Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 16, 2026.

Nanoparticle-Based Drug Delivery in Cancer Therapy and Its Role in Overcoming Drug Resistance

Yihan Yao, Yunxiang Zhou, Lihong Liu and 7 more

Frontiers in Molecular Biosciences · 2020 · Review · CC BY

doi:10.3389/fmolb.2020.00193

Abstract

Nanotechnology has been extensively studied and exploited for cancer treatment as nanoparticles can play a significant role as a drug delivery system. Compared to conventional drugs, nanoparticle-based drug delivery has specific advantages, such as improved stability and biocompatibility, enhanced permeability and retention effect, and precise targeting. The application and development of hybrid nanoparticles, which incorporates the combined properties of different nanoparticles, has led this type of drug-carrier system to the next level. In addition, nanoparticle-based drug delivery systems have been shown to play a role in overcoming cancer-related drug resistance. The mechanisms of cancer drug resistance include overexpression of drug efflux transporters, defective apoptotic pathways, and hypoxic environment. Nanoparticles targeting these mechanisms can lead to an improvement in the reversal of multidrug resistance. Furthermore, as more tumor drug resistance mechanisms are revealed, nanoparticles are increasingly being developed to target these mechanisms. Moreover, scientists have recently started to investigate the role of nanoparticles in immunotherapy, which plays a more important role in cancer treatment. In this review, we discuss the roles of nanoparticles and hybrid nanoparticles for drug delivery in chemotherapy, targeted therapy, and immunotherapy and describe the targeting mechanism of nanoparticle-based drug delivery as well as its function on reversing drug resistance.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 16, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Finding new and innovative treatments for cancer is a major problem across the world. With an increase in the number of methods that can treat cancer and the concept of an individualized treatment, the therapeutic efficacy of some malignant tumors has greatly improved. Chemotherapy is a conventional and widely used cancer treatment method. While chemotherapy works through a number of different mechanisms, its major function includes indiscriminately killing vigorously growing cells, including tumor and normal cells, which causes some serious side effects including bone marrow suppression, hair loss, and gastrointestinal reactions. Therefore, developing drugs that more accurately target tumor cells, instead of normal cells, has been the purpose of a large proportion of cancer-related research in the past few decades. Although the emergence of targeted therapy has made great progress in precision therapy, there are still many unavoidable adverse effects, and the development of drug resistance has always been a problem. Currently, cancer remains the second leading cause of death, and current therapies for many cancers are inadequate. Hence, increasingly more studies are seeking precise therapy of cancer and solutions for drug resistance.

Over the last few decades, nanotechnology has been increasingly used in medicine, including applications for diagnosis, treatment, and tumor targeting in a safer and more effective manner. Nanoparticle (NP)-based drug delivery systems have shown many advantages in cancer treatment, such as good pharmacokinetics, precise targeting of tumor cells, reduction of side effects, and drug resistance. NPs used in drug delivery systems are usually designed or chosen based on their size and characteristics according to the pathophysiology of the tumors. Mechanically, nano-carriers in cancer therapy target to tumor cells through the carrier effect of NPs and the positioning effect of the targeting substance after being absorbed. Next, they release the drugs to tumor cells in order to induce killing. Drugs located on the inside of the nano-carriers include traditional chemotherapy agents and nucleic acids, indicating that they can play a role in both cytotoxic and gene therapy. In addition, for some poorly soluble drugs, NPs offer a platform that can help encapsulate them and deliver the drugs into circulation. Due to the size and surface characteristics of NPs and their function of enhancing permeability and retention, nano-carriers can increase the half-life of drugs and induce their accumulation into tumor tissues. Meanwhile, the targeting system protects normal cells from the cytotoxicity of drugs, which helps ease the adverse effects of cancer therapy. For example, doxorubicin-loaded PEGylated liposomes reduced cardiotoxicity compared to free doxorubicin. Additionally, nanoparticle albumin-bound paclitaxel exhibited less side effects and allowed higher tolerated doses than solvent-based taxanes. In addition to chemotherapy and gene therapy, various studies have reported the application of NP drugs in immunotherapy and ablation treatment for cancer. The nanoparticle-based drug delivery system is believed to enhance immunotherapy, as well as reverse the tumor immunosuppressive microenvironment.

In recent years, an increasing number of nanotherapeutic drugs have been commercialized or entered the clinical stage. The first phase I clinical trial that used a targeted nanoparticle-based system to deliver small interfering RNA (siRNA) in patients with solid cancers was conducted in 2010. Another clinical study reported a more favorable tumor treatment efficacy of an actively targeted polymeric nanoparticle containing the chemotherapeutic docetaxel (DTXL) compared to a solvent-based DTXL formulation. The development of hybrid NPs has made even more progress in the arena of NP-based drug delivery systems. Hybrid NPs combine the properties of different NPs, thereby enhancing the function and stability of each drug delivery system. In addition, NPs have shown certain advantages when it comes to anti-tumor multidrug resistance (MDR), as they provide platforms for drug combination therapy as well as inhibit the function of some mechanisms of drug resistance, such as efflux transporters on cell membranes. Nowadays, nanoparticle-based therapy has been reported to have potential in overcoming MDR in several types of cancers, including breast cancer, ovarian cancer, and prostate cancer. Nanotechnology in medicine has opened a new stage of cancer treatment, and the combination of these two fields deserves more in-depth research. This review outlines the basic principles of the application of the nano-carrier system in cancer therapy, presents the current challenges, and describes the directions of future research.

NPs in Cancer Therapy

The NPs used in medical treatment usually have specific sizes, shapes, and surface characteristics as these three aspects have a major influence on the efficiency of the nano-drug delivery and thus control therapeutic efficacy. NPs with a diameter range of 10 to 100 nm are generally considered suitable for cancer therapy, as they can effectively deliver drugs and achieve enhanced permeability and retention (EPR) effect. Smaller particles can easily leak from the normal vasculature (less than 1–2 nm) to damage normal cells and can be easily filtered by kidneys (less than 10 nm in diameter), while particles that are larger than 100 nm are likely to be cleared from circulation by phagocytes. Moreover, the surface characteristics of NPs can influence their bioavailability and half-life. For instance, NPs that are coated with hydrophilic materials such as polyethylene glycol (PEG) lessen the opsonization and therefore avoid clearance by the immune system. Therefore, NPs are generally modified to become hydrophilic, which increases the time period of drugs in circulation and enhances their penetration and accumulation in tumors. Collectively, the various characteristics of NPs determine their therapeutic effect in cancer management. Different types of NPs for cancer therapy are shown in Figure 1 and the following text will describe their respective advantages in tumor treatment.

Organic NPs

Organic NPs have been widely explored for decades and contain many types of materials. Liposome, the first nano-scale drug approved for clinical application, consists of an outer lipid layer and a core entrapping either hydrophobic or hydrophilic drug. Liposomes can carry out many functions by modifying the lipid layer structure, including imitating the biophysical characteristics (e.g., mobility and deformation) of living cells, which can help achieve the purpose of more effective therapeutic drug delivery. With decades of research, the development of liposomes has gone through several generations. With regard to cancer therapy, liposomes provide a good platform for in vivo delivery of many anti-tumor drugs, such as doxorubicin and paclitaxel, among other chemotherapeutic agents, as well as nucleic acids. In the field of breast and prostate cancer, the application of liposomes has been increasingly common. Multiple paclitaxel liposomes have been demonstrated to have higher anti-tumor efficiency and improved bioavailability compared to free paclitaxel. Liposomal doxorubicin has been proven to reduce cardiotoxicity and has comparable efficacy in breast cancer. Furthermore, liposome-based nanosystems have also offered an option for drug combination, which can enhance the therapeutic effect and even reverse the drug resistance. Nowadays, more varieties of liposome-based drugs have entered into clinical use for cancer treatment.

Polymer-based NPs are another type of NP with specific structural arrangements for drug delivery formed by different monomers. Polylactic-co-glycolic acid (PLGA), a common polymeric NP, encompasses co-polymerization of glycolic acid and lactic acid. Given its better biocompatibility and biodegradation, as well as the EPR effect, PLGA is widely used as a carrier for drug delivery. Additionally, dendrimers are another class of polymers that have been applied to nanomedicine. They are versatile and biocompatible macromolecules that are characterized by a three-dimensional branch structure. Their multiple functional groups on the surface enhance the capability of loading and delivering therapeutic agents. Furthermore, polymeric micelles, which are characterized by polymer self-assembly into nano-aggregates as they are composed of amphiphilic copolymers, constitute another kind of widely investigated polymer NPs. The hydrophobic core enables the insoluble anticancer drugs to be absorbed and delivered smoothly, while the hydrophilic segment increases stability, thus reducing the uptake of the drug by the reticuloendothelial system and prolonging their time period in circulation.

Inorganic NPs

Inorganic NPs have the advantages of a higher surface area to volume ratio. They have a wide and easily modified surface conjugation chemistry and facile preparation, although this usually occurs at the expense of poorer biocompatibility and biodegradability. The inorganic NPs that have been studied include gold NPs (AuNPs), carbon nanotubes (CNTs), quantum dots, magnetic NPs (MNPs), and silica NPs (SNPs). AuNPs are the most widely studied inorganic NPs, and mixed monolayer-protected clusters based on the gold core are considered to be a promising candidate in the drug delivery system. The gold core is inert and non-toxic, and surface-functionalized AuNPs have been proven to enhance drug accumulation in tumors as well as to overcome the drug resistance. Moreover, AuNPs are thought to be involved in multimodal cancer treatment including gene therapy, photothermal therapy and immunotherapy.

carbon nanotubes are a type of tubular material that have been shown to have broad potential in the drug delivery field due to their unique biological, physical, and chemical properties. As a result, they have been used to deliver anticancer agents including doxorubicin, paclitaxel, and methotrexate siRNA for a variety of cancers. Meanwhile, CNTs produce heat when they are exposed to near-infrared radiation, which could be applied to thermal ablation for cancer therapy.

Mesoporous silica nanoparticle carriers are a type of SNPs which are suitable for drug delivery. The large internal pore volume enables them to encapsulate the maximum amount of anticancer drugs, and the supramolecular components act as a cap, allowing capture and release of drugs. Due to better pharmacokinetics and treatment efficacy, as well as high stability, SNPs are considered one of the best vehicles for drug delivery. Moreover, porous silicon NPs have shown great potential in immunotherapy as its immunoadjuvant properties include promotion of antigen cross presentation, polarization of lymphocytes and secretion of interferon-γ (IFN-γ).

Magnetic NPs (MNPs) used for drug delivery usually contain metal or metal oxide NPs. In order to improve the stability and biocompatibility, MNPs are commonly coated with organic materials, including polymers and fatty acids. They have been shown to demonstrate high efficacy in chemotherapy and gene therapy for cancer treatment. Furthermore, magnetic hyperthermia using MNPs can achieve thermal ablation of tumors, which offers alternative cancer treatment.

Hybrid NPs

As both organic and inorganic NPs have their own advantages and disadvantages, combining the two in a single hybrid drug delivery system endows the multifunctional carrier with better biological properties that can enhance treatment efficacy as well as reduce drug resistance.

Lipid-polymer hybrid NPs, which consist of an inner polymeric core and a lipid shell, have been demonstrated to be a promising drug delivery platform in the treatment of pancreatic cancer, breast cancer, and metastatic prostate cancer. This type of hybrid NPs combines the high biocompatibility of lipids with the structural integrity provided by polymer NPs, and are therefore capable of encapsulating both hydrophilic and hydrophobic drugs in order to achieve a better therapeutic effect. Meanwhile, this system can be effectively internalized by cancer cells and avoids fast clearance by the reticuloendothelial system.

The combination of organic and inorganic hybrid nano-materials is a common method of NP design. For example, a liposome-silica hybrid (LSH) nanoparticle consists of a silica core and a surrounding lipid bilayer and has been synthesized and shown to be valid in delivering drugs to kill prostate and breast cancer cells. The LSH nanoparticle has also been reported to offer a platform for the synergistic delivery of gemcitabine and paclitaxel to pancreatic cancer in a mouse model of the disease. created an advanced nano-in-micro platform by assembling the porous silicon NPs and giant liposomes onto a microfluidic chip, and co-delivery of synthesized DNA nanostructures and drugs in this platform was proven to significantly enhance cell death of doxorubicin-resistant breast cancer cells. Furthermore, CNTs and the chitosan hybrid NP used in the vectorization of methotrexate to lung cancer cells tend to increase anticancer activity while reducing drug toxicity on normal cells. Moreover, half-shells of metal multilayers (such as manganese and gold) and PLGA hybrid NPs have the potential of combining targeted drug delivery and hyperthermia, which can enhance the destruction of tumor cells.

The hybridization of natural biomaterial with organic or inorganic NPs is another method for NP design. For example, cell membrane coating nanotechnology is emerging and has increasingly gained more attention. This technology tends to bestow the NPs with biological characteristics directly by coating NPs with naturally derived cell membranes, which enhances the potency and safety of conventional NPs. The coatings include cell membranes derived from leukocytes, red blood cells, platelets, cancer cells, and even bacteria. have shown that coating nanoporous silicon particles with a cell membrane which is purified from leukocytes can prevent the nano-carrier from clearance by phagocytes, and the characteristics of this hybrid particle allow the drug to have extended time period in circulation, leading to increased accumulation in the tumor. Similarly, some studies have utilized cancer cell membrane-cloaked mesoporous silica NPs for cancer treatment, which improves the stability and targeting ability of nano-carriers. Moreover, the development of dual-membrane coated NPs can further enhance the function of NPs. For instance, erythrocyte-platelet hybrid and erythrocyte-cancer hybrid membrane-coated NPs were proven to exhibit better stability and longer circulation life.

Furthermore, proposed a multistage NP delivery system to achieve deep penetration into tumors by changing the size and characteristics of NPs at different stages. In their study, the size change of NPs was achieved by protease degradation of the cores of 100-nm gelatin NPs within the tumor microenvironment in order to release 10-nm quantum dot NPs.

Mechanisms of Targeting

Targeting of cancer cells specifically is a vital characteristic of nano-carriers for drug delivery, as it enhances the therapeutic efficacy while protecting normal cells from cytotoxicity. Numerous studies have been carried out to explore the targeting design of NP-based drugs. In order to better address the challenges of tumor targeting and the nano-carrier system design, it is crucial to first understand tumor biology and the interaction between nano-carriers and tumor cells. The targeting mechanisms can be broadly divided into two categories, passive targeting and active targeting (Figure 2).

Passive Targeting

Passive targeting is designed to utilize the different characteristics of tumor and normal tissue. In passive targeting, the drugs are successfully delivered to the target site in order to play a therapeutic role. High proliferation of cancer cells induces neovascularization, and large pores in the vascular wall lead to a worsening permselectivity of tumor vessels compared to normal vessels. The rapid and defective angiogenesis enables macromolecules, including NPs, to leak from blood vessels that supply the tumor and accumulate within tumor tissue. Meanwhile, the poor lymphatic drainage associated with cancer increases the retention of NPs, allowing the nano-carriers to release their contents to tumor cells. These processes cause the EPR effect, one of the driving forces of passive targeting. The EPR effect is influenced by the size of NPs, as many studies have demonstrated that smaller NPs have better penetrability but do not leak into normal vessels. On the other hand, larger particles are more likely to be cleared by the immune system.

In addition to the EPR effect, the tumor microenvironment is also an important factor in the passive delivery of nanomedicines. Glycolysis is one of the metabolic characteristics of cancer cells and is the main source of energy for cancer cell proliferation. Glycolysis yields an acidic environment and reduces the pH of the tumor microenvironment. Subsequently, some pH-sensitive NPs are triggered by the low pH level and are able to release drugs within the vicinity of cancer cells.

However, there are some limitations with regards to passive targeting, including non-specific drug distribution, non-universal existence of the EPR effect and different permeability of blood vessels across various tumors.

Active Targeting

Active targeting specifically targets cancer cells through direct interactions between ligands and receptors. The ligands on the surface of NPs are selected to target the molecules that are overexpressed on the surface of cancer cells, which allows them to distinguish targeted cells from healthy cells. The interaction between ligands on NPs and the receptors on the surface of cancer cells induces receptor-mediated endocytosis, which allows internalized NPs to successfully release therapeutic drugs. Therefore, active targeting is particularly suitable for macromolecular drug delivery, such as proteins and siRNAs. The types of targeting moieties include monoclonal antibodies, peptides, amino acids, vitamins, and carbohydrates. These ligands specifically bind to receptors on targeted cells, and the widely investigated receptors include transferrin receptor, folate receptor, glycoproteins, and the epidermal growth factor receptor (EGFR).

Targeting to Cancer Cells

Transferrin, a type of serum glycoprotein, functions to transport iron into cells. Transferrin receptors are overexpressed in most solid tumor cells and are expressed at low levels in normal cells. Thus, transferrin-conjugated NPs are used as an active targeting method to deliver drugs for cancer treatment. Compared to unmodified NPs, transferrin-modified NPs have been shown to exhibit higher cellular uptake efficiency and enhanced intracellular delivery of drugs. Moreover, evidence indicates that transferrin-conjugated polymeric NPs play a significant role in overcoming drug-resistant chemotherapy.

Folic acid, a type of vitamin, is essential in nucleotide synthesis. It is internalized by a folate receptor that is expressed on few normal cell types. However, the alpha isoform of folate receptor (FR-α) is overexpressed in approximately 40% of human cancers, while FR-β is expressed on the surface of hematopoietic cancers. Thus, the folate receptor-targeting strategy by folate-conjugated nanomaterials has been widely used for cancer treatments.

In addition, cancer cells usually express various types of glycoproteins, including lectins, which are non-immunological proteins that recognize and specifically bind to certain carbohydrates. Targeting cancer cell-surface carbohydrates by lectins conjugated to NPs constitutes the direct lectin targeting pathway, while inversely targeting lectins on cancer cells using carbohydrates moieties that are incorporated into NPs is referred to as the reverse lectin targeting pathway.

Epidermal growth factor receptor is a member of the ErbB family of tyrosine kinase receptors. EGFR, which is overexpressed in varieties of cancers, is involved in several processes of tumor growth and progression and has already been utilized as a target for cancer treatment. For example, targeting human epidermal receptor-2 (HER-2) is a common therapy for HER-2 positive breast and gastric cancer. Hence, NPs that have been designed to incorporate modified ligands that bind to EGFR in order to target EGFR-overexpressed cancer cells is a promising method of drug delivery. Furthermore, conjugating two cancer-specific ligands into a single NP is another way of active targeting, as it can help improve target specificity.

Targeting to Endothelium

Some NPs do not directly target cancer cells but instead have an effect on angiogenesis, which is another method of cancer treatment. The interaction between vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) plays an essential role in vascularization. Additionally, targeting VEGFR-2 and VEGFR-3, two major VEGF receptors, simultaneously by liposomes has been shown to enhance therapeutic efficacy.

Integrins are cell surface receptors for extracellular matrix proteins that play an important role in tumor cell migration and invasion. The αvβ3 integrin is highly expressed in tumor neovascular endothelial cells, rather than the resting endothelial and normal cells, and is important in the calcium-dependent pathway that induces endothelial cell migration. Hood et al. have reported the favorable treatment efficacy of cationic NPs coupled with an αvβ3 integrin-targeting ligand for gene delivery into tumor-bearing mice. In addition, αvβ3 integrin is associated with VEGFR-2 signaling, and blocking αvβ3 integrin-binding can lead to a reduction in VEGF signaling, indicating that targeting αvβ3 integrin can enhance the effectiveness of anti-VEGFR treatment.

Vascular cell adhesion molecule-1 (VCAM-1) is an immunoglobulin-like glycoprotein that is also expressed on the surface of the tumor endothelium and is involved in angiogenesis by interacting with vascular endothelial cells. Overexpression of VCAM-1 can be observed in various cancers, indicating its potential role in the active targeting of NPs for drug delivery. A study by have reported the high efficiency of VCAM-1 targeted NPs in a breast cancer model.

Moreover, matrix metalloproteinase (MMP), a component of the tumor microenvironment, is engaged in extracellular matrix remodeling and tumor neovascularization. MMP-sensitive NPs have been reported to play a potential antitumor effect in several types of cancers, including breast cancer, pancreatic cancer, and melanoma.

Mechanisms of NPs in Overcoming Drug Resistance

Drug resistance is still a major problem in cancer treatment, despite the fact that methods of cancer therapy are increasing. Multidrug resistance leads to a failure of various types of cancer treatments, leading to cancer progression and poor prognosis. The mechanisms of tumor drug resistance include cellular and physiological factors, such as overexpression of ATP binding cassette (ABC) transporters (e.g., efflux transporter), defective apoptotic machineries, interstitial fluid pressure, and acidic and hypoxic tumor microenvironment. Nanotechnology applied to drug delivery for cancer treatment has been shown to play a significant role in overcoming drug resistance (Table 1).

Targeting Efflux Transporters

Efflux transporters belong to a family of ABC transporters that have been proven to play essential roles in drug resistance. Efflux transporters reduce intercellular drug concentration by pumping the drug out of the cell, leading to a failure of treatment. Among them, P-glycoprotein (P-gp), one of the most widely investigated efflux transporters, is overexpressed in several drug-resistant tumors. In addition, high expression of P-gp has been associated with poor treatment-response in many tumors, such as breast and ovarian cancer. A myriad of studies have demonstrated that some chemotherapeutics-loaded NPs can bypass the exposure of anti-tumor drugs to efflux transporters, since NPs largely enter the cell through endocytosis instead of diffusion and release the drug at a perinuclear site within the cell, away from cell membranes and efflux pumps. The nanoparticle-based drug delivery system can modify the control of drug release. For example, several researches have utilized low pH level and redox as triggers for drug release in NPs. Furthermore, NPs, such as polymers, also act as MDR modulators. For instance, micelles based on amphiphilic diblock polymer of N-(2-hydroxypropyl) methacrylamide (HPMA) and poly (propylene oxide) block (PPO) are able to inhibit P-gp.

Combination therapy is another strategy to treat drug-resistant cancers. To this end, NP-based combination therapy has been able to overcome the problem of pharmacokinetic differences between different drugs by assembling multiple therapeutic agents within a single drug carrier, thereby fighting drug resistance and improving the therapeutic effect of cancer therapy. In addition to bypassing efflux transporters, inhibiting their expression and function would be another option to cope with efflux transporter-mediated drug resistance. This strategy can be achieved by designing NPs that encapsulate both efflux pump inhibitors and chemotherapeutics, or by reducing the ATP that is supplied to the efflux pump. As COX-2 has been shown to be involved in P-gp-mediated multidrug resistance in cancer, a selective COX-2 inhibitor can down-regulate the P-gp expression. Indeed, a recent study conducted by confirmed that co-delivery of COX-2 inhibitors and doxorubicin by NPs reversed the multidrug resistance of breast cancer cells. Furthermore, several studies have revealed that co-delivery of P-gp-targeted siRNA and anticancer drugs by NPs helps overcome drug-resistant cancers, which is exerted through inhibiting the expression of ABC transporters. A recent study revealed the effectiveness of overcoming drug resistance in lung cancer therapy by combining miRNA-495 and doxorubicin into a cancer cell membrane-coated silica nanoparticle, results of which indicated that miR-495 effectively down-regulated P-gp expression in multidrug-resistant cancer cells.

In addition, reported that nanoparticle-mediated drug delivery to the tumor neovasculature was able to overcome P-gp-expressing multidrug resistant cancer by targeting KDR receptors, which are highly expressed in the tumor vasculature. This system showed a more effective anti-tumor function when compared to chemotherapeutic and P-gp inhibitor combination therapy.

Targeting Apoptotic Pathway

Defective apoptotic machineries enable cancer cells to evade apoptosis and increase survival, thereby contributing to drug resistance in cancer. The defective apoptotic pathway is often triggered by deregulating Bcl-2 and nuclear factor kappa B (NF-κB). Bcl-2 is a widely investigated anti-apoptotic protein, is highly expressed in many cancers, and is a key player in drug resistance, suggesting its potential as a target for reversing drug resistance. Accumulating evidence has indicated that co-delivery of Bcl-2-targeted siRNA and chemotherapeutics by NPs is an alternative to overcoming drug resistance in cancer. Moreover, NF-κB inhibitors have been used in NP-based combination therapy, including pyrrolidine dithiocarbamate (PDTC) and curcumin.

In addition to suppressing anti-apoptotic moieties, the activation of pro-apoptotic compounds can also be used to combat apoptotic pathway-mediated drug resistance. For example, combining ceramide with the chemotherapeutic drug paclitaxel augments the therapeutic efficacy of various drug-resistant tumor models. On the other hand, a recent study revealed that ceramide is able to restore the expression of wild-type p53 protein, an important tumor suppressor, by modulating alternative pre-mRNA splicing. In this process, NPs offers a more effective platform to deliver ceramide into cancer cells that carry p53 missense mutations, an important cancer phenomenon. As p53 plays a significant role in apoptosis, reinstating p53 function or other tumor suppressors is considered a potential way to overcome drug resistance in cancer. Therefore, p53 gene therapy utilizing a nanoparticle-based delivery system has been further researched. Transfecting the p53 gene by cationic solid lipid NPs and PLGA has been reported in lung and breast cancer cells, respectively. These results show the effective induction of apoptosis and inhibition of tumor growth.

Furthermore, some NP-based drug delivery systems function by inhibiting efflux pumps, as well as promoting apoptosis. utilized an amphiphilic cationic NP complex encapsulating paclitaxel and the Bcl-2 convertor gene in order to inhibit drug-resistant liver cancer cell growth. Findings from the study showed that this NP complex impaired P-gp-induced drug efflux and the activation of apoptosis. This work is a pioneer study that was able to successfully overcome both pump- and non-pump-mediated drug resistance. In addition, co-delivery of doxorubicin and resveratrol in NPs have shown significant cytotoxicity on doxorubicin-resistant breast cancer cells by inducing apoptosis through the down-regulation of Bcl-2 and NF-κB expression, as well as through the inhibition of efflux transporter expression. Similarly, another study demonstrated the effectiveness of folic acid-conjugated planetary ball-milled NPs that were encapsulated with resveratrol and docetaxel for the treatment of multidrug-resistant prostate cancer. Results indicated that the expression of anti-apoptotic genes was down-regulated, while the ABC-transporter markers were inhibited. Moreover, mitochondria-targeted NPs also showed an effect on both efflux transporters and apoptotic pathway. Targeting to mitochondria led to a reduction in ATP production, which is required by ABC transporters. Additionally, paclitaxel-loaded TPP-Pluronic F127-hyaluronic acid nanomicelles caused mitochondrial outer membrane permeabilization (MOMP), which resulted in the release of cytochrome C and activation of caspase-3 and caspase-9, leading to apoptosis of drug-resistant lung cancer cells.

Targeting Hypoxia

Hypoxia is another factor that contributes to multidrug resistance. Due to irregular blood vessels, as well as the increased oxygen demand of rapidly proliferating cancer cells, some cancer cells are often in a hypoxic state. Hypoxia induces the drug resistance of tumors in many ways. For instance, slowly dividing cells in hypoxic regions can escape from cytotoxic chemotherapeutics such as alkylating agents and antibiotics. Additionally, hypoxia produces a gradient of oxygen within the tumor, thereby increasing tumor heterogeneity and promoting a more aggressive phenotype. Besides, hypoxia has also been proven to mediate the overexpression of drug efflux proteins. During the process, hypoxia-inducible factor 1α (HIF-1α) plays an essential role, and overexpression of HIF-1α has been observed in many human cancers. Therefore, targeting HIF-1α is another treatment method for overcoming drug resistance.

There is also an extensive study on the application of NPs in the treatment of hypoxia. Silencing the HIF-1α gene is one of the ways to inhibit hypoxic environment. Several studies have reported the effectiveness of nanosystems containing HIF-1α siRNA to overcome drug resistance in cancer. HIF-1α inhibitors have also shown therapeutic efficacy in reducing hypoxia-mediated drug resistance. In addition to directly inhibiting the function of HIF-1, indirect inhibition of HIF-1 signaling has also been previously considered. For example, the PI3K/Akt/mTOR pathway can regulate the expression of HIF-1α, and the inhibition of this pathway down-regulates HIF-1α expression, thereby enhancing the sensitivity of MDR cells to cancer treatment. In this process, NPs, such as PLGA-PEG and PEGylated and non-PEGylated liposomes, can offer better platforms to achieve combination therapy. In addition, heat shock protein 90 (HSP90) is required for HIF-1 transcriptional activity, and inhibition of HSP90 can also down-regulate HIF-1α expression. The HSP90 inhibitor in 17AAG-loaded NPs has been shown to dramatically improve bladder cancer treatment.

The Role of NPs in Cancer Immunotherapy

The development of immunotherapy has brought cancer treatment into a new era. NPs not only play an important role in delivery chemotherapy but have also shown great potential for applications in immunotherapy. Cancer immunotherapy is mainly achieved by activating the anti-tumor immune response. NP-associated immunotherapy includes nanovaccines, artificial antigen-presenting cells (aAPCs), and targeting of the immunosuppressed tumor microenvironment (TME).

Nanovaccines deliver tumor-associated antigens (TAAs) and adjuvants to APCs, such as dendritic cells (DCs). Additionally, NPs can be used as adjuvants themselves to increase APC antigen presentation and promote DC maturation, leading to the activation of the anti-tumor function of cytotoxic T cells. NPs, such as liposomes, gold NPs, PLGA NPs, micelles, and dendrimers all have the capability of cytoplasmic delivery of TAAs into DCs, thus enhancing the immune response against tumor cells. Among different types of NPs, inorganic NPs such as mesoporous silica and polymers such as acetylated dextran (AcDEX) have been shown to function as an adjuvant in immunotherapy, leading to a stimulation of the immune response. Unlike nanovaccines, artificial APCs function with MHC-antigen complexes and co-stimulatory molecules that directly bind to T cell receptors (TCRs) and co-stimulatory receptors on T cells, respectively, resulting in T cell activation. Targeting the immunosuppressive TME is mainly achieved by targeting tumor-associated macrophages (TAMs), myeloid derived suppressor cells (MDSCs), and regulatory T cells (Tregs), all of which are important cell types in the TME. Furthermore, in order to minimize interactions with the reticuloendothelial system, NPs are usually modified with PEG.

In addition, the combination of chemotherapy and immunotherapy is a promising strategy of cancer treatment. For example, one study showed that co-loading of the chemotherapeutic agent Nutlin-3a and the cytokine GM-CSF in spermine-modified AcDEX NPs led to improved proliferation of cytotoxic CD8(+) T cells and stimulated immune response, leading to tumor cell death while avoiding toxicity in immune cells. Alternative approaches of combined chemo-immunotherapy includes co-delivery of chemotherapeutics and monoclonal antibodies into porous silicon NPs, which have been effective in stimulating complement activation, antibody-dependent cell cytotoxicity (ADCC), and immune response against cancer cells.

Conclusion and Future Perspectives

Nanotechnology applied to cancer therapy has led to a new era of cancer treatment. Various types of NPs, including organic and inorganic NPs, have already been widely used in the clinical treatment of several cancer types. Compared to traditional drugs, NP-based drug delivery systems are associated with improved pharmacokinetics, biocompatibility, tumor targeting, and stability, while simultaneously playing a significant role in reducing systemic toxicity and overcoming drug resistance. These advantages enable NP-based drugs to be widely applied to chemotherapy, targeted therapy, radiotherapy, hyperthermia, and gene therapy. Moreover, nanocarrier delivery systems provide improved platforms for combination therapy, which helps overcome mechanisms of drug resistance, including efflux transporter overexpression, defective apoptotic pathway, and hypoxia tumor microenvironment. According to different mechanisms of MDR, NPs that are loaded with varieties of targeting agents combined with cytotoxic agents can achieve the reversal of drug resistance.

With increasing research, various types of hybrid NPs have shown improved properties for delivery and aroused more attention. Further studies on the biological characteristics of individual cancers will lead to more precise research directions for these drugs. Furthermore, designing hybrid NPs that are more suitable for cancer therapy and engineering NPs that target cancer cells more specifically using targeting moieties merits further exploration. Notably, the interactions between NPs and the immune system are complex. The NP size, shape, composition, and surface are all the factors that affect the interactions of NPs with the immune system. Although nanovaccines and artificial APCs have demonstrated increased efficacy compared to traditional immunotherapy, the clinical efficacy of this treatment remains unsatisfactory, and the safety and tolerance of these new approaches need to be further investigated. Moreover, developing immunomodulatory factor-loaded NPs may improve the effectiveness of vaccines for immunotherapy. Accordingly, a better understanding of the TME and a further investigation of the crosstalk between NP-based drug delivery systems and tumor immunity are warranted for drug design and exploitation.

Author Contributions

YY, YZ, AS, and SW conceptualized the research project. YY, LL, YX, and YW drafted the manuscript. YZ, AS, and QC reviewed and modified the manuscript. AS and YD supervised the research and led the discussion. All authors approved the final version of the manuscript.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References 180

  1. 1.

    Acharya S. Sahoo S. K. (2011 ). PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect. Adv. Drug Deliv. Rev. 63 170–183.

    Not in our library10.1016/j.addr.2010.10.008

  2. 2.

    Agarwal R. Kaye S. B. (2003 ). Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat. Rev. Cancer 3 502–516.

    Not in our library10.1038/nrc1123

  3. 3.

    Alexis F. Basto P. Levy-Nissenbaum E. Radovic-Moreno A. F. Zhang L. Pridgen E. (2008 ). HER-2-targeted nanoparticle-affibody bioconjugates for cancer therapy. ChemMedChem 3 1839–1843.

    Not in our library10.1002/cmdc.200800122

  4. 4.

    Alimoradi H. Greish K. Barzegar-Fallah A. Alshaibani L. Pittalà V. (2018 ). Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity. Int. J. Nanomed. 13 7771–7787.

    Not in our library10.2147/ijn.s187089

  5. 5.

    Allen J. D. Brinkhuis R. F. van Deemter L. Wijnholds J. Schinkel A. H. (2000 ). Extensive contribution of the multidrug transporters P-glycoprotein and Mrp1 to basal drug resistance. Cancer Res. 60 5761–5766.

    Not in our library

  6. 6.

    Almeida P. V. Shahbazi M. A. Mäkilä E. Kaasalainen M. Salonen J. Hirvonen J. (2014 ). Amine-modified hyaluronic acid-functionalized porous silicon nanoparticles for targeting breast cancer tumors. Nanoscale 6 10377–10387.

    Not in our library10.1039/c4nr02187h

  7. 7.

    Amreddy N. Babu A. Muralidharan R. Panneerselvam J. Srivastava A. Ahmed R. (2018 ). Recent advances in nanoparticle-based cancer drug and gene delivery. Adv. Cancer Res. 137 115–170.

    Not in our library10.1016/bs.acr.2017.11.003

  8. 8.

    Amreddy N. Muralidharan R. Babu A. Mehta M. Johnson E. V. Zhao Y. D. (2015 ). Tumor-targeted and pH-controlled delivery of doxorubicin using gold nanorods for lung cancer therapy. Int. J. Nanomed. 10 6773–6788.

    Not in our library10.2147/ijn.s93237

  9. 9.

    Apte R. S. Chen D. S. Ferrara N. (2019 ). VEGF in signaling and disease: beyond discovery and development. Cell 176 1248–1264.

    Not in our library10.1016/j.cell.2019.01.021

  10. 10.

    Bahrami B. Hojjat-Farsangi M. Mohammadi H. Anvari E. Ghalamfarsa G. Yousefi M. (2017 ). Nanoparticles and targeted drug delivery in cancer therapy. Immunol. Lett. 190 64–83.

    Not in our library10.1016/j.imlet.2017.07.015

  11. 11.

    Bai F. Wang C. Lu Q. Zhao M. Ban F. Q. Yu D. H. (2013 ). Nanoparticle-mediated drug delivery to tumor neovasculature to combat P-gp expressing multidrug resistant cancer. Biomaterials 34 6163–6174.

    Not in our library10.1016/j.biomaterials.2013.04.062

  12. 12.

    Balasubramanian S. Girija A. R. Nagaoka Y. Iwai S. Suzuki M. Kizhikkilot V. (2014 ). Curcumin and 5-fluorouracil-loaded, folate- and transferrin-decorated polymeric magnetic nanoformulation: a synergistic cancer therapeutic approach, accelerated by magnetic hyperthermia. Int. J. Nanomed. 9 437–459.

    Not in our library10.2147/ijn.s49882

  13. 13.

    Basoglu H. Goncu B. Akbas F. (2018 ). Magnetic nanoparticle-mediated gene therapy to induce Fas apoptosis pathway in breast cancer. Cancer Gene Ther 25 141–147.

    Not in our library10.1038/s41417-018-0017-2

  14. 14.

    Bauleth-Ramos T. Shahbazi M. A. Liu D. F. Fontana F. Correia A. Figueiredo P. (2017 ). Nutlin-3a and cytokine co-loaded spermine-modified acetalated dextran nanoparticles for cancer chemo-immunotherapy. Adv. Funct. Mater. 27:14

    Not in our library10.1002/adfm.201703303

  15. 15.

    Bertrand N. Wu J. Xu X. Kamaly N. Farokhzad O. C. (2014 ). Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv. Drug Deliv. Rev. 66 2–25.

    Not in our library10.1016/j.addr.2013.11.009

  16. 16.

    Braunová A. Kostka L. Sivák L. Cuchalová L. Hvězdová Z. Laga R. (2017 ). Tumor-targeted micelle-forming block copolymers for overcoming of multidrug resistance. J. Control Release 245 41–51.

    Not in our library10.1016/j.jconrel.2016.11.020

  17. 17.

    Cagel M. Tesan F. C. Bernabeu E. Salgueiro M. J. Zubillaga M. B. Moretton M. A. (2017 ). Polymeric mixed micelles as nanomedicines: achievements and perspectives. Eur. J. Pharm. Biopharm. 113 211–228.

    Not in our library10.1016/j.ejpb.2016.12.019

  18. 18.

    Carita A. C. Eloy J. O. Chorilli M. Lee R. J. Leonardi G. R. (2018 ). Recent advances and perspectives in liposomes for cutaneous drug delivery. Curr. Med. Chem. 25 606–635.

    Not in our library10.2174/0929867324666171009120154

  19. 19.

    Carmeliet P. Jain R. K. (2000 ). Angiogenesis in cancer and other diseases. Nature 407 249–257.

    Not in our library10.1038/35025220

  20. 20.

    Chen A. M. Zhang M. Wei D. Stueber D. Taratula O. Minko T. (2009 ). Co-delivery of doxorubicin and Bcl-2 siRNA by mesoporous silica nanoparticles enhances the efficacy of chemotherapy in multidrug-resistant cancer cells. Small 5 2673–2677.

    Not in our library10.1002/smll.200900621

  21. 21.

    Chen X. Zhang Y. Tang C. Tian C. Sun Q. Su Z. (2017 ). Co-delivery of paclitaxel and anti-survivin siRNA via redox-sensitive oligopeptide liposomes for the synergistic treatment of breast cancer and metastasis. Int. J. Pharm. 529 102–115.

    Not in our library10.1016/j.ijpharm.2017.06.071

  22. 22.

    Chen Y. Gao D. Y. Huang L. (2015 ). In vivo delivery of miRNAs for cancer therapy: challenges and strategies. Adv. Drug Deliv. Rev. 81 128–141.

    Not in our library10.1016/j.addr.2014.05.009

  23. 23.

    Chen Y. Zhu X. Zhang X. Liu B. Huang L. (2010 ). Nanoparticles modified with tumor-targeting scFv deliver siRNA and miRNA for cancer therapy. Mol. Ther. 18 1650–1656.

    Not in our library10.1038/mt.2010.136

  24. 24.

    Cheng C. A. Deng T. Lin F. C. Cai Y. Zink J. I. (2019 ). Supramolecular Nanomachines as Stimuli-Responsive Gatekeepers on Mesoporous Silica Nanoparticles for Antibiotic and Cancer Drug Delivery. Theranostics 9 3341–3364.

    Not in our library10.7150/thno.34576

  25. 25.

    Cheng H. Wu Z. Wu C. Wang X. Liow S. S. Li Z. (2018 ). Overcoming STC2 mediated drug resistance through drug and gene co-delivery by PHB-PDMAEMA cationic polyester in liver cancer cells. Mater. Sci. Eng. C Mater. Biol. Appl. 83 210–217.

    Not in our library10.1016/j.msec.2017.08.075

  26. 26.

    Cheng J. Gu Y. J. Cheng S. H. Wong W. T. (2013 ). Surface functionalized gold nanoparticles for drug delivery. J. Biomed. Nanotechnol. 9 1362–1369.

    Not in our library10.1166/jbn.2013.1536

  27. 27.

    Cheow W. S. Hadinoto K. (2011 ). Factors affecting drug encapsulation and stability of lipid-polymer hybrid nanoparticles. Colloids Surf. B Biointerfaces 85 214–220.

    Not in our library10.1016/j.colsurfb.2011.02.033

  28. 28.

    Chintamani, Singh J. P. Mittal M. K. Saxena S. Bansal A. Bhatia A. (2005 ). Role of p-glycoprotein expression in predicting response to neoadjuvant chemotherapy in breast cancer–a prospective clinical study. World J. Surg. Oncol. 3:61.

    Not in our library10.1186/1477-7819-3-61

  29. 29.

    Choi K. Y. Correa S. Min J. Li J. Roy S. Laccetti K. H. (2019 ). Binary Targeting of siRNA to Hematologic Cancer Cells In Vivo using Layer-by-Layer Nanoparticles. Adv. Funct. Mater. 29:1900018.

    Not in our library10.1002/adfm.201900018

  30. 30.

    Choi S. H. Jin S. E. Lee M. K. Lim S. J. Park J. S. Kim B. G. (2008 ). Novel cationic solid lipid nanoparticles enhanced p53 gene transfer to lung cancer cells. Eur. J. Pharm. Biopharm. 68 545–554.

    Not in our library10.1016/j.ejpb.2007.07.011

  31. 31.

    Cirillo G. Vittorio O. Kunhardt D. Valli E. Voli F. Farfalla A. (2019 ). Combining Carbon Nanotubes and Chitosan for the Vectorization of Methotrexate to Lung Cancer Cells. Materials 12:2889.

    Not in our library10.3390/ma12182889

  32. 32.

    Colapicchioni V. Palchetti S. Pozzi D. Marini E. S. Riccioli A. Ziparo E. (2015 ). Killing cancer cells using nanotechnology: novel poly(I:C) loaded liposome-silica hybrid nanoparticles. J. Mater. Chem. B 3 7408–7416.

    Not in our library10.1039/c5tb01383f

  33. 33.

    Cortes J. Saura C. (2010 ). Nanoparticle albumin-bound (nab (TM))-paclitaxel: improving efficacy and tolerability by targeted drug delivery in metastatic breast cancer. EJC Suppl. 8 1–10.

    Not in our library10.1016/s1359-6349(10)70002-1

  34. 34.

    Cui Y. N. Xu Q. X. Davoodi P. Wang D. P. Wang C. H. (2017 ). Enhanced intracellular delivery and controlled drug release of magnetic PLGA nanoparticles modified with transferrin. Acta Pharmacol. Sin. 38 943–953.

    Not in our library10.1038/aps.2017.45

  35. 35.

    Cun X. Chen J. Li M. He X. Tang X. Guo R. (2019 ). Tumor-Associated Fibroblast-Targeted Regulation and Deep Tumor Delivery of Chemotherapeutic Drugs with a Multifunctional Size-Switchable Nanoparticle. ACS Appl. Mater. Interfaces 11 39545–39559.

    Not in our library10.1021/acsami.9b13957

  36. 36.

    Cuvier C. Roblot-Treupel L. Millot J. M. Lizard G. Chevillard S. Manfait M. (1992 ). Doxorubicin-loaded nanospheres bypass tumor cell multidrug resistance. Biochem. Pharmacol. 44 509–517.

    Not in our library10.1016/0006-2952(92)90443-m

  37. 37.

    Dadwal A. Baldi A. Kumar Narang R. (2018 ). Nanoparticles as carriers for drug delivery in cancer. Artif. Cells Nanomed. Biotechnol. 46 295–305.

    Not in our library10.1080/21691401.2018.1457039

  38. 38.

    Danhier F. Feron O. Préat V. (2010 ). To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J. Control Release 148 135–146.

    Not in our library10.1016/j.jconrel.2010.08.027

  39. 39.

    Davis M. E. Zuckerman J. E. Choi C. H. Seligson D. Tolcher A. Alabi C. A. (2010 ). Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464 1067–1070.

    Not in our library10.1038/nature08956

  40. 40.

    Decuzzi P. Pasqualini R. Arap W. Ferrari M. (2009 ). Intravascular delivery of particulate systems: does geometry really matter? Pharm. Res. 26 235–243.

    Not in our library10.1007/s11095-008-9697-x

  41. 41.

    Dehaini D. Wei X. Fang R. H. Masson S. Angsantikul P. Luk B. T. (2017 ). Erythrocyte-platelet hybrid membrane coating for enhanced nanoparticle functionalization. Adv. Mater. 29:1606209.

    Not in our library10.1002/adma.201606209

  42. 42.

    Desgrosellier J. S. Cheresh D. A. (2010 ). Integrins in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer 10 9–22.

    Not in our library10.1038/nrc2748

  43. 43.

    Devalapally H. Duan Z. Seiden M. V. Amiji M. M. (2007 ). Paclitaxel and ceramide co-administration in biodegradable polymeric nanoparticulate delivery system to overcome drug resistance in ovarian cancer. Int. J. Cancer 121 1830–1838.

    Not in our library10.1002/ijc.22886

  44. 44.

    Dienst A. Grunow A. Unruh M. Rabausch B. Nör J. E. Fries J. W. (2005 ). Specific occlusion of murine and human tumor vasculature by VCAM-1-targeted recombinant fusion proteins. J. Natl. Cancer Inst. 97 733–747.

    Not in our library10.1093/jnci/dji130

  45. 45.

    Eloy J. O. Petrilli R. Topan J. F. Antonio H. M. R. Barcellos J. P. A. Chesca D. L. (2016 ). Co-loaded paclitaxel/rapamycin liposomes: development, characterization and in vitro and in vivo evaluation for breast cancer therapy. Colloids Surf. B Biointerfaces 141 74–82.

    Not in our library10.1016/j.colsurfb.2016.01.032

  46. 46.

    Fan L. Li F. Zhang H. Wang Y. Cheng C. Li X. (2010 ). Co-delivery of PDTC and doxorubicin by multifunctional micellar nanoparticles to achieve active targeted drug delivery and overcome multidrug resistance. Biomaterials 31 5634–5642.

    Not in our library10.1016/j.biomaterials.2010.03.066

  47. 47.

    Fang R. H. Kroll A. V. Gao W. Zhang L. (2018 ). Cell Membrane Coating Nanotechnology. Adv. Mater. 30:e1706759.

    Not in our library10.1002/adma.201706759

  48. 48.

    Farokhzad O. C. Langer R. (2009 ). Impact of nanotechnology on drug delivery. ACS Nano 3 16–20.

    Not in our library10.1021/nn900002m

  49. 49.

    Fontana F. Liu D. Hirvonen J. Santos H. A. (2017a ). Delivery of therapeutics with nanoparticles: what’s new in cancer immunotherapy? Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 9:e1421.

    Not in our library10.1002/wnan.1421

  50. 50.

    Fontana F. Shahbazi M. A. Liu D. Zhang H. Mäkilä E. Salonen J. (2017b ). Multistaged Nanovaccines Based on Porous Silicon@Acetalated Dextran@Cancer Cell Membrane for Cancer Immunotherapy. Adv. Mater. 29:1603239.

    Not in our library10.1002/adma.201603239

  51. 51.

    Gao F. Wu J. Niu S. Sun T. Li F. Bai Y. (2019 ). Biodegradable, pH-Sensitive Hollow Mesoporous Organosilica Nanoparticle (HMON) with Controlled Release of Pirfenidone and Ultrasound-Target-Microbubble-Destruction (UTMD) for Pancreatic Cancer Treatment. Theranostics 9 6002–6018.

    Not in our library10.7150/thno.36135

  52. 52.

    Gao F. Zhang J. Fu C. Xie X. Peng F. You J. (2017 ). iRGD-modified lipid-polymer hybrid nanoparticles loaded with isoliquiritigenin to enhance anti-breast cancer effect and tumor-targeting ability. Int. J. Nanomed. 12 4147–4162.

    Not in our library10.2147/ijn.s134148

  53. 53.

    Geisberg C. A. Sawyer D. B. (2010 ). Mechanisms of anthracycline cardiotoxicity and strategies to decrease cardiac damage. Curr. Hypertens. Rep. 12 404–410.

    Not in our library10.1007/s11906-010-0146-y

  54. 54.

    Guo Y. Wang D. Song Q. Wu T. Zhuang X. Bao Y. (2015 ). Erythrocyte Membrane-Enveloped Polymeric Nanoparticles as Nanovaccine for Induction of Antitumor Immunity against Melanoma. ACS Nano 9 6918–6933.

    Not in our library10.1021/acsnano.5b01042

  55. 55.

    Hajizadeh F. Moghadaszadeh Ardebili S. Baghi Moornani M. Masjedi A. Atyabi F. Kiani M. (2020 ). Silencing of HIF-1α/CD73 axis by siRNA-loaded TAT-chitosan-spion nanoparticles robustly blocks cancer cell progression. Eur. J. Pharmacol. 882:173235.

    Not in our library10.1016/j.ejphar.2020.173235

  56. 56.

    Han B. Yang Y. Chen J. Tang H. Sun Y. Zhang Z. (2020 ). Preparation, Characterization, and Pharmacokinetic Study of a Novel Long-Acting Targeted Paclitaxel Liposome with Antitumor Activity. Int. J. Nanomed. 15 553–571.

    Not in our library10.2147/ijn.s228715

  57. 57.

    Han G. Ghosh P. Rotello V. M. (2007 ). Functionalized gold nanoparticles for drug delivery. Nanomedicine 2 113–123.

    Not in our library10.2217/17435889.2.1.113

  58. 58.

    He J. Gong C. Qin J. Li M. Huang S. (2019 ). Cancer Cell Membrane Decorated Silica Nanoparticle Loaded with miR495 and Doxorubicin to Overcome Drug Resistance for Effective Lung Cancer Therapy. Nanoscale Res. Lett. 14:339.

    Not in our library10.1186/s11671-019-3143-3

  59. 59.

    Hood J. D. Bednarski M. Frausto R. Guccione S. Reisfeld R. A. Xiang R. (2002 ). Tumor regression by targeted gene delivery to the neovasculature. Science 296 2404–2407.

    Not in our library10.1126/science.1070200

  60. 60.

    Hoopes P. J. Moodie K. L. Petryk A. A. Petryk J. D. Sechrist S. Gladstone D. J. (2017 ). Hypo-fractionated radiation, magnetic nanoparticle hyperthermia and a viral immunotherapy treatment of spontaneous canine cancer. Proc. SPIE Int. Soc. Opt. Eng. 10066:1006605

    Not in our library10.1117/12.2256213

  61. 61.

    Hrkach J. Von Hoff D. Mukkaram Ali M. Andrianova E. Auer J. Campbell T. (2012 ). Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci. Transl. Med. 4:128ra139.

    Not in our library10.1126/scitranslmed.3003651

  62. 62.

    Hu C. M. Kaushal S. Tran Cao H. S. Aryal S. Sartor M. Esener S. (2010 ). Half-antibody functionalized lipid-polymer hybrid nanoparticles for targeted drug delivery to carcinoembryonic antigen presenting pancreatic cancer cells. Mol. Pharm. 7 914–920.

    Not in our library10.1021/mp900316a

  63. 63.

    Hu Y. Hoerle R. Ehrich M. Zhang C. (2015 ). Engineering the lipid layer of lipid-PLGA hybrid nanoparticles for enhanced in vitro cellular uptake and improved stability. Acta Biomater. 28 149–159.

    Not in our library10.1016/j.actbio.2015.09.032

  64. 64.
    The use of lipid-based nanocarriers for targeted pain therapies · 2013
    No notice
  65. 65.

    Iwase Y. Maitani Y. (2012 ). Preparation and in vivo evaluation of liposomal everolimus for lung carcinoma and thyroid carcinoma. Biol. Pharm. Bull. 35 975–979.

    Not in our library10.1248/bpb.35.975

  66. 66.

    Jain R. K. (1994 ). Barriers to drug delivery in solid tumors. Sci. Am. 271 58–65.

    Not in our library10.1038/scientificamerican0794-58

  67. 67.

    Jiang Q. Liu Y. Guo R. Yao X. Sung S. Pang Z. (2019 ). Erythrocyte-cancer hybrid membrane-camouflaged melanin nanoparticles for enhancing photothermal therapy efficacy in tumors. Biomaterials 192 292–308.

    Not in our library10.1016/j.biomaterials.2018.11.021

  68. 68.

    Jiang Y. Huo S. Hardie J. Liang X. J. Rotello V. M. (2016 ). Progress and perspective of inorganic nanoparticle-based siRNA delivery systems. Expert. Opin. Drug Deliv. 13 547–559.

    Not in our library10.1517/17425247.2016.1134486

  69. 69.
    Role of hypoxia in cancer therapy by regulating the tumor microenvironment · 2019
    No notice
  70. 70.

    Kalyane D. Raval N. Maheshwari R. Tambe V. Kalia K. Tekade R. K. (2019 ). Employment of enhanced permeability and retention effect (EPR): nanoparticle-based precision tools for targeting of therapeutic and diagnostic agent in cancer. Mater. Sci. Eng. C Mater. Biol. Appl. 98 1252–1276.

    Not in our library10.1016/j.msec.2019.01.066

  71. 71.

    Kamaly N. Xiao Z. Valencia P. M. Radovic-Moreno A. F. Farokhzad O. C. (2012 ). Targeted polymeric therapeutic nanoparticles: design, development and clinical translation. Chem. Soc. Rev. 41 2971–3010.

    Not in our library10.1039/c2cs15344k

  72. 72.

    Khiste S. K. Liu Z. Roy K. R. Uddin M. B. Hosain S. B. Gu X. (2020 ). Ceramide-rubusoside nanomicelles, a potential therapeutic approach to target cancers carrying p53 missense mutations. Mol. Cancer Ther. 19 564–574.

    Not in our library10.1158/1535-7163.mct-19-0366

  73. 73.

    Kipp J. E. (2004 ). The role of solid nanoparticle technology in the parenteral delivery of poorly water-soluble drugs. Int. J. Pharm. 284 109–122.

    Not in our library10.1016/j.ijpharm.2004.07.019

  74. 74.

    Kong F. Zhang X. Zhang H. B. Qu X. M. Chen D. Servos M. (2015 ). Inhibition of Multidrug Resistance of Cancer Cells by Co-Delivery of DNA Nanostructures and Drugs Using Porous Silicon Nanoparticles@Giant Liposomes. Adv. Funct. Mater. 25 3330–3340.

    Not in our library10.1002/adfm.201500594

  75. 75.
    pH-responsive and targeted delivery of curcumin via phenylboronic acid-functionalized ZnO nanoparticles for breast cancer therapy · 2019
    No notice
  76. 76.

    Legge C. J. Colley H. E. Lawson M. A. Rawlings A. E. (2019 ). Targeted magnetic nanoparticle hyperthermia for the treatment of oral cancer. J. Oral Pathol. Med. 48 803–809.

    Not in our library10.1111/jop.12921

  77. 77.

    Lei W. Sun C. Jiang T. Gao Y. Yang Y. Zhao Q. (2019 ). Polydopamine-coated mesoporous silica nanoparticles for multi-responsive drug delivery and combined chemo-photothermal therapy. Mater. Sci. Eng. C Mater. Biol. Appl. 105:110103.

    Not in our library10.1016/j.msec.2019.110103

  78. 78.

    Lemière J. Carvalho K. Sykes C. (2015 ). Cell-sized liposomes that mimic cell motility and the cell cortex. Methods Cell Biol. 128 271–285.

    Not in our library10.1016/bs.mcb.2015.01.013

  79. 79.

    Li W. Liu Z. Fontana F. Ding Y. Liu D. Hirvonen J. T. (2018 ). Tailoring porous silicon for biomedical applications: from drug delivery to cancer immunotherapy. Adv. Mater. 30:e1703740.

    Not in our library10.1002/adma.201703740

  80. 80.

    Li W. Zhang H. Assaraf Y. G. Zhao K. Xu X. Xie J. (2016 ). Overcoming ABC transporter-mediated multidrug resistance: molecular mechanisms and novel therapeutic drug strategies. Drug Resist. Updat. 27 14–29.

    Not in our library10.1016/j.drup.2016.05.001

  81. 81.

    Li Y. Xiao Y. Lin H. P. Reichel D. Bae Y. Lee E. Y. (2019 ). In vivo β-catenin attenuation by the integrin α5-targeting nano-delivery strategy suppresses triple negative breast cancer stemness and metastasis. Biomaterials 188 160–172.

    Not in our library10.1016/j.biomaterials.2018.10.019

  82. 82.

    Lia N. G. Shib Z. H. Tang Y. P. Duan J. A. (2009 ). Selective matrix metalloproteinase inhibitors for cancer. Curr. Med. Chem. 16 3805–3827.

    Not in our library10.2174/092986709789178037

  83. 83.

    Lim E. K. Chung B. H. Chung S. J. (2018 ). Recent advances in pH-sensitive polymeric nanoparticles for smart drug delivery in cancer therapy. Curr. Drug Targets 19 300–317.

    Not in our library10.2174/1389450117666160602202339

  84. 84.

    Litman T. Brangi M. Hudson E. Fetsch P. Abati A. Ross D. D. (2000 ). The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter. MXR (ABCG2). J. Cell Sci. 113(Pt 11), 2011–2021.

    Not in our library10.1242/jcs.113.11.2011

  85. 85.

    Liu C. M. Chen G. B. Chen H. H. Zhang J. B. Li H. Z. Sheng M. X. (2019 ). Cancer cell membrane-cloaked mesoporous silica nanoparticles with a pH-sensitive gatekeeper for cancer treatment. Colloids Surf. B Biointerfaces 175 477–486.

    Not in our library10.1016/j.colsurfb.2018.12.038

  86. 86.

    Liu L. Wei Y. Zhai S. Chen Q. Xing D. (2015 ). Dihydroartemisinin and transferrin dual-dressed nano-graphene oxide for a pH-triggered chemotherapy. Biomaterials 62 35–46.

    Not in our library10.1016/j.biomaterials.2015.05.036

  87. 87.

    Long Q. Lin T. Y. Huang Y. Li X. Ma A. H. Zhang H. (2018 ). Image-guided photo-therapeutic nanoporphyrin synergized HSP90 inhibitor in patient-derived xenograft bladder cancer model. Nanomedicine 14 789–799.

    Not in our library10.1016/j.nano.2017.12.014

  88. 88.

    Low P. S. Kularatne S. A. (2009 ). Folate-targeted therapeutic and imaging agents for cancer. Curr. Opin. Chem. Biol. 13 256–262.

    Not in our library10.1016/j.cbpa.2009.03.022

  89. 89.

    Luan X. Guan Y. Y. Liu H. J. Lu Q. Zhao M. Sun D. (2018 ). A tumor vascular-targeted interlocking trimodal nanosystem that induces and exploits hypoxia. Adv. Sci. 5:1800034.

    Not in our library10.1002/advs.201800034

  90. 90.

    Luo E. Song G. Li Y. Shi P. Hu J. Lin Y. (2013 ). The toxicity and pharmacokinetics of carbon nanotubes as an effective drug carrier. Curr. Drug Metab. 14 879–890.

    Not in our library10.2174/138920021131400110

  91. 91.

    Madani S. Y. Naderi N. Dissanayake O. Tan A. Seifalian A. M. (2011 ). A new era of cancer treatment: carbon nanotubes as drug delivery tools. Int. J. Nanomed. 6 2963–2979.

    Not in our library10.2147/ijn.s16923

  92. 92.

    Maeda H. (2001 ). The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv. Enzyme Regul. 41 189–207.

    Not in our library10.1016/s0065-2571(00)00013-3

  93. 93.

    Mandriota G. Di Corato R. Benedetti M. De Castro F. Fanizzi F. P. Rinaldi R. (2019 ). Design and application of cisplatin-loaded magnetic nanoparticle clusters for smart chemotherapy. ACS Appl. Mater. Interfaces 11 1864–1875.

    Not in our library10.1021/acsami.8b18717

  94. 94.

    Mansour A. M. Drevs J. Esser N. Hamada F. M. Badary O. A. Unger C. (2003 ). A new approach for the treatment of malignant melanoma: enhanced antitumor efficacy of an albumin-binding doxorubicin prodrug that is cleaved by matrix metalloproteinase 2. Cancer Res. 63 4062–4066.

    Not in our library

  95. 95.

    Meng H. Wang M. Liu H. Liu X. Situ A. Wu B. (2015 ). Use of a lipid-coated mesoporous silica nanoparticle platform for synergistic gemcitabine and paclitaxel delivery to human pancreatic cancer in mice. ACS Nano 9 3540–3557.

    Not in our library10.1021/acsnano.5b00510

  96. 96.
    Combination Therapy using Co-encapsulated Resveratrol and Paclitaxel in Liposomes for Drug Resistance Reversal in Breast Cancer Cells in vivo · 2016
    No notice
  97. 97.

    Minko T. (2004 ). Drug targeting to the colon with lectins and neoglycoconjugates. Adv. Drug Deliv. Rev. 56 491–509.

    Not in our library10.1016/j.addr.2003.10.017

  98. 98.

    Misra R. Acharya S. Sahoo S. K. (2010 ). Cancer nanotechnology: application of nanotechnology in cancer therapy. Drug Discov. Today 15 842–850.

    Not in our library10.1016/j.drudis.2010.08.006

  99. 99.

    Misra R. Sahoo S. K. (2011 ). Coformulation of doxorubicin and curcumin in poly(D,L-lactide-co-glycolide) nanoparticles suppresses the development of multidrug resistance in K562 cells. Mol. Pharm. 8 852–866.

    Not in our library10.1021/mp100455h

  100. 100.

    Mottaghitalab F. Farokhi M. Fatahi Y. Atyabi F. Dinarvand R. (2019 ). New insights into designing hybrid nanoparticles for lung cancer: diagnosis and treatment. J. Control Release 295 250–267.

    Not in our library10.1016/j.jconrel.2019.01.009

  101. 101.

    Murakami M. Cabral H. Matsumoto Y. Wu S. Kano M. R. Yamori T. (2011 ). Improving drug potency and efficacy by nanocarrier-mediated subcellular targeting. Sci. Transl. Med. 3:64ra62.

    Not in our library10.1126/scitranslmed.3001385

  102. 102.

    Muralidharan R. Babu A. Amreddy N. Basalingappa K. Mehta M. Chen A. (2016 ). Folate receptor-targeted nanoparticle delivery of HuR-RNAi suppresses lung cancer cell proliferation and migration. J. Nanobiotechnol. 14:47.

    Not in our library10.1186/s12951-016-0201-1

  103. 103.

    Najafi-Hajivar S. Zakeri-Milani P. Mohammadi H. Niazi M. Soleymani-Goloujeh M. Baradaran B. (2016 ). Overview on experimental models of interactions between nanoparticles and the immune system. Biomed. Pharmacother. 83 1365–1378.

    Not in our library10.1016/j.biopha.2016.08.060

  104. 104.

    Nanjwade B. K. Bechra H. M. Derkar G. K. Manvi F. V. Nanjwade V. K. (2009 ). Dendrimers: emerging polymers for drug-delivery systems. Eur. J. Pharm. Sci. 38 185–196.

    Not in our library10.1016/j.ejps.2009.07.008

  105. 105.

    Navarro G. Sawant R. R. Biswas S. Essex S. Tros de Ilarduya C. Torchilin V. P. (2012 ). P-glycoprotein silencing with siRNA delivered by DOPE-modified PEI overcomes doxorubicin resistance in breast cancer cells. Nanomedicine 7 65–78.

    Not in our library10.2217/nnm.11.93

  106. 106.

    Nicholson R. I. Gee J. M. Harper M. E. (2001 ). EGFR and cancer prognosis. Eur. J. Cancer 37(Suppl. 4), S9–S15.

    Not in our library10.1016/s0959-8049(01)00231-3

  107. 107.

    Nisato R. E. Tille J. C. Jonczyk A. Goodman S. L. Pepper M. S. (2003 ). alphav beta 3 and alphav beta 5 integrin antagonists inhibit angiogenesis in vitro. Angiogenesis 6 105–119.

    Not in our library10.1023/b:agen.0000011801.98187.f2

  108. 108.

    Obaid G. Chambrier I. Cook M. J. Russell D. A. (2015 ). Cancer targeting with biomolecules: a comparative study of photodynamic therapy efficacy using antibody or lectin conjugated phthalocyanine-PEG gold nanoparticles. Photochem. Photobiol. Sci. 14 737–747.

    Not in our library10.1039/c4pp00312h

  109. 109.

    O’Brien M. E. Wigler N. Inbar M. Rosso R. Grischke E. Santoro A. (2004 ). Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann. Oncol. 15 440–449.

    Not in our library10.1093/annonc/mdh097

  110. 110.

    Orleth A. Mamot C. Rochlitz C. Ritschard R. Alitalo K. Christofori G. (2016 ). Simultaneous targeting of VEGF-receptors 2 and 3 with immunoliposomes enhances therapeutic efficacy. J. Drug Target 24 80–89.

    Not in our library10.3109/1061186x.2015.1056189

  111. 111.

    Palazzolo S. Bayda S. Hadla M. Caligiuri I. Corona G. Toffoli G. (2018 ). The clinical translation of organic nanomaterials for cancer therapy: a focus on polymeric nanoparticles, micelles, liposomes and exosomes. Curr. Med. Chem. 25 4224–4268.

    Not in our library10.2174/0929867324666170830113755

  112. 112.

    Pan H. Myerson J. W. Hu L. Marsh J. N. Hou K. Scott M. J. (2013 ). Programmable nanoparticle functionalization for in vivo targeting. FASEB J. 27 255–264.

    Not in our library10.1096/fj.12-218081

  113. 113.

    Park H. Yang J. Lee J. Haam S. Choi I. H. Yoo K. H. (2009 ). Multifunctional nanoparticles for combined doxorubicin and photothermal treatments. ACS Nano 3 2919–2926.

    Not in our library10.1021/nn900215k

  114. 114.

    Parodi A. Quattrocchi N. van de Ven A. L. Chiappini C. Evangelopoulos M. Martinez J. O. (2013 ). Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions. Nat. Nanotechnol. 8 61–68.

    Not in our library10.1038/nnano.2012.212

  115. 115.

    Patil Y. B. Swaminathan S. K. Sadhukha T. Ma L. Panyam J. (2010 ). The use of nanoparticle-mediated targeted gene silencing and drug delivery to overcome tumor drug resistance. Biomaterials 31 358–365.

    Not in our library10.1016/j.biomaterials.2009.09.048

  116. 116.

    Paulis L. E. Mandal S. Kreutz M. Figdor C. G. (2013 ). Dendritic cell-based nanovaccines for cancer immunotherapy. Curr. Opin. Immunol. 25 389–395.

    Not in our library10.1016/j.coi.2013.03.001

  117. 117.

    Pelicano H. Martin D. S. Xu R. H. Huang P. (2006 ). Glycolysis inhibition for anticancer treatment. Oncogene 25 4633–4646.

    Not in our library10.1038/sj.onc.1209597

  118. 118.

    Perica K. De León Medero A. Durai M. Chiu Y. L. Bieler J. G. Sibener L. (2014 ). Nanoscale artificial antigen presenting cells for T cell immunotherapy. Nanomedicine 10 119–129.

    Not in our library10.1016/j.nano.2013.06.015

  119. 119.

    Perrault S. D. Walkey C. Jennings T. Fischer H. C. Chan W. C. (2009 ). Mediating tumor targeting efficiency of nanoparticles through design. Nano Lett. 9 1909–1915.

    Not in our library10.1021/nl900031y

  120. 120.

    Prabha S. Labhasetwar V. (2004 ). Nanoparticle-mediated wild-type p53 gene delivery results in sustained antiproliferative activity in breast cancer cells. Mol. Pharm. 1 211–219.

    Not in our library10.1021/mp049970

  121. 121.

    Qin L. Wu L. Jiang S. Yang D. He H. Zhang F. (2018 ). Multifunctional micelle delivery system for overcoming multidrug resistance of doxorubicin. J. Drug Target 26 289–295.

    Not in our library10.1080/1061186x.2017.1379525

  122. 122.

    Reddy K. R. Guan Y. Qin G. Zhou Z. Jing N. (2011 ). Combined treatment targeting HIF-1α and Stat3 is a potent strategy for prostate cancer therapy. Prostate 71 1796–1809.

    Not in our library10.1002/pros.21397

  123. 123.

    Rey S. Schito L. Wouters B. G. Eliasof S. Kerbel R. S. (2017 ). Targeting Hypoxia-inducible factors for antiangiogenic cancer therapy. Trends Cancer 3 529–541.

    Not in our library10.1016/j.trecan.2017.05.002

  124. 124.

    Riley R. S. Day E. S. (2017 ). Gold nanoparticle-mediated photothermal therapy: applications and opportunities for multimodal cancer treatment. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 9:e1449.

    Not in our library10.1002/wnan.1449

  125. 125.

    Ruoslahti E. (2002 ). Specialization of tumour vasculature. Nat. Rev. Cancer 2 83–90.

    Not in our library10.1038/nrc724

  126. 126.

    Saad M. Garbuzenko O. B. Minko T. (2008 ). Co-delivery of siRNA and an anticancer drug for treatment of multidrug-resistant cancer. Nanomedicine 3 761–776.

    Not in our library10.2217/17435889.3.6.761

  127. 127.

    Samadian H. Hosseini-Nami S. Kamrava S. K. Ghaznavi H. Shakeri-Zadeh A. (2016 ). Folate-conjugated gold nanoparticle as a new nanoplatform for targeted cancer therapy. J. Cancer Res. Clin. Oncol. 142 2217–2229.

    Not in our library10.1007/s00432-016-2179-3

  128. 128.

    Saneja A. Kumar R. Mintoo M. J. Dubey R. D. Sangwan P. L. Mondhe D. M. (2019 ). Gemcitabine and betulinic acid co-encapsulated PLGA-PEG polymer nanoparticles for improved efficacy of cancer chemotherapy. Mater. Sci. Eng. C Mater. Biol. Appl. 98 764–771.

    Not in our library10.1016/j.msec.2019.01.026

  129. 129.

    Santi M. Maccari G. Mereghetti P. Voliani V. Rocchiccioli S. Ucciferri N. (2017 ). Rational Design of a Transferrin-Binding Peptide Sequence Tailored to Targeted Nanoparticle Internalization. Bioconjug. Chem. 28 471–480.

    Not in our library10.1021/acs.bioconjchem.6b00611

  130. 130.

    Satsangi A. Roy S. S. Satsangi R. K. Tolcher A. W. Vadlamudi R. K. Goins B. (2015 ). Synthesis of a novel, sequentially active-targeted drug delivery nanoplatform for breast cancer therapy. Biomaterials 59 88–101.

    Not in our library10.1016/j.biomaterials.2015.03.039

  131. 131.

    Schneider E. Hunke S. (1998 ). ATP-binding-cassette (ABC) transport systems: functional and structural aspects of the ATP-hydrolyzing subunits/domains. FEMS Microbiol. Rev. 22 1–20.

    Not in our library10.1111/j.1574-6976.1998.tb00358.x

  132. 132.

    Semenza G. L. (2007 ). Evaluation of HIF-1 inhibitors as anticancer agents. Drug Discov. Today 12 853–859.

    Not in our library10.1016/j.drudis.2007.08.006

  133. 133.

    Shao K. Singha S. Clemente-Casares X. Tsai S. Yang Y. Santamaria P. (2015 ). Nanoparticle-based immunotherapy for cancer. ACS Nano 9 16–30.

    Not in our library10.1021/nn5062029

  134. 134.

    Sherje A. P. Jadhav M. Dravyakar B. R. Kadam D. (2018 ). Dendrimers: a versatile nanocarrier for drug delivery and targeting. Int. J. Pharm. 548 707–720.

    Not in our library10.1016/j.ijpharm.2018.07.030

  135. 135.

    Shi J. Xiao Z. Kamaly N. Farokhzad O. C. (2011 ). Self-assembled targeted nanoparticles: evolution of technologies and bench to bedside translation. ACC Chem. Res. 44 1123–1134.

    Not in our library10.1021/ar200054n

  136. 136.

    Siegel R. L. Miller K. D. Jemal A. (2020 ). Cancer statistics, 2020. CA Cancer J. Clin. 70 7–30.

    Not in our library10.3322/caac.21590

  137. 137.
    Emerging functions of the EGFR in cancer · 2017
    No notice
  138. 138.

    Singh S. K. Lillard J. W. Jr. Singh R. (2018 ). Reversal of drug resistance by planetary ball milled (PBM) nanoparticle loaded with resveratrol and docetaxel in prostate cancer. Cancer Lett. 427 49–62.

    Not in our library10.1016/j.canlet.2018.04.017

  139. 139.
    Transferrin-Conjugated Polymeric Nanoparticle for Receptor-Mediated Delivery of Doxorubicin in Doxorubicin-Resistant Breast Cancer Cells · 2019
    Not checked
  140. 140.

    Soma C. E. Dubernet C. Bentolila D. Benita S. Couvreur P. (2000 ). Reversion of multidrug resistance by co-encapsulation of doxorubicin and cyclosporin A in polyalkylcyanoacrylate nanoparticles. Biomaterials 21 1–7.

    Not in our library10.1016/s0142-9612(99)00125-8

  141. 141.

    Su X. Wang Z. Li L. Zheng M. Zheng C. Gong P. (2013 ). Lipid-polymer nanoparticles encapsulating doxorubicin and 2′-deoxy-5-azacytidine enhance the sensitivity of cancer cells to chemical therapeutics. Mol. Pharm. 10 1901–1909.

    Not in our library10.1021/mp300675c

  142. 142.

    Sui H. Zhou S. Wang Y. Liu X. Zhou L. Yin P. (2011 ). COX-2 contributes to P-glycoprotein-mediated multidrug resistance via phosphorylation of c-Jun at Ser63/73 in colorectal cancer. Carcinogenesis 32 667–675.

    Not in our library10.1093/carcin/bgr016

  143. 143.

    Susa M. Iyer A. K. Ryu K. Hornicek F. J. Mankin H. Amiji M. M. (2009 ). Doxorubicin loaded Polymeric Nanoparticulate Delivery System to overcome drug resistance in osteosarcoma. BMC Cancer 9:399.

    Not in our library10.1186/1471-2407-9-399

  144. 144.

    Sykes E. A. Chen J. Zheng G. Chan W. C. (2014 ). Investigating the impact of nanoparticle size on active and passive tumor targeting efficiency. ACS Nano 8 5696–5706.

    Not in our library10.1021/nn500299p

  145. 145.

    Tang B. Peng Y. Yue Q. Pu Y. Li R. Zhao Y. (2020 ). Design, preparation and evaluation of different branched biotin modified liposomes for targeting breast cancer. Eur. J. Med. Chem. 193:112204.

    Not in our library10.1016/j.ejmech.2020.112204

  146. 146.

    Tang X. Li A. Xie C. Zhang Y. Liu X. Xie Y. (2020 ). The PI3K/mTOR dual inhibitor BEZ235 nanoparticles improve radiosensitization of hepatoma cells through apoptosis and regulation DNA repair pathway. Nanoscale Res. Lett. 15:63.

    Not in our library10.1186/s11671-020-3289-z

  147. 147.

    Torchilin V. P. (2005 ). Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug Discov. 4 145–160.

    Not in our library10.1038/nrd1632

  148. 148.

    Vadde R. Vemula S. Jinka R. Merchant N. Bramhachari P. V. Nagaraju G. P. (2017 ). Role of hypoxia-inducible factors (HIF) in the maintenance of stemness and malignancy of colorectal cancer. Crit. Rev. Oncol. Hematol. 113 22–27.

    Not in our library10.1016/j.critrevonc.2017.02.025

  149. 149.

    van Vlerken L. E. Duan Z. Little S. R. Seiden M. V. Amiji M. M. (2010 ). Augmentation of therapeutic efficacy in drug-resistant tumor models using ceramide coadministration in temporal-controlled polymer-blend nanoparticle delivery systems. AAPS J. 12 171–180.

    Not in our library10.1208/s12248-010-9174-4

  150. 150.

    Venturoli D. Rippe B. (2005 ). Ficoll and dextran vs. globular proteins as probes for testing glomerular permselectivity: effects of molecular size, shape, charge, and deformability. Am. J. Physiol. Renal. Physiol. 288 F605–F613.

    Not in our library10.1152/ajprenal.00171.2004

  151. 151.

    Viktorsson K. Lewensohn R. Zhivotovsky B. (2005 ). Apoptotic pathways and therapy resistance in human malignancies. Adv. Cancer Res. 94 143–196.

    Not in our library10.1016/s0065-230x(05)94004-9

  152. 152.

    Wang D. Dong H. Li M. Cao Y. Yang F. Zhang K. (2018a ). Erythrocyte-Cancer Hybrid Membrane Camouflaged Hollow Copper Sulfide Nanoparticles for Prolonged Circulation Life and Homotypic-Targeting Photothermal/Chemotherapy of Melanoma. ACS Nano 12 5241–5252.

    Not in our library10.1021/acsnano.7b08355

  153. 153.

    Wang H. Agarwal P. Zhao G. Ji G. Jewell C. M. Fisher J. P. (2018b ). Overcoming Ovarian Cancer Drug Resistance with a Cold Responsive Nanomaterial. ACS Cent. Sci. 4 567–581.

    Not in our library10.1021/acscentsci.8b00050

  154. 154.
    Targeted production of reactive oxygen species in mitochondria to overcome cancer drug resistance · 2018
    Retracted
  155. 155.

    Wang H. Zhang F. Wen H. Shi W. Huang Q. Huang Y. (2020 ). Tumor- and mitochondria-targeted nanoparticles eradicate drug resistant lung cancer through mitochondrial pathway of apoptosis. J. Nanobiotechnol. 18:8.

    Not in our library10.1186/s12951-019-0562-3

  156. 156.

    Wang Q. Alshaker H. Böhler T. Srivats S. Chao Y. Cooper C. (2017 ). Core shell lipid-polymer hybrid nanoparticles with combined docetaxel and molecular targeted therapy for the treatment of metastatic prostate cancer. Sci. Rep. 7:5901.

    Not in our library10.1038/s41598-017-06142-x

  157. 157.

    Wang X. Liu X. Li Y. Wang P. Feng X. Liu Q. (2017 ). Sensitivity to antitubulin chemotherapeutics is potentiated by a photoactivable nanoliposome. Biomaterials 141 50–62.

    Not in our library10.1016/j.biomaterials.2017.06.034

  158. 158.

    Wang Y. Gao S. Ye W. H. Yoon H. S. Yang Y. Y. (2006 ). Co-delivery of drugs and DNA from cationic core-shell nanoparticles self-assembled from a biodegradable copolymer. Nat. Mater. 5 791–796.

    Not in our library10.1038/nmat1737

  159. 159.

    Wong C. Stylianopoulos T. Cui J. Martin J. Chauhan V. P. Jiang W. (2011 ). Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc. Natl. Acad. Sci. U.S.A. 108 2426–2431.

    Not in our library10.1073/pnas.1018382108

  160. 160.

    Xia S. Yu S. Yuan X. (2005 ). Effects of hypoxia on expression of P-gp and mutltidrug resistance protein in human lung adenocarcinoma A549 cell line. J. Huazhong Univ. Sci. Technolog. Med. Sci. 25 279–281.

    Not in our library10.1007/bf02828142

  161. 161.

    Xiao Q. Zhu X. Yuan Y. Yin L. He W. (2018 ). A drug-delivering-drug strategy for combined treatment of metastatic breast cancer. Nanomedicine 14 2678–2688.

    Not in our library10.1016/j.nano.2018.06.012

  162. 162.
    Mesoporous Silica Nanoparticles for Protein Protection and Delivery · 2019
    No notice
  163. 163.

    Yang Q. Jones S. W. Parker C. L. Zamboni W. C. Bear J. E. Lai S. K. (2014 ). Evading immune cell uptake and clearance requires PEG grafting at densities substantially exceeding the minimum for brush conformation. Mol. Pharm. 11 1250–1258.

    Not in our library10.1021/mp400703d

  164. 164.

    Yang R. Xu J. Xu L. Sun X. Chen Q. Zhao Y. (2018 ). Cancer cell membrane-coated adjuvant nanoparticles with mannose modification for effective anticancer vaccination. ACS Nano 12 5121–5129.

    Not in our library10.1021/acsnano.7b09041

  165. 165.

    Yari H. Nkepang G. Awasthi V. (2019 ). Surface modification of liposomes by a lipopolymer targeting prostate specific membrane antigen for theranostic delivery in prostate cancer. Materials 12:756.

    Not in our library10.3390/ma12050756

  166. 166.

    Yoon H. Y. Selvan S. T. Yang Y. Kim M. J. Yi D. K. Kwon I. C. (2018 ). Engineering nanoparticle strategies for effective cancer immunotherapy. Biomaterials 178 597–607.

    Not in our library10.1016/j.biomaterials.2018.03.036

  167. 167.

    Yu B. Song N. Hu H. Chen G. Shen Y. Cong H. (2018 ). A degradable triple temperature-, pH-, and redox-responsive drug system for cancer chemotherapy. J. Biomed. Mater. Res. A 106 3203–3210.

    Not in our library10.1002/jbm.a.36515

  168. 168.

    Zang X. Zhao X. Hu H. Qiao M. Deng Y. Chen D. (2017 ). Nanoparticles for tumor immunotherapy. Eur. J. Pharm. Biopharm. 115 243–256.

    Not in our library10.1016/j.ejpb.2017.03.013

  169. 169.

    Zhang F. Correia A. Mäkilä E. Li W. Salonen J. Hirvonen J. J. (2017 ). Receptor-mediated surface charge inversion platform based on porous silicon nanoparticles for efficient cancer cell recognition and combination therapy. ACS Appl. Mater. Interfaces 9 10034–10046.

    Not in our library10.1021/acsami.7b02196

  170. 170.

    Zhang R. X. Ahmed T. Li L. Y. Li J. Abbasi A. Z. Wu X. Y. (2017 ). Design of nanocarriers for nanoscale drug delivery to enhance cancer treatment using hybrid polymer and lipid building blocks. Nanoscale 9 1334–1355.

    Not in our library10.1039/c6nr08486a

  171. 171.

    Zhang J. Wang L. You X. Xian T. Wu J. Pang J. (2019 ). Nanoparticle therapy for prostate cancer: overview and perspectives. Curr. Top. Med. Chem. 19 57–73.

    Not in our library10.2174/1568026619666190125145836

  172. 172.

    Zhang S. Guo N. Wan G. Zhang T. Li C. Wang Y. (2019 ). pH and redox dual-responsive nanoparticles based on disulfide-containing poly(β-amino ester) for combining chemotherapy and COX-2 inhibitor to overcome drug resistance in breast cancer. J. Nanobiotechnol. 17:109.

    Not in our library10.1186/s12951-019-0540-9

  173. 173.

    Zhang J. Zhang Q. Lou Y. Fu Q. Chen Q. Wei T. (2018 ). Hypoxia-inducible factor-1α/interleukin-1β signaling enhances hepatoma epithelial-mesenchymal transition through macrophages in a hypoxic-inflammatory microenvironment. Hepatology 67 1872–1889.

    Not in our library10.1002/hep.29681

  174. 174.

    Zhang L. Chan J. M. Gu F. X. Rhee J. W. Wang A. Z. Radovic-Moreno A. F. (2008 ). Self-assembled lipid–polymer hybrid nanoparticles: a robust drug delivery platform. ACS Nano 2 1696–1702.

    Not in our library10.1021/nn800275r

  175. 175.

    Zhao M. D. Li J. Q. Chen F. Y. Dong W. Wen L. J. Fei W. D. (2019 ). Co-Delivery of Curcumin and Paclitaxel by “Core-Shell” targeting amphiphilic copolymer to reverse resistance in the treatment of ovarian cancer. Int. J. Nanomed. 14 9453–9467.

    Not in our library10.2147/ijn.s224579

  176. 176.

    Zhao X. Li F. Li Y. Wang H. Ren H. Chen J. (2015 ). Co-delivery of HIF1α siRNA and gemcitabine via biocompatible lipid-polymer hybrid nanoparticles for effective treatment of pancreatic cancer. Biomaterials 46 13–25.

    Not in our library10.1016/j.biomaterials.2014.12.028

  177. 177.

    Zhao Y. Huan M. L. Liu M. Cheng Y. Sun Y. Cui H. (2016 ). Doxorubicin and resveratrol co-delivery nanoparticle to overcome doxorubicin resistance. Sci. Rep. 6:35267.

    Not in our library10.1038/srep35267

  178. 178.

    Zhou Q. Zhang L. Yang T. Wu H. (2018 ). Stimuli-responsive polymeric micelles for drug delivery and cancer therapy. Int. J. Nanomed. 13 2921–2942.

    Not in our library10.2147/ijn.s158696

  179. 179.

    Zitvogel L. Apetoh L. Ghiringhelli F. Kroemer G. (2008 ). Immunological aspects of cancer chemotherapy. Nat. Rev. Immunol. 8 59–73.

    Not in our library10.1038/nri2216

  180. 180.

    Zylberberg C. Matosevic S. (2016 ). Pharmaceutical liposomal drug delivery: a review of new delivery systems and a look at the regulatory landscape. Drug Deliv. 23 3319–3329.

    Not in our library10.1080/10717544.2016.1177136

Cited by papers we hold 13

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.