Medicine in Drug Discovery 6 (2020) 100024

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Medicine in Drug Discovery

journal homepage: https://www.journals.elsevier.com/medicine-in-drug-discovery

Review Article

Combination therapy based on nano codelivery for overcoming cancer

drug resistance
Hairui Wang a,b, Yongzhuo Huang b,c,
⁎
a
Taizhou University, School of Advanced Study, Institute of Natural Medicine and Health Product, Taizhou 318000, China
b
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China
c
NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, Shanghai 201203, China

A R T I C L E I N F O A B S T R A C T

Article history: Multidrug resistance (MDR) has long been a major obstacle in the treatment of malignant tumors. Combination ther-
Received 12 November 2019 apy provides a viable and promising strategy to overcome MDR. This article discusses the advantages of nano-based
Received in revised form 26 December 2019 combination therapy and proposes a 3R delivery principle (right place, right time, and right dose) as a reference for
Accepted 21 March 2020
development of cancer nanomedicine containing drug combinations. The article also reviews the strategies of nano-
Available online 31 March 2020
based codelivery, with emphasis on the techniques designed to overcome chemoresistance, enhance drug targeting de-
livery, and reduce immunosuppression.
© 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction Drug resistance is manifested in many forms, including insufficient drug

accumulation in the tumor, prevention of drug entry into the cells, increase
Malignant tumors are severe life-threatening diseases causing more in drug efflux, and enhanced DNA repair [5–7]. Based on the particular
than two millions of deaths in China each year [1]. The cancer treatment modes of resistance, two mechanisms are well recognized, namely intrinsic
methods available today include chemotherapy, hormone therapy, radio- and acquired resistance. These mechanisms are influenced by the tumor
therapy, surgery, immunotherapy, and targeted therapy [2]. Drug-based cells, as well as the tumor microenvironment (TME) [8,9], which may
treatments, such as chemotherapy, are commonly used to kill tumor cells. serve as a biological and physical barrier against intratumoral drug penetra-
However, certain types of cancer cells are insensitive to drugs and resistant tion and diffusion, thereby diminishing the anti-tumor efficacy. This shows
to treatment, which eventually leads to tumor recurrence and metastasis that in order to improve the efficiency of tumor treatment, it is necessary to
[3,4]. In fact, effective treatment is primarily hindered by the rapid devel- cultivate a profound understanding of MDR causes. It is also essential to de-
opment of drug resistance. For example, 90% of chemotherapy failures in velop new technologies and treatment strategies that circumvent MDR. For
patients with metastatic cancer are attributed to multidrug resistance example, one of the useful strategies is the clinical use of a combination of
(MDR) [5]. two or more anticancer drugs to treat many types of tumors [10].
This review briefly summarizes the mechanisms of antitumor drug resis-
tance, discusses the unique advantages of co-delivery technology in over-
coming MDR, and introduces the recent research progress.
Abbreviations: ALDH, Aldehyde dehydrogenase; AML, Acute myeloid leukemia; CTLA-4,
Cytotoxic T lymphocyte-associated antigen-4; CT, Chemotherapy; CAFs, Cancer-associated fi-
broblasts; c-Met, c-mesenchymal-epithelial transition factor; EMT, Epithelial-mesenchymal 2. Multidrug resistance
transition; EGFR, Epidermal growth factor receptor; ESCC, Esophageal squamous cell carci-
noma; FEN1, Flap endonuclease 1; FGF2, Fibroblast growth factor 2; CB-839, Glutaminase 1
inhibitor; MAPK, Mitogen-activated protein kinase; MHC I, Major histocompatibility complex MDR refers to the resistance of tumor cells to various types of drugs via
class I; MPP, Mitochondrial membrane penetrating peptide; PTT, Photothermal therapy; PDT, different mechanisms [11]. In general, MDR is associated with chemother-
Photodynamic therapy; pFAK, Phosphorylated FAK; PD-1, Programmed cell death-1; NQO1, apy failure and increased cancer-related mortality [12]. The complex TME
Quinone oxidoreductase isozyme I; TPGS, Tocopheryl polyethylene glycol succinate; TIME, forms due to the active interaction of tumor cells with the extracellular en-
Tumor immunity in the microenvironment; Tregs, T regulatory cells.
⁎ Corresponding author at: Shanghai Institute of Materia Medica, Chinese Academy of vironment, which may promote the development of MDR and tumor metas-
Sciences, 501 Haike Rd, Shanghai 201203, China. tasis [13]. Tumor cells often exhibit a variety of drug resistance
E-mail address: [email protected]. (Y. Huang). mechanisms due to the complexity and heterogeneity of the TME. These

http://dx.doi.org/10.1016/j.medidd.2020.100024
2590-0986/© 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
H. Wang, Y. Huang / Medicine in Drug Discovery 6 (2020) 100024

Fig. 1. Typical MDR mechanisms. Reprinted with permission from ref. [17].

mechanisms fall into either the cellular or non-cellular category, depending 3. Combination therapy to overcome tumor resistance
on whether they are governed by the internal or external environment of
cancer cells [14]. They may also be divided into pharmacokinetic and phar- 3.1. Why drug combination?
macodynamic resistance pathways [15]. The most common mechanisms of
tumor cell drug resistance include (1) decreased drug inflow, (2) increased Combination therapy have been shown to enhance treatment efficiency
drug efflux (related to drug efflux transporters), (3) enhanced DNA repair, in cancer patients, compared to monotherapy [43–45]. At optimum syner-
(4) altered drug-specific targets, and (5) changed apoptosis pathways gistic ratio, the reasonable combination of multiple drugs can significantly
[16], as illustrated in Fig. 1 [17]. For example, the up-regulation of efflux improve the therapeutic effect [46,47]. In addition to enhancing drug effi-
transporters after chemotherapy can actively remove their substrates from cacy, combination therapy reduces the therapeutic dose needed for treat-
tumor cells, leading to unmet intracellular drug concentrations and poor ment, minimizes the adverse reactions, and hinders the development of
therapeutic efficacy [18,19]. drug resistance via synergistic and complementary molecular mechanisms
Therapeutic strategies for targeting drug efflux, cancer stem cell (CSCs)- [48]. The development of combination cancer therapies (e.g., combined
mediated drug escape, abnormal tumor metabolism, immune suppression, chemo drugs, chemo and immunotherapies, chemo and targeted therapies,
epithelial-mesenchymal transition (EMT), and abnormal apoptosis have chemo and gene therapies, and targeted therapies and immunotherapies)
been proposed to overcome MDR. These strategies are summarized in requires a better understanding of tumor biology, molecular pathways,
Table 1. and the interactions between tumors and their microenvironments

Table 1
Various therapeutic strategies for overcoming tumor MDR.
Resistance mechanism Tumor Model Treatment strategy Ref

Efflux pumps NCI/RES-ADR Inhibiting the efflux pump [20,21]

Upregulated expression of inhibitors of apoptosis proteins Many types of cancer Survivin-targeted therapies [22]
Overexpression membrane transporters MCF-7/ADR Chemotherapy and (P-gp) siRNA [23,24]
Enhanced DNA repair MCF-7 cells and MB231 cells Targeting FEN1 [25]
Failure to undergo apoptosis Glioblastoma Downgrade caspase-8 [26–28]
Tumor-associated macrophage (TAM) Pancreatic ductal adenocarcinoma Targeting CCR2 or CSF1R [29]
Epithelial-mesenchymal transition A549T Targeting lipid metabolism [30]
FGF2 activates ER+ breast cancer Targeting FGF2 [31]
Enhanced ALDH activity Triple-negative breast tumors Inhibiting ALDH enzyme activity [32]
Autophagy upregulation in CSCs CSC from multiple tumor cells Regulating autophagy [33,34]
BCL-2 H1975-AVR cells Targeting the BCL-2 family proteins [35,36]
Multidrug resistance-associated protein 1 (MRP1) Bcap-37 − human breast cancer Co-delivery paclitaxel and MRP1 siRNA [37]
Hypoxia MCF7/ADR Co-deliver DOX and Metformin [38]
Overexpresses efflux pump MDA-MD-231 Effectively deliver DOX to mitochondria [39]
Antiapoptosis MCF-7/ADR tumor Inducing cell paraptosis [40]
Mitochondrial Oxidative Phosphorylation (OXPHOS) AML and various cancers Decrease mitochondrial OXPHOS activity [41]
EGFR Several cancers EGFR-targeted therapy [42]

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In vitro screening tests of drug combinations are typically conducted by

simultaneously adding the drugs to the cultured cells so as to achieve nearly
identical drug exposure. Among the available methods of drug delivery,
nanotechnology-based co-encapsulation is a useful tool that ensures identi-
cal spatial and temporal drug distribution in the target tumor cells. This
method also is an important means of overcoming tumor resistance [56],
as it generates higher concentrations of drugs in tumor cells, increases
drug stability, and reduces side effects. Furthermore, nanocarriers can be
used to deliver different kinds of drugs, irrespective of their physical proper-
ties (water solubility, size, etc.), and to optimize the outcome of combination
Fig. 2. Drug synergistic delivery. Two or more drugs achieve synergistic effects therapy. Different strategies of drug and nanocarrier combinations have
through the same or different pathways. Reproduced with permission from ref. been investigated, including free drug (A) + nanodrug (B), nanodrug (A)
[53].
+ nanodrug (B), and nanodrugs (A/B co-encapsulation) (Fig. 3) [47]. The
third strategy is considered to be the representative pattern for nano-based
[7,49–51]. The action patterns of combined drugs may be either synergistic combination therapy, due to the unique advantage of codelivery. An exam-
or sequential. In this article, we focus on the former. ple of a nano codelivery drug system is the liposome-encapsulated combina-
tion Vyxeos® that has been approved by the FDA for the treatment of some
types of poor prognosis acute myeloid leukemia.
3.2. How to enhance the efficiency of combination therapy?
3.3. “3R” delivery in nano-based combination therapy
Drug synergy can be achieved by increasing intracellular retention via
enhanced drug absorption or reduced drug elimination [45]. The combina- The in vivo fate of drugs is an essential factor that governs the efficacy of
tion index (CI) calculation according to the equation presented in Fig. 2 di- pharmacotherapy. Based on the “3R” delivery principle, drugs should effi-
rectly reflects the extent of synergy between drugs [48]. The IC50(A) and ciently reach the right place (i.e. pathological organs or cells) at the right
IC50(B) variables in the equation represent the concentrations at which time and with the right dose. When it comes to combination therapy, the
drugs A and B achieve a 50% cell growth inhibition rate, respectively, application of this principle is a prerequisite for the attainment of successful
while the IC50(A)pair and IC50(B)pair variables represent the concentrations treatment synergy. The nanoparticles used in combination therapy have a
at which the combined drugs yield a growth inhibition rate of 50%. CI tendency to accumulate in the tumor, which facilitates the delivery of the
values of 1, < 1, and > 1 are indicative of addition, synergistic, and antag- drugs to the right place. Moreover, co-encapsulation ensures that the com-
onistic effects, respectively [52]. bined drugs achieve a relatively identical bio-fate, and their therapeutic ac-
Traditional combinations of free drugs do not usually exhibit good syn- tivities will be executed simultaneously at a fixed dose combination
ergy due to variations in drug properties such as solubility, permeation, sta- (Fig. 4).
bility, half-life, distribution in tumors, and metabolism. Furthermore, the
difference between in vitro and in vivo bio-fates impedes the prediction 3.3.1. Right place, right dose, and right time
of drug combination outcomes, resulting in a poor translation of the cellular The therapeutic function of most cancer drugs entails the inhibition of
screening results. Therefore, to bridge the in vitro and in vivo studies via tumor cell growth and reproduction. Ideally, drugs should be distributed
synchronized drug action is essential for the development of drug combina- preferentially in tumor cells, with minimal exposure to normal tissues and
tion therapy. The rational design of combined drug administration that re- cells. The enhanced permeability and retention (EPR) effect has long been
spects the well-accepted principles of combination chemotherapy, such as considered as the major mechanism of tumor-targeting delivery of nano-
different pharmacological mechanisms of the combined drugs carriers. However, there has recently been great controversy over this
(e.g., targeting different cell cycles), no cross-resistance, no overlapping mechanism [57], considering that the available preclinical research results
side effects, and synergistic antitumor effects [54,55], is also important. are not in agreement. For example, murine models, the most commonly

Fig. 3. Schematic of different design strategies for the combination of two drugs with nanocarriers. Figure adapted from ref. [47].

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Fig. 4. A schematic illustration of pharmacotherapy that is characterized by 3R delivery principle.

used experimental animals in cancer research, typically show significant For a long time, nanomedicine has been regarded as the primary means
EPR effect, but large animals rarely do. Also, In a cancer study conducted of effectively delivering drugs to tumor cells via the so-called “passive” or
on dogs with spontaneous tumors, it was found that most carcinomas “active” targeting. However, no strong clinical data currently exists to sup-
contained considerable amounts of accumulated liposome, but the soft tis- port the claim of drug delivery to the right place. In addition to the failure of
sue sarcomas did not [58]. Therefore, it is believed that the EPR effect clinical trials, the unproductive R&D of nanomedicines has prompted scien-
largely depends on tumor histology, and that it is more likely to occur in tists to rethink the fact that “nanomedicine research has almost exclusively
fast-growing vascular tumors like carcinomas (leaky blood vessels) than focused on tumor targeted drug delivery” [63]. Consequently, the focus of
in slow-growing non-vascular tumors such as sarcomas [59]. cancer medicine research may shift from targeted drug delivery to combi-
So far, there has been little evidence of the EPR effect in human patients. nation therapy, particularly considering that the latter provides an ideal ap-
Commercially available nanomedicines, such as nab-paclitaxel and PEGylated plication of nanomedicines that have the unique advantage of achieving
liposomal doxorubicin (DOX), show little improvement in patients' overall sur- multiple drug codelivery. With the aid of nanocarriers, co-encapsulated
vival [60,61], which undermines the efficiency of nanomedicine in targeting drugs are delivered to the same “right place”, thereby laying the foundation
tumors. In fact, this efficiency is far lower than the value assumed by most re- for synergistic action. Prior to the development of nano-based codelivery
searchers, even in animal models. A meta-analysis of the published nanoparti- techniques, it was quite difficult to realizing a precise combinatory dose
cle delivery researches shows that the estimated median efficiency of delivery in the targeted tissues and cells. However, nano-based codelivery tech-
is only 0.7% of the injected nanoparticle dose [62]. niques can ensure the delivery of a precise dose ratio of drugs into tumor

Fig. 5. (A) Plasma drug concentration after intravenous injection of cytarabine and daunorubicin in the form of nanoparticles or free drugs. (B) Survival rates of cytarabine
and daunorubicin in mice treated with different drug molar ratios. Reproduced with permission from refs. [53,54].

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Fig. 6. Strategies of functionalized liposome delivery for solid tumor therapy. (A) Conventional liposomes can reach tumor tissues through EPR effect. (B) PEGylated
liposomes can increase circulation time. (C) Functionalized liposomes modified with appropriate ligands can reach the target site and release the drug. (D) Responsive
liposomes activate drug release only under specific environmental conditions. Figure adapted from ref. [68].

cells. This is an especially advantageous characteristic, considering that The hypoxia, acidity, and upregulation of certain proteases in the TME
therapeutic efficiency strongly depends on the ratio of combined drugs. can promote MDR [73,74]. For example, an acidic TME induces high ex-
For example, the precise delivery of the liposomal combination Vyxeos® pression of hypoxia inducible factor 1 (HIF-1) and p-glycoproteins, leading
in the optimum cytarabine to daunorubicin drug ratio of 5 to 1 extends to chemotherapy resistance [75]. In addition, weak base drugs are neutral-
the survival rate three times more than the dose ratio of 1 to 1 (Fig. 5b). ized under acidic conditions, and they tend to accumulate in acidic organ-
Compared to free drugs, nanomedicines can extend drug half-life, elles (e.g., lysosomes), thereby failing to reach the target sites
thereby increasing drug accumulation in the tumor. More importantly, (e.g., nucleus). This is the reason why tumor cells are readily resistant to
the release of drugs from nano-carriers can be controlled. To minimize weakly alkaline chemo drugs [76,77]. Table 2 lists the cells in TME and
the undesirable side effects, the drugs should be timely released into the the factors that are associated with drug resistance.
tumor cells so as not leak into the circulation system. Another key advan-
tage of nanomedicines is that they can ensure a relatively identical pharma- 5. Overcoming chemoresistance via codelivery
cokinetic behavior of the co-encapsulated drugs. A typical example is the
cytarabine and daunorubicin drugs that exhibit similar pharmacokinetic 5.1. Codelivery of small drugs
profiles in liposomal combination Vyxeos®, but show great difference as
free drugs (Fig. 5a). Kang et al. developed a mannosylated liposomal codelivery system of
doxorubicin (DOX) and dihydroartemisinin (DHA) for the treatment of
3.3.2. Design of nano-based codelivery systems for cancer therapy drug-resistant colon cancer [78]. DHA, a derivative of artemisinin, is clini-
Stimuli-responsive “smart” systems have been extensively used to con- cally used as an effective antimalarial drug, and its potential for anticancer
trol the release of drugs from nanomedicines by endogenous or exogenous has been established. DHA in the codelivery system re-sensitized HCT8/
stimuli [64,65], such as changes in temperature, pH, and tumor-associated ADR tumor cells to DOX, thereby efficiently suppressing the drug-
enzyme expression [66,67]. Surface modification is another common resistant colon cancer via different MDR reversal mechanisms, such as pref-
method that facilitates intratumor drug accumulation and release. Fig. 6 erential nuclear accumulation, enhanced apoptosis, and the induction of
presents the delivery strategies of functionalized liposomes. autophagy. Moreover, the codelivered DOX/DHA system downregulated
Bcl-xl, an important signaling pathway associated with chemoresistance,
4. TME and drug resistance resulting in an anti-MDR effect. Interestingly, mannose receptors are
overexpressed in drug-resistant colon cancer cells (HCT8/ADR). Therefore,
TME refers to the internal and external environment in which tumor colon tumor codelivery could be efficiently achieved using a simple design
cells live and develop. This microenvironment is comprised of the tumor of mannosylated nanoparticles.
cells themselves, as well as fibroblasts, immune cells, stromal and intersti- Zhao et al. established a mannose modification strategy for the design of
tial cells, microvessels, and infiltrated biomolecules (e.g., cytokines, mannosylated albumin nanoparticles for codelivery of disulfiram/copper
chemokines, metabolites, and nutrients that support tumor growth) complexes (DSF/Cu2+) and regorafenib (Rego). The system served to over-
[69,70]. The TME constitutes a dual barrier against drug therapy. As a phys- come drug resistance in colon cancer by modulating the TME [79]. The
ical barrier, TME decreases drug intratumor penetration and diffusion. complexation of DSF, a drug that has been widely used over the past six de-
Meanwhile, as a biological barrier, it regulates genetic mutations, epige- cades to control alcoholism, with Cu2+, yields a cytotoxic product to the
netic changes, and subtype polarization via crosstalk networks, biomole- colon cancer cells. Meanwhile, Rego contributes to the anti-angiogenesis
cules, and extracellular vesicles, thereby inducing drug resistance. Further and repolarization of tumor-associated macrophages (TAM). As for albu-
details regarding TME and drug resistance are presented in Fig. 7 [71,72]. min, it is an important nutrient to cancer cells that are characterized by

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Fig. 7. Effect of treatment-activated TME on drug resistance. (A) Healthy person. (B) Diagnosis of solid tumor (e.g., lung adenocarcinoma). (C) Appearance of drug-resistant
phenotypes after treatment. (D) Association between mortality and tumor recurrence or metastasis. (E) Effect of combination therapies targeting both, cancer cells and TME
on treatment sensitivity and response. (F) Effect of combination therapy on treatment outcomes. Reproduced with permission from ref. [71].

overexpressed albumin-binding proteins (e.g., SPARC). Therefore, the use This enhanced the therapeutic effect of the drug codelivery system on
of albumin nanoparticles for codelivery promoted the uptake of the com- drug-resistant NSCLC.
bined DSF/Cu and Rego drugs by the cancer cells.
Jin et al. reported another codelivery system based on the activatable 5.2. Codelivery of small drugs and DNA
cell-penetrating peptide-modified liposomes. This system was composed
of simvastatin and paclitaxel, and used to overcome epithelial- Intrinsic apoptosis dysfunction is a common cause of
mesenchymal transition (EMT)-related resistance in non-small cell lung chemoresistance. The activation of TRAIL-mediated extrinsic path-
cancer (NSCLC) [30]. The cell-penetration ability of this delivery system ways could potentially induce apoptosis, resulting in the
could be conditionally blocked and reinstalled by protease cleavage in the resensitization of chemoresistant tumors. Xu et al. developed a nano
tumor, which allowed for the activation of intratumor penetration and in- system for the codelivery of TRAIL DNA and monensin [80]. This sys-
tracellular uptake. As a key driving factor of drug resistance, EMT is signif- tem was composed of low-molecular-weight PEI (LMW-PEI) and sulf-
icant in the drug-resistant A549/T cells. Simvastatin reverses EMT, possibly hydryl cyclodextrin moieties that were crosslinked by disulfide
via the mechanism of cholesterol metabolism (Fig. 8). In addition, the bonds; the cyclodextrin component also served as a carrier of hydro-
codelivery liposomes promoted the M2-to-M1 repolarization of TAM, phobic monensin, an antibiotic and potential antitumor drug, via
thereby reducing the secretion of TGF-β, the primary inducer of EMT. host-guest inclusion, thus forming a structure termed Moβ-CD-SSPEI

Table 2
A list of factors promoting therapeutic resistance in tumor cells. Reproduced with permission from ref. [72]. (More details are available in the reference).
Proteins or miRNAs Resistant to Molecular mechanism

MDSCs IL-10 Immunotherapy, Sunitinib Depletion of tumor immunity

TANs OSM Anti-angiogenic therapy Expression of VEGF
Bv8 Anti-angiogenic therapy Vascularization and angiogenesis
CAFs sFRP2 Vemurafenib Loss of redox effector factor 1
P-gp Multi drug resistance Induction of drug efflux
miRNA-21 Paclitaxel Targeting apoptotic protease activating factor 1
TAMs Cathepsin B Paclitaxel ECM degradation
MMPs Anti-angiogenetic therapy ECM degradation
MFG-E8 Cisplatin Activation of Stat3
PGE2 Immunotherapy Induction of immune suppression
IDO Immunotherapy Depletion of T cell trytophan
Tumor cells VEGF-C Verapamil Expression of MDR1
GM-CSF Radiotherapy Recruitment of circulating tumor cell
WNT16B Mitoxanthrone, Docetaxel Activation of Wnt pathway
miRNA-34a;miRNA-452 Adriacin, Docetaxel Expression of PTEN and P-go
PAI-1 Radiotherapy Activation of AKT, ERK pathway

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Fig. 8. Protease legumain-activatable liposomes can disrupt lipid rafts (cholesterol-rich domains) and suppress the integrin-β3 and FAK signaling pathways and re-sensitize
the drug-resistant cancer cells to paclitaxel. The liposomes are able to re-polarize TAM via cholesterol-associated LXR/ABCA1 regulation, resulting in the increased TNF-α and
attenuated TGF-β. This effect promotes the remodeling of the TME and suppresses EMT. Reprinted with permission from ref. [30].

Fig. 9. Preparation of the RGD-γ-PGA/Moβ-CD-SSPEIpDNA nanocomplex. The inter-molecular crosslink of LMW-PEI with cyclodextrin is achieved via disulfide bonds.
Subsequently, monensin is loaded onto cyclodextrin via guest-host complexation. Moβ-CD-SSPEIpDNA binds with DNA, thereby forming the bioreducible polyplex cores
that are later coated with γ-PGA or RGD-γ-PGA. Reprinted with permission from ref. [80].

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(Fig. 9). The Moβ-CD-SSPEI bound to DNA, thereby forming the results indicated that this treatment strategy effectively overcame cancer
bioreducible polyplex cores that were subsequently coated with drug resistance (Fig. 10).
poly-γ-glutamic acid (γ-PGA) or RGD-γ-PGA via charge interaction,
forming the nanocomplex. This redox-sensitive gene delivery system
facilitated the disassembly of the crosslinked LMW-PEI in tumor 5.4. Codelivery of small drugs and proteins
cells and promoted the efficient release of TRAIL DNA and monensin.
As a death receptor (DR) agonist, monensin sensitized cancer cells to Tang et al. designed a nano-codelivery system capable of overcom-
TRAIL protein therapy by upregulating DR5. The anti-tumor efficacy ing MDR and metastasis. This system is composed of trichosanthin
of the proposed codelivery system was demonstrated in the drug- (TCS) protein and albendazole (ABZ) (Fig. 11) [82]. First, recombinant
resistant HCT8/ADR colon tumor model. TCS containing low-molecular-weight protamine, a cell-penetrating
peptide (CPP), was prepared (termed rTL). Then, ABZ was loaded onto
5.3. Codelivery of small drugs and peptides the negatively charged albumin-coated silver nanoparticles (ABZ@
BSA/Ag NP). The interaction between the oppositely charged compo-
To overcome doxorubicin resistance, Wang et al. proposed a novel DOX- nents resulted in the self-assembly of the rTL/ABZ@BSA/Ag NP
peptide conjugate self-assembly system characterized by tumor homing, codelivery system. In vitro studies showed that this system effectively
pH- and ultrasound-responsiveness [81]. In addition to DOX, the codelivery inhibited the proliferation of drug-resistant tumor cells (A549/T and
system consisted of ELP-C8 and LHRH. ELP-C8 is an elastin-like polypeptide HCT8/ADR) by destroying the cytoskeleton, blocking the cell cycle,
that carried DOX drug by conjugating to C8 peptide. Meanwhile, the LHRH downregulating P-gp, and promoting apoptosis. The in vivo results con-
peptide ligand is a luteinizing hormone that can specifically target the firmed that the rTL/ABZ@BSA/Ag NP codelivery system efficiently sup-
highly expressed receptors on tumor cells. The ELP-C8 and LHRH-ELP-C8 pressed tumor growth and lung metastasis in the mice with A549/T
were successfully expressed in Escherichia coli by genetic engineering, and drug-resistant subcutaneous tumors. Therefore, combinations of rTL
then purified and conjugated with DOX. High-intensity focused ultrasound and ABZ can be used as a potential therapeutic strategy to overcome
(HIFU) was used to further enhance intracellular drug delivery. In vivo MDR in tumors.

Fig. 10. Design of an LHRH-ELP-DOX codelivery system combined with HIFU-enhanced chemotherapy for the treatment of DOX-resistant tumors. (A) Synthesis route of Dox
nanoconjugates. (B) Acceleration of DOX release under acidic conditions (HIFU promotes the cleavage of the hydrazone bond between Dox and LHRH-ELP-C8).
(C) Ultrasound further enhances the efficiency of LHRH-ELP-DOX in treating DOX-resistant tumors. Reprinted with permission from ref. [81].

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Fig. 11. The schematic illustration of the rTL/ABZ@BSA/Ag NPs for combination therapy. Reprinted with permission from ref. [82].

6. Overcoming resistance to molecular-targeting therapy by mutations (EGRPT790M ) that are associated with gefitinib resistance.
Codelivery This is mainly due to the effect of the mutated methionine
(M) residue in blocking the interaction between gefitinib and the ac-
Molecular-targeting therapy has become the mainstream in NSCLC tive EGFR pocket [83]. Peng et al. proposed a novel HER-2 antibody
treatment. Gefitinib is the first approved epidermal growth factor recep- and mannose-modified liposomal codelivery system (tLGV) for the
tor (EGFR) tyrosine kinase inhibitor (TKI). This drug is applied in the treatment of EGRPT790M-mutated NSCLC. This system contains gefi-
treatment of metastatic NSCLC with EGFR mutations (i.e. exon 19 dele- tinib and vorinostat that modulated the redox microenvironment for
tions or exon 21 L858R substitutions). However, nearly all the patients promoting the degradation of EGRPT790M [84]. Vorinostat is a histone
receiving TKI therapy would develop drug resistance. In fact, approxi- deacetylase (HDAC) inhibitor that stimulated TAM repolarization. The
mately 50% of these patients eventually develop secondary T790M liposomal system repolarized the M2 phenotype to M1 and promoted

Fig. 12. A scheme of tLGV delivery and therapeutic mechanism for the treatment of EGFRT790M-positive NSCLC. Reprinted with permission from ref. [84].

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Fig. 13. Preparation of the mannose-modified lactoferrin nanoparticles and the antitumor mechanisms. (A) The mannose-modified lactoferrin nanoparticles are co-
loaded with shikonin and JQ1 by heat-driven self-assembly. (B) The system can minimize immunosuppression by inhibiting glycolysis, reducing the production of lactic
acid, and repolarizing TAM into M1 subtype. The system also induces ICD and promotes the infiltration of cytotoxic T lymphocytes into the tumors. Reprinted with
permission from ref. [95].

ROS generation in cancer cells, resulting in the modulation of the in- 7. Overcoming immunosuppression by codelivery
tracellular redox condition via the ROS/NOX3/MsrA axis. The redox
condition promoted the degradation of EGFRT790M, ultimately leading The occurrence and development of tumors are closely related to the
to the resensitization of resistant tumor cells to gefitinib (Fig. 12). body's immune system that can either suppress or promote tumor progres-
Yin et al. developed another liposomal codelivery system for the sion [86]. As they evolve, cancer cells recruit immunosuppressive cells and
treatment of EGFRT790M-positive NSCLC. They used a PD-L1 nanobody secrete soluble components to form an immunosuppressive network. This
as a targeting ligand for liposomal codelivery of simvastatin and gefi- leads to immune evasion and drug resistance, which ultimately promotes
tinib. This system could reverse gefitinib resistance by remodeling the the growth/progression of the tumor [87]. In general, immunosuppression
TME (e.g., neovascularization, macrophage polarization, and innate im- is closely related to a variety of immune cells (e.g., TAM and Tregs), as well
munity) [85]. as to some non-immune cells, such as fibroblasts and endothelial cells in
TME [88–90]. This indicates that the tumor immune microenvironment

Fig. 14. Potential strategies for overcoming drug resistance.

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Table 3
The latest combined drug therapy applications used to overcome drug resistance.
Drug delivery system Treatment strategy Payload Tumor type Ref

Mitochondria targeting nanoparticulate system Down-regulating pump resistance-related proteins P-gp siRNA and mitochondria MCF-7/ADR [97]
complex
Dual stimuli-responsive Pt(IV) prodrug Targeting NQO1 Three hybrid compounds A549 [98]
Synergistic therapy (CT, PDT, and PTT) Inhibiting drug efflux TPGS & DOX MCF-7/ADR [99]
NP − peptide−drug bioconjugate Improving drug delivery efficiency DOX peptides H69AR [100]
pH/Redox Dual-Responsive Polyplex Endo-lysosomal escape MDR1 siRNA & DOX MCF-7/ADR [101]
A folate-decorated polymersome Co-loaded chemotherapy drugs and P-gp inhibitors Tariquidar & DOX & paclitaxel MDR MCF-7 [102]
Antibody-drug conjugate c-Met-targeting c-Met mAb and microtubule HCC827 [103]
inhibitor
Combination EGFR+FGFR inhibitors Overcoming EMT Gefitinib and BGJ398 PC9 [104]
Drug delivery micelles Synergistic therapy of Image-guided PDT and CT PTX & tariquidar & fluorophore SKOV-3/MDR [105]
pH-and photothermal-driven multistage delivery Hyperthermia and chemotherapy DOX and Gold nanocages MCF-7/ADR [106]
nanoplatforms
Polymer-drug conjugates Bypassed drug efflux pumps DOX and MPP MCF-7/ADR [107]
Zinc oxide nanoparticle Increasing ROS generation synergistic autophagy Zinc oxide and DOX MCF-7/ADR [108]
CB-839 plus metformin Targeting glutamine-addiction CB-839 and metformin ESCC [109]
Implantable hierarchical-structured micelle−/drug-loaded Inhibiting drug efflux, increasing the intracellular DOX DOX and Apatinib MCF-7/ADR [110]
fiber device accumulation
Dual pH-sensitive liposomal system Charge reversal promotes drug release inhibition drug Paclitaxel and NO donor A549/T [111]
efflux
Liposome Sequential release promotes drug accumulation in tumor Dexamethasone (DEX) and KBv [112]
Docetaxel (DTX)

(TIME) is regulated by a highly complicated network and significantly af- reactions. Future nanomedicine research should address safety, biocompat-
fects the efficacy of immunotherapy [91]. ibility, availability, and toxicity issues. In addition, research efforts should
Tumor metabolism abnormality plays a key role in immunosuppression also focus on providing a profound understanding of the molecular regula-
and drug resistance [92,93]. For example, the Warburg effect, a hallmark of tory mechanism in tumors and TME. Such information is needed to design
cancer, is characterized by increased aerobic glycolysis, which enhances new drug delivery systems that are likely to achieve great success in cancer
the production of lactate, a known immunosuppressive metabolite in treatment.
TIME and an important driving factor of TAM2 polarization [94].
Wang et al. developed a mannose-modified lactoferrin nanosystem for Conflict of Interest
biomimetic delivery of shikonin (SHK) and JQ1. The system prepared via
heat-driven self-assembly served to reprogram the TIME and the glucose The authors declare that there are no conflicts of interest.
metabolism [95]. The reprogramming effect was achieved by targeting
the highly expressed mannose receptor and LRP-1 on tumor cells and Credit Author Statement
TAM, repolarizing TAM from M2 to M1 subtype, inducing immunogenic
tumor cell death (ICD), suppressing glycolysis, and promoting the H.W. and Y.H. wrote the manuscript.
intratumoral infiltration of CD8+ T cells. In addition, JQ1 reduced the ex-
pression of PD-L1 on tumor cells, thus, yielding a synergic effect and acti- Acknowledgments
vating anticancer immunity (Fig. 13).
We are thankful for the support of NFSC (81925035, 81673382, and
8. Summary of codelivery-based therapeutic applications 81521005), Strategic Priority Research Program of CAS (XDA12050307),
National Special Project for Significant New Drugs Development
Stimuli-sensitive nanosystems are responsive to the changes of pH, ROS, (2018ZX09711002-010-002), CAS Scientific Research and Equipment De-
or enzymes in TME. These systems are capable of releasing drugs rapidly velopment Project (YZ201437), and Fudan-SIMM Joint Research Fund
and efficiently in tumor cells. Li et al. provided a comprehensive summary (FU-SIMM20174009) for support.
of the nanometer drug delivery systems used to overcome MDR [96]. These
systems were based on extracellular (light or heat), intracellular (pH, ROS, References
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