPI/pDNA nanocomplexes in MCF-7/ADR was more than that in MCF cells, this could be deduced that the Pluronic had prior selective effects to the MDR cells [149]. This indicated that the P-gp was downregulated and the drug efflux was weakened [147,150]. Thus, dendrimer-based nano-delivery system can be considered as a suitable carrier for chemotherapeutics as well as for genetic materials, however, it could be targeted by incorporating cancer cell specific ligands to deliver the complex specifically to the targeted cancer cells to act and reverse developed MDR characteristics.

3.6. Liposome based approaches against MDR Liposomes are the intracellular vesicles, the function of which is to deliver organic substances (nutrients and drugs) in and out of the cell and between different parts of a cell. Liposomes are normally shaped by “pinching off” a portion of the phospholipid bilayer of the cell. The outer layer of the liposome will be merged into the cell membrane of the recognized cell, thus help in transportation of hydrophilic substances to the target site [151]. Similar to other nanocarriers described above, liposomal deliveries are also projected towards reversal or improved delivery of chemotherapeutics in the MDR cells. For example, resveratrol with PTX was delivered via the PEGylated liposome for the treatment of drug-resistant tumor. The result showed that the composite liposome enhanced the cytotoxic effect against the drug resistance MCF-7/ADR tumor cells and induced significant necrosis and apoptosis of the cell as compared to free drug. By liposomal drug delivery, the bioavailability and the pharmacokinetic profile of the anti-cancer drugs were improved, including tumor retention of the incorporated drugs. By the help of the liposomal approach, the poor chemotherapeutic agents 607

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incorporated cisplatin into the cytoplasm of the resistance cancer cells. The LR-peptide loaded with pH-sensitive liposomes showed the activity of cell inhibition at short incubation time, whereas the conventional liposomes are unable to exhibit cell inhibition activity, however, incubation for longer duration resulted in similar efficacy [162]. Similarly, epirubicin (Epi) was incorporated in PEGylated liposomal delivery as an anticancer delivery system [163], where reversal of drug resistance mechanism of Epi via targeting MDR1, MDR-associated protein 1 (MRP1), MRP2 and BCL-2/CL-was utilized [164]. This shown that PEGylated liposomal Epi and antisense oligonucleotides could reduce Bcl-2 expression and induced the expression of BAX, p53 (normally trigger for apoptosis), caspase-3, -8 and -9 (possibly increase chemosensitivity of cancer cells) [165]. Recent approach on cationic PEGylated liposomal delivery of Epi together with an antimicrobial peptide, hepcidin 2–3, resulted in programmed cell death of tested cervical cancer cell, where modulation of autophagy, apoptosis, MDR transporter and/or necroptosis triggered to assist reducing acquired resistance against treated chemotherapeutic agent [166]. Moreover, a liposomal tool could protect the drug from degradation and metabolism, thus could enhance the permeability and retention with improved internalization mechanisms. Therefore, liposomes could be a suitable tool to be used as the drug carrier because it can significantly reduce the incident of the MDR tumor, shortening the time taken for drug delivery and increase the therapeutic index of the anticancer drug.

Simultaneously, the cytotoxic effect towards the Hep-2 laryngeal cancer cells was also enhanced by the GE11 peptide-conjugated liposomes when compared with free drug treatment. Therefore, such increased activities resulted in significantly enhanced anti-tumor activity and significant improvement in the process of apoptosis of cancer cells using GE11 peptide-conjugated liposomes. In vivo experimental results in the Hep-2 xenograft-bearing nude mouse model was as per the in vitro findings with reduced toxicities than free DTX [154]. Another study demonstrated the approach against MDR in MCF-7/ ADR mice via co-delivery of the nanoliposome encapsulated of the combination of drugs, DOX and PEGylated C16 ceramide (Lip-DOX-Cer) [156]. This co-delivery method given the probable synergistic benefits for the combined drugs to simultaneously target the drug-resistant tumor, where the total dose of injected lipid was also reduced by this co-delivery approach [157]. The superior anti-tumor activity of LipADR-Cer over the Lip-ADR was observed in mice bearing MCF-7/ADR or HL-60/ADR xenograft tumor, which could be explained by the enhancement of both, cytotoxic effect of the PEG-C16 ceramide and glucosylceramide synthase overexpression in the drug-resistant tumor. PEG-C16 ceramide can increase cellular intake of the anti-cancer drug, whereas Lip-ADR-Cer did not show any toxicity against normal cells, suggesting the potential of treating resistant cancer cells [156]. Through the process of conjugation of the DOX-liposome (DL) to the surface of the microbubbles (MB) by the help of the biotin-avidin linkage, the DLMC is successfully developed. In due course of experiments, the resistant breast cancer cells, MCF-7/ADR were incubated with the drug-loaded complex DLMC, followed by the exposure of ultrasound. The result of which indicated more rapid cellular uptake, enhancement of nuclear accumulation and lesser efflux of the drug compared to those treated by using DOX only (DL), DOX and verapamil under same circumstances, same ultrasound exposure or DLMC treatment without using ultrasound. Moreover, the improvement in the delivery of the drug and the cellular uptake also accompanied with the intensification of the cytotoxic effect against the MCF-7/ADR, decrease the viability of the MCF-7/ADR cells, and more frequent apoptosis of the breast cancer cells. The MCF-7/ADR with exposure in ultrasound had shown a significant surge of ROS, enhanced the damage of DNA, and apparent dropping of the P-gp within the cells [158]. Therefore, by using the DLMC with the help of ultrasound, it can improve the drug delivery avoiding the drug-resistant problem as well as increase the therapeutic index of the anti-cancer drug. Similarly, DOX and PTX were co-delivered via crosslinked multilamellar vesicles (cMLV) to enhance drug accumulation and retention for improved cytotoxicity against MDR cell [159]. This delivery reported to reduce the expression of P-gp and lower apoptotic threshold of drug. cMLV caused internalization through caveolin-dependent endocytosis and trafficked through the endosome-lysosome network for drug release [160]. In the research by Liu et al., it was shown that codelivery of DOX and PTX in cMLV was effectively enhanced cytotoxicity in drug-resistant cells by increasing drug accumulation and retention of drug, which might be due to the ability of nanoparticles [159,161]. Besides, co-administration of DOX and PTX via cMLV could produce a synergistic effect in suppressing P-gp expression. Thus, co-administration of DOX and PTX in cMLV formulation shown increased efficiency over cMLV monotherapy by increasing apoptotic response [159]. The liposomal vesicles were designed and characterized for the LRpeptide. The hydrophilic LR-helps to decrease the drug resistivity of the cancer cells through downregulation of human thymidylate synthase and thereby helps in the reversal of cisplatin resistance. This tool was used to evaluate the advantages of pH-responsive feature in enhancing the delivery of chemotherapeutic agents, intracellularly. In due course, there were two different liposomal deliveries were formulated, the conventional liposome and pH-sensitive liposomes. The LR-peptide loaded liposome vesicles were able to decrease drug resistance response of cancer cells because changes in the pH-triggered (at the pH 5.5) in altering of the size of the liposomes and causes the release of the

3.7. Inorganic nanoparticular approaches to combat against MDR Inorganic nanocarriers to approach against MDR are gaining interest due to their nanoporous structure, which can encapsulate the therapeutics agents within their nanoenvironment. Photodynamic or photothermal, magnetism, energy irradiation transferring property to heat or hyperthermia characteristics make this inorganic nanoparticular approach a potential tool against MDR [167]. A pH-responsive TPGS-functionalized polydopamine-coated mesoporous silica NPs (MSN-DOX@PDA-TPGS-NP) were reported to deliver DOX to the drugresistant lung cancer (A549) cell lines. The authors reported an outstanding capacity of MSN-DOX@PDA-TPGS-NP towards overcoming the MDR in resistant A549 cells, compared to the free DOX or DOXloaded NPs without TPGS [168]. Simultaneously, multi-stimuli responsive mesoporous silica NPs were also focused on in vivo experiments to reveal its multiple actions against MDR. Thus, Yang and team had developed sulfhydryl and amino-co-functionalized mesoporous silica NPs (SH/NH2-S-NPs), which was further architected with HA via the sulfhydryl groups for targeting the cancer cells. Such multifunctional silica NPs achieved the enzyme and redox-sensitive release of the incorporated DOX within the MCF-7/ADR cellular stimuli, which deliver the formulation to the targeted cells. Simultaneously, the tool was found to escape endolysosomal metabolism, and able to remain within the cytoplasm to achieve the strongest cytotoxicity and apoptosis by the resistant breast cancer cells. Such a delivery tool was found to possess improved tumor targeting potential with enhanced therapeutic efficacy in tumor-bearing xenograft mouse to reverse MDR cancer [169]. Thus, it could be demonstrated that this silica NP platform can be decorated to deliver hydrophilic and hydrophobic therapeutics targeted to the cancer cells. Studies also demonstrated delivery options of genetic materials to modify MDR expressions in cancer cells. With this aim, Sun and team developed a novel silica NPs to entrap larger genetic material (siRNA) and smaller drug molecule (DOX) within the shell and core. Such genetic materials, upon release within the cancer microenvironment, were found to down-regulate expression of MDR protein, P-gp on the cell surface. The additional co-delivery system was found to regulate cancer progression in a better way to fight effectively against MDR cancer [170]. Exploration of carbon nanotube (CNT) in medicine has gained remarkable recognition to provide a synthetic but viable 608

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which few are at various stages in the clinical research. CYT-6091 a novel nanocarrier, made by binding recombinant human tumor necrosis factor alpha (rhTNF) to the surface of colloidal gold NPs, was tested in Phase I clinical trial against advanced stage solid tumor. Surprisingly, the outcome of the trial results displayed that the toxic dose of rhTNF can be administered systemically in the CYT-6091 dosage form to target advanced stages of non-resectable cancers [179]. Another candidate, CPC634, CriPec®-polymeric NPs with DTX, was projected towards application in platinum-based chemotherapy-resistant ovarian cancer patients. Such formulation was designed to accumulate within the tumor microenvironment, localized drug release, with enhanced therapeutic efficacy [180]. Primary treatment report revealed to overcome the shortfalls of conventional DTX therapies, and thus stepped to the next stage, in Phase I study [181]. Further, to avoid development of resistance in cancer cells towards chemotherapeutic agents, and to obtain the synergistic effect, the combination approach of medications is well accepted. With the goal, liposomal delivery of irinotecan HCl and floxuridine combination study was conducted in patients with advanced colorectal cancer [182]. Similarly, the combination of daunorubicin-cytarabine and gemtuzumab ozogamicin [183]/daunorubicincytarabine and venetoclax [184] are also projected in acute myeloid leukemia patients using the liposomal platform. These findings are in agreement that the increased research in nanotechnology field has brought several components to the patient's bedside at different stages of clinical stages, however, a more to focus towards the treatment of MDR patients.

microenvironment for a potential delivery tool in MDR cancer [122,126]. A recent report on effective delivery of ruthenium complexes using multi-walled CNT platform was projected towards hepatocellular carcinoma. Such modernized delivery was showed enhanced endocytosis of ruthenium polypyridyl complex resistant in the R-HepG2 cells [126]. Similarly, P-gp targeted multi-walled CNT decorated with cancer targeting anti-Pgp antibody showed cancer-specific delivery to the resistant cancer cells. This research group coated the multi-walled CNT with phospholipid–poly(ethylene glycol), displayedmaximum cellular uptake with minimum nonspecific cell interactions. Further surface modification with anti-Pgp antibody resulted in P-gp mediated cellular internalization, where photo-irradiation caused dramatic cytotoxicity, particularly in tumor spheroids to the MDR cancer cells [171]. Therefore, functionalized CNT is another platform to explore widely for effective delivery, treatment, and control of cancer to overcome multidrug resistance. While exploring the effectivity of inorganic NPs in cancer, the potential of gold NPs is immense to show excellent diagnostic and therapeutic platform [172,173]. A multi-modal capability of thiolated biotin-conjugated pH-responsive DNA-conjugated gold nanorod containing DOX showed to release the entrapped components at acidic environment (pH 5) and by the effect of near-infrared light, enhanced cellular uptake and decreased efflux in MDR MCF-7/ADR cell [174]. The recent interest of delivering multifunctional cisplatin loaded gold NPs in the thermo-responsive alginate nanogel platform displayed dual action of the chemotherapeutic agent and photothermal effect against CT26 colorectal tumor to result in dramatic suppression of tumor growth with prolonged animal survival rate. Such a dual approach found to be beneficial towards decreased dose-associated side effects of individual components and to remove microscopic residue to prevent cancer relapse [173].

5. Conclusion and future trends MDR is a common phenomenon of cancer cells due to pathological changes of the intracellular and intercellular levels, where the cells attain resistance towards one type of chemotherapeutic agent and reflected by resistance to several other chemotherapeutics with different types or mechanism of action. Reversal of MDR is highly being essential to establish an effective treatment of chemotherapeutic, and nanotechnology has extensively been expanded as the potential carrier to carry reversing of MDR in cancer. However, strategy to overcome MDR would be better achieved through co-delivery of chemotherapeutics and P-gp inhibitor through nanoparticulate drug delivery. For further improvement in the reversal mechanism of MDR may require local codelivery of chemotherapeutics and P-gp inhibitor, where a targeted approach with a specific ligand could target a particular cancer type. This phenomenon can lead to detect the malignant cells using the active targeting moiety, internalization of the carrier, controlled release of the chemotherapeutics, help to overcome MDR, destroying the cancer cells without producing severe toxicity to the normal cells. This delivery system can be further improved where the delivery system can be monitored with the progress in real time.

4. Clinical advancement of nanotechnology in MDR cancer Bringing the engineered nanocarriers within the clinical use would enhance expectancy for better tomorrow in cancer therapy. Even though the journey of new therapeutics or novel delivery of established therapeutic needs to experience major limitations and challenges, several nanocarrier based deliveries have crossed the barriers of the laboratory to the bedside of the patients. Numbers of nanocarriers registered for clinical research to accomplish their performance towards an improvement of life expectancy in cancer. Numbers of them are showing superior therapeutic potential with improved safety profile against cancer compared to conventional treatments [175]. Regulatory agencies have approved different novel nanocarriers to market the deliveries, where Abraxane®-PTX bound to albumin NP, was approved in 2005 by the FDA for the treatment of metastatic breast cancer. Such preparation was evident of decreased toxicities compared to other conventional preparations of PTX (Taxol, Kolliphor, etc). Simultaneously, the administration of higher dose Abraxane® has reported to be well tolerated with superior efficacy [11,176]. Similarly, Janssen has brought to the society with liposomal DOX preparation, Doxil®/Caelyx®, which is also approved by the FDA in 1995 for the treatment of Kaposi's sarcoma in patients with human immunodeficiency virus. Although this formulation is equally effective, severe toxicities of conventional DOX preparation, such as cardiotoxicity, was not observed with this novel formulation [176,177]. These two formulations are continuously in use in the original indications along with other possible disease conditions effectively for more than one decade, proving its efficacy. Recently, a combined liposomal therapy of daunorubicin and cytarabine, Vyxeos®, was approved to obtain enhanced efficacy in acute myeloid leukemia condition. Vyxeos® is found to improve the survival period and tolerable toxicities as reported in Phase III clinical trial outcome [175,178]. Extensive researches trying to bring novel formulation to combat against MDR under this nanotechnology platform and consequence of

Declarations of interest None.

Acknowledgement The authors would like to acknowledge the School of Pharmacy, International Medical University for providing resources and support in completing this work.

Disclosures There is no conflict of interest and disclosures associated with the manuscript. 609

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