Hyaluronan-modified nanoparticles for tumor-targeting

ABSTRACT

Introduction: Hyaluronan (HA), a natural polysaccharide, is produced in large amounts by the human body. Since its receptor CD44 is highly expressed in many types of cancers, HA is a promising ligand for cancer-targeting nanoparticles (NPs). Since the enhanced permeability and retention (EPR) effect-based strategy faces difficulties in terms of efficiency in clinical studies, studies focusing on HA-modified NPs that can actively target cancer cells should be prominent for further progress in NP-based cancer treatment.

Areas covered: Various materials combined with HA composed of lipid nanoparticles and polymers as well as iron, gold and other metals have been examined. In addition, their cargos have been quite diverse and include small molecule drugs, imaging agents, proteins and nucleic acids. We summarize recent studies on varieties of NPs and describe the properties of HA as a ligand of CD44.

Expert opinion: In spite of a number of studies on HA-based NPs, there is few examples of HA-based NPs in clinical. In order to make a progress in clinical study, an evaluation methodology of HA-NPs should be unified and normalized.     

Doxorubicin-Bound Albumin Nanoparticles Containing a TRAIL Protein for Targeted Treatment of Colon Cancer

Purpose

We developed a new nanoparticle formulation comprised of human serum albumin (HSA) for co-delivery of doxorubicin (Dox) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with the goal of apoptotic synergy in the treatment of colon cancer.

Methods

TRAIL (0.2, 0.4, 1.0%)- and Dox-loaded HSA nanoparticles (TRAIL/Dox HSA NPs) were prepared by using the nab^TM technology. Morphological and physicochemical characterizations were investigated by dynamic light scattering and transmission electron microscopy. Synergistic cytotoxicity, apoptotic activity, and potential penetration into mass tumor were determined in HCT116 cell-based systems. Furthermore, antitumor efficacy and tumor targeting were also investigated.

Results

TRAIL/Dox HSA NPs were uniformly spherical with sizes of 60?~?120 nm. The encapsulation efficacy of Dox and TRAIL was 68.9–77.2% and 80.4–86.0%, respectively. TRAIL 1.0%/Dox HSA NPs displayed the best inhibition of HCT116 colon cancer cells; inhibition was 6 times higher than achieved with Dox HSA NPs. The TRAIL 1.0%/Dox HSA NPs formulation was studied further. Flow cytometry analysis and TUNEL assay revealed that TRAIL 1.0%/Dox HSA NPs had markedly greater apoptotic activity than Dox HSA NPs. In HCT116 tumor-bearing BALB/c nu/nu mice, TRAIL 1.0%/Dox HSA NPs had significantly higher antitumor efficacy than Dox HSA NPs (tumor volume; 933.4 mm³ vs. 3183.7 mm³, respectively). TRAIL 1.0%/Dox HSA NPs penetrated deeply into tumor masses in a HCT116 spheroid model and localized in tumor sites after tail vein injection.

Conclusions

Data indicate that TRAIL 1.0%/Dox HSA NPs offer advantages of co-delivery of Dox and TRAIL in tumors, with potential synergistic apoptosis-based anticancer therapy.

     

The cellular immunotherapy of integrated photothermal anti-oxidation Pd–Se nanoparticles in inhibition of the macrophage inflammatory response in rheumatoid arthritis

Reducing the inflammatory response is a major goal in the therapy of rheumatoid arthritis (RA). Herein, we integrated palladium nanoparticles (Pd NPs) with selenium nanoparticles (Se NPs) and obtained a multiple nanosystem (Pd@Se-HA NPs) that could simultaneously scavenge hydroxyl radicals (⋅OH) and provide a photothermal effect. The Pd@Se-HA NPs were constructed by a simple self-assembly method in which Se NPs were electrostatically bonded to Pd NPs; hyaluronic acid (HA) was linked to the NPs by ester bonding to provide macrophage targeting ability. The experiments show that the combined therapy of eliminating ⋅OH with Se NPs and utilizing PTT with Pd NPs could effectively reduce the inflammatory response in macrophages more effectively than either individual NP treatment. In addition, the outer layer of HA could specifically target the CD44 receptor to enhance the accumulation of Pd@Se NPs at the lesion, further enhancing the therapeutic effect. After treatment for 15 days, the Pd@Se-HA NPs nearly eliminated the inflammatory response in the joints of mice in an induced RA model, and prevented joint damage and degradation.KEY WORDS: Rheumatoid arthritis, Inflammatory response, Photothermal therapy, Anti-oxidation therapy, Core‒shell structure     

Targeted and controlled drug delivery system loading artersunate for effective chemotherapy on CD44 overexpressing cancer cells

Poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles with negative surface charge were reversed to positive by cationic surfactant-DDAB before being coated with an anionic polymer, hyaluronic acid, to improve their site-specific intracellular delivery against CD44 receptor overexpressing cancer cells. Incorporating artesunate (ART)—a promising anticancer drug into PLGA/HA nanoparticles, is expected not only to overcome its poor aqueous solubility and stability but also enhance the activities. The obtained particles were characterized by dynamic light scattering, zeta potential measurements, and transmission electron microscopy (TEM). Cancer cell internalization of the NPs was evaluated by flow cytometry and cytotoxicity of the NPs was tested by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay. PLGA/HA nanoparticles showed greater extent of cellular uptake to SCC-7 and MCF-7 cells, indicating their affinity with CD44 receptor-mediated endocytosis. Almost 60 % of ART was released into the outer media after 48 h. In vitro fluorescence sorting demonstrated that PLGA/HA had highly efficient targeting and accumulation into CD44 receptor overexpression cells. The significant reduction in cell viability as well as greater induction of apoptosis suggested a potential in anticancer therapy of ART loaded PLGA/HA.     

CD44 directed nanomicellar payload delivery platform for selective anticancer effect and tumor specific imaging of triple negative breast cancer

Triple negative breast cancer (TNBC) is a highly aggressive tumor subtype, lacking estrogen, progesterone and human epidermal growth factor-2 (HER-2) receptors. Thus, early detection and targeted therapy of TNBC is an urgent need. Herein, we have developed a CD44 targeting Hyaluronic Acid (HA) decorated biocompatible oligomer, containing FDA approved vitamin E TPGS and Styrene Maleic Anhydride (SMA) (HA-SMA-TPGS) for targeting TNBC. The self-assembling HA-SMA-TPGS was encapsulated with poorly water soluble, potent curcumin analogue (CDF) to form nanomicelles (NM), HA-SMA-TPGS-CDF has demonstrated excellent nanoparticle characteristics for parenteral delivery. The targeted NM can selectively kill TNBC cells through CD44 mediated apoptosis pathway. Tumor imaging using phase-2 clinical trial near infrared (NIR)-fluorescent dye (S0456) conjugate, HA-SMA-TPGS-S0456 showed excellent TNBC tumor accumulation with minimum liver and spleen uptake. To our best of knowledge, for the first time, we are reporting a promising platform for CD44 mediated multimodal NIR imaging and cytotoxin delivery to TNBC.     

Nanoparticle Surface Charges Alter Blood–Brain Barrier Integrity and Permeability

Purpose: The blood–brain barrier (BBB) presents both a physical and electrostatic barrier to limit brain permeation of therapeutics. Previous work has demonstrated that nanoparticles (NPs) overcome the physical barrier, but there is little known regarding the effect of NP surface charge on BBB function. Therefore, this work evaluated: (1) effect of neutral, anionic and cationic charged NPs on BBB integrity and (2) NP brain permeability.

Methods: Emulsifying wax NPs were prepared from warm oil-in-water microemulsion precursors using neutral, anionic or cationic surfactants to provide the corresponding NP surface charge. NPs were characterized by particle size and zeta potential. BBB integrity and NP brain permeability were evaluated by in situ rat brain perfusion.

Results: Neutral NPs and low concentrations of anionic NPs were found to have no effect on BBB integrity, whereas, high concentrations of anionic NPs and cationic NPs disrupted the BBB. The brain uptake rates of anionic NPs at lower concentrations were superior to neutral or cationic formulations at the same concentrations.

Conclusions: (1) Neutral NPs and low concentration anionic NPs can be utilized as colloidal drug carriers to brain, (2) cationic NPs have an immediate toxic effect at the BBB and (3) NP surface charges must be considered for toxicity and brain distribution profiles.     

Bisphosphonate-coated BSA nanoparticles lack bone targeting after systemic administration

A polymeric conjugate of polyethyleneimine-graft-poly(ethylene glycol) and 2-(3-mercaptopropylsulfanyl)-ethyl-1,1-bisphosphonic acid (PEI-PEG-thiolBP) was prepared and used for surface coating of bovine serum albumin (BSA) nanoparticles (NPs) designed for bone-specific delivery of bone morphogenetic protein-2 (BMP-2). The NP coating was achieved with a dialysis and an evaporation method, and the obtained NPs were characterized by particle size, ζ-potential, morphology, and cytotoxicity in vitro. The particle size and surface charge of the NPs could be effectively tuned by the PEG and thiolBP substitution ratios of the conjugate, the coating method, and the polymer concentration used for coating. The PEG modification on PEI reduced the toxicity of PEI and the coated NPs, based on in vitro assessment with human C2C12 cells and rat bone marrow stromal cells. On the basis of an alkaline phosphatase (ALP) induction assay, the NP-encapsulated BMP-2 displayed full retention of its bioactivity, except for BMP-2 in PEI-coated NPs. By encapsulating ¹²⁵I-labeled BMP-2, the polymer-coated NPs were assessed for hydroxyapatite (HA) affinity; all NP-encapsulated BMP-2 showed significant affinity to HA as compared with free BMP-2 in vitro, and the PEI-PEG-thiolBP coated NPs improved the in vivo retention of BMP-2 compared with uncoated NPs. However, the biodistribution of NPs after intravenous injection in a rat model indicated no beneficial effects of thiolBP-coated NPs for bone targeting. Our results suggested that the BP-conjugated NPs are useful for localized delivery of BMP-2 in bone repair and regeneration, but they are not effective for bone targeting after intravenous administration.     

Effects of poly(ethylene glycol) grafting density on the tumor targeting efficacy of nanoparticles with ligand modification

Abstract

To evaluate the effects of poly(ethylene glycol) (PEG) grafting density on the tumor targeting efficacy of nanoparticles (NPs) with ligand modification, various amounts of PEG were conjugated to linoleic acid and poly(β-malic acid) double grafted chitosan (LMC) NPs bearing similar substitution degree of folate (FA). Increased particle size, decreased surface charge, reduced contact angle, retarded drug release and suppressed protein adsorption of LMC NPs were detected after surface modification. Compared to LMC NPs, FA-modified LMC NPs (FA-LMC NPs) remarkably enhanced tumor specificity. For PEG-modified FA-LMC NPs, increased drug accumulation in tumor tissues and reduced cellular uptake were observed with the increase of PEG grafting density. In regard to in vivo antitumor efficacy, FA-LMC NPs with moderate PEG grafting density (8.9%) significantly outperformed FA-LMC NP. Therefore, PEG modification with moderate grafting density could be a promising approach to coordinating with the tumor targeting efficacy of ligand-modified NPs.     

Surfactant protein D (SP-D) alters cellular uptake of particles and nanoparticles

Abstract

Surfactant protein D (SP-D) is primarily expressed in the lungs and modulates pro- and anti-inflammatory processes to toxic challenge, maintaining lung homeostasis. We investigated the interaction between NPs and SP-D and subsequent uptake by cells involved in lung immunity. Dynamic light scattering (DLS) and scanning electron microscopy (SEM) measured NP aggregation, particle size and charge in native human SP-D (NhSP-D) and recombinant fragment SP-D (rfhSP-D). SP-D aggregated NPs, especially following the addition of calcium. Immunohistochemical analysis of A549 epithelial cells investigated the co-localization of NPs and rfhSP-D. rfhSP-D enhanced the co-localisation of NPs to epithelial A549 cells in vitro. NP uptake by alveolar macrophages (AMs) and lung dendritic cells (LDCs) from C57BL/6 and SP-D knock-out mice were compared. AMs and LDCs showed decreased uptake of NPs in SP-D deficient mice compared to wild-type mice. These data confirmed an interaction between SP-D and NPs, and subsequent enhanced NP uptake.     

Effect of ligand density,receptor density,and nanoparticle size on cell targeting

It is generally accepted that the presentation of multiple ligands on a nanoparticle (NP) surface can improve cell targeting; however, little work has been done to determine whether an optimal ligand density exists. We have recently developed a site-specific bioconjugation strategy that allows for distinct control of ligand density on a NP through the combined utilization of expressed protein ligation (EPL) and copper-free click chemistry. This EPL-Click conjugation strategy was applied to create superparamagnetic iron oxide (SPIO) NPs labeled with HER2/neu targeting affibodies at differing ligand densities. It was discovered that an intermediate ligand density provided statistically significant improvements in cell binding in comparison with higher and lower ligand densities. This intermediate optimal ligand density was conserved across NPs with differing hydrodynamic diameters, different HER2/neu targeting ligands and also to cells with lower receptor densities. Additionally, an intermediate optimal ligand density was also evident when NPs were labeled with folic acid.From the Clinical EditorThe authors of this study investigated optimal ligand density with SPIO-based labeling and concluded that intermediate density appears to have the most optimal labeling properties from the standpoint of its T2* shortening effect.     

Curcumin: a calixarene derivative micelle potentiates anti-breast cancer stem cells effects in xenografted,triple-negative breast cancer mouse models

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease with no approved targeted therapy. Curcumin has shown therapeutic potential against TNBC, but it shows low bioavailability and low efficacy when administered as a free drug. Here we describe a novel vehicle for in vivo delivery of curcumin based on the phosphorylated calixarene POCA4C6. Curcumin-loaded POCA4C6 micelles (CPM) were prepared using the thin-film method and they showed a unilamellar structure with an average particle size of 3.86?nm. The micelles showed high curcumin encapsulation efficiency and loading was based on liquid chromatography-tandem mass spectrometry. Studies with cell cultures suggest that CPM can sustainably release curcumin in a pH-dependent manner. The micelles efficiently inhibited proliferation, invasion, migration and tumor spheroid formation by BT-549 human breast cancer cells. These effects involved increased apoptosis and reduced levels of nuclear β-catenin and androgen receptor. After injection into tumor xenografts, CPM persisted in the tumor tissue and efficiently inhibited tumor growth without causing obvious systemic toxicity. CPM also significantly reduced levels of CD44⁺/CD133⁺ breast cancer stem cells. Our results highlight the potential of CPM as an effective therapy against TNBC.     

Anti-miRNA21 and resveratrol-loaded polysaccharide-based mesoporous silica nanoparticle for synergistic activity in gastric carcinoma

Abstract

Anti-miR21 and resveratrol (RSV)-loaded mesoporous silica nanoparticles (MSNs) conjugated with hyaluronic acid (HA) were developed to enhance therapeutic efficacy in gastric carcinoma. The surface conjugation of HA, which acts as a targeting ligand to the overexpressed CD44 receptor on gastric cancer cells, was clearly identified by the presence of a greyish shell on the dark MSNs. Confocal laser-scanning microscopy and flow cytometry analysis showed higher cellular internalisation of HA/RSVmirNP compared to RSVmirNP. In vitro cytotoxicity and apoptosis assays confirmed the superior anticancer effect of the optimised formulation and synergistic effects of anti-miR21 and RSV in gastric cancer cells. Importantly, HA/RSVmirNP showed significant (p?<?.001) reductions in the tumour burden compared to the other group. Indeed, HA/RSVmirNP showed a threefold higher tumour regression effect compared to that of free RSV and a twofold tumour regression effect compared to that of RSVmirNP, indicating its anticancer efficacy. The percentage of TUNEL-positive cells was significantly higher in HA/RSVmirNP-treated cells compared to any other group, indicating that the mechanism underlying the superior anticancer efficacy of HA/RSVmirNP included apoptosis and cell necrosis. Thus, a combination of anti-miR21 and RSV in a targeted nanocarrier might be a promising drug delivery system for gastric cancer therapy.     

Positive hyaluronan/PEI/DNA complexes as a target-specific intracellular delivery to malignant breast cancer

In the present study, The PEI/DNA (PD) complexes was first prepared with positive surface charge under a suitable N/P ratio of 10. The redundant positive charge was partially and excessively shielded by a polysaccharide, hyaluronic acid (HA), in aqueous solution. The HA/PEI/DNA ternary complexes were characterized by assessing the zeta potential and size, then transferred to MDA-MB-435, MDA-MB-231, and MCF-7 cell lines with different amounts of HA-specific CD44 receptors on the surface. Consequently, The transfection efficiency of all the prepared complexes show a little increased to MCF-7 (low CD44 level) while a large increased to MDA-MB-231 and MDA-MB-435 cells (high CD44 level) with adding HA. Also, when HA:PEI charge ratio was 7.5%, the ternary complexes show the highest transfection efficiency. The prepared ternary complexes exhibited increased 2–13-fold fluorescence intensity and lower cell toxicity compared to the PD (N/P, 10). These results indicated that the positive HA/PEI/DNA ternary complexes (HA:PEI charge ratio, 7.5%) can target malignant breast cancer cells with high CD44 level and might be a promising candidate vector for gene therapy.     

Prodrug-based nano-drug delivery system for co-encapsulate paclitaxel and carboplatin for lung cancer treatment

Context: Paclitaxel (PTX) and carboplatin (CBP) are widely used for the combined chemotherapy of non-small cell lung cancer (NSCLC). However, the development of multidrug resistance of cancer cells, as well as systemic toxic side effects resulting from nonspecific localization of anticancer drugs to non-tumor areas are major obstacles to the success of chemotherapy in treating cancers.

Objective: This study aimed to engineer a prodrug-based nano-drug delivery system for co-encapsulate hydrophilic (CBP) and hydrophobic anti-tumor drugs (PTX). This system was expected to resolve the multidrug resistance cause by single drug, and the dual-drug-loaded liposome was also planned to specifically target the cancer cells without obvious influence on normal cells and tissues.

Methods: In this paper, PLGA-PEG-CBP was synthesized by the conjugation between the carboxylic group of PLGA-PEG-COOH and the amino group of CBP. Then, self-assembled nanoparticles for combination delivery of PTX and PLGA-PEG-CBP (PTX/CBP NPs) were prepared by solvent displacement technique. The in vitro and in vivo anti-tumor efficacy was assessed in NCL-H460 human non-small cell lung carcinoma cell line.

Results: PTX/CBP NPs achieved the highest cytotoxic effect among all formulations in vitro, as compared with single drug delivery NPs. In vivo investigation on NSCLC animal models showed that co-delivery of PTX and CBP possessed high tumor-targeting capacity and strong anti-tumor activity.

Conclusions: The PTX/CBP NPs constructed in this research offers an effective strategy for targeted combinational lung cancer therapy.     

Non-covalent ligand conjugation to biotinylated DNA nanoparticles using TAT peptide genetically fused to monovalent streptavidin

DNA nanoparticles (DNA NPs), which self-assemble from DNA plasmids and poly-L-lysine (pLL)-polyethylene glycol (PEG) block copolymers, transfect several cell types in vitro and in vivo with minimal toxicity and immune response. To further enhance the gene transfer efficiency of DNA NP and control its tropism, we established a strategy to efficiently attach peptide ligands to DNA NPs. The non-covalent biotin–streptavidin (SA) interaction was used for ligand conjugation to overcome problems associated with covalent conjugation methods. A fusion protein of SA with the HIV-1 TAT peptide was cloned, expressed, purified and attached to biotinylated DNA NPs. A modified SA system with tetrameric structure but monovalent biotin binding capacity was adopted and shown to reduce the aggregation of biotinylated DNA NPs compared to neutravidin. Compared to unmodified DNA NPs, TAT modified DNA NPs significantly enhanced in vitro gene transfer, particularly at low DNA concentrations. Studies of cellular uptake and cellular distribution of the DNA NPs indicated that attaching TAT enhanced binding of DNA NPs to cell surface but not internalization at high DNA concentrations. In vivo studies showed that TAT modified DNA NPs mediated equal level of gene transfer to the mouse airways via the luminal route compared to unmodified DNA NPs.     

Cellular interactions of therapeutically delivered nanoparticles

Introduction: Nanoparticles (NPs) are used extensively in drug delivery. They are administered through various routes in the host, and their uptake by the cellular environment has been observed in several pathways. After uptake, NPs interact with cells to different extents, depending on their size, shape, surface properties, ligands tagged to the surface and tumor architecture. Complete understanding of such cellular uptake mechanisms and interactions of NPs is important for their effective use in drug delivery.

Areas covered: This article describes the various cellular pathways for NP uptake, and the factors affecting NP uptake and interactions with cells. Understanding these two important aspects will help in the future design of NPs for effective and targeted drug delivery.

Expert opinion: Surface charge and ligands tagged on the surface of NPs play a critical role in their uptake and interaction with cells; so surface modifications of NPs can offer increased drug delivery effectiveness, for example, the coupling of ligands on the surface of NPs can increase cellular binding, and NPs in biological fluids can be coated with proteins and as such can exert biological effects. All of the factors affecting NP uptake need to be investigated thoroughly before interpreting any NP–cellular interactions.     

Effects of synthetic <Emphasis Type="Italic">para</Emphasis>-nonylphenol isomers administered chronically throughout pregnancy and lactation on reproductive system of mouse pups

The aim of this study was to analyze the effects of synthetic para-nonylphenol isomers administered chronically throughout pregnancy and lactation on the reproductive system of mouse pups. The two synthetic isomers used in this study showed higher (3E22NP) or lower (44NP) estrogen receptor (ER) binding activity on in vitro yeast assay than a commercial NP (NPmix). Female mice were implanted with a tube filled with one of three NPs and estradiol-17β (E2) before mating. The tube was kept in the mice throughout pregnancy and lactation period, until their pups had weaned at 28 days of age (PND 28). The data indicated that in males, NPs decreased body weight in some dose groups on PND28 and increased weights of testes and epididymides. However, the rate of seminiferous tubules having elongate spermatids (steps10–16) decreased significantly in NPs and E2 treated groups, except for the 44NP groups. In female mice, NPs and E2 increased weights of ovaries, uterus and vagina in the pups in some dose groups on PND 28. However, there were no differences in the day of vaginal opening and numbers of corpus lutea. The present study demonstrates that the effects of these two isomers of NP on the pup reproduction at PND 28 are not quite different, despite them showing different levels of ER binding activity using in vitro yeast assay.     

CeO2 nanoparticles alter the outcome of species interactions

Despite considerable research on the environmental impacts of nanomaterials, we know little about how they influence interactions between species. Here, we investigated the acute (12 d) and chronic (64 d) toxicities of cerium oxide nanoparticles (CeO₂ NPs) and bulk particles (0–200?mg/L) to three ciliated protist species (Loxocephalus sp., Paramecium aurelia, and Tetrahymena pyriformis) in single-, bi-, and multispecies microcosms. The results show that CeO₂ NPs strongly affected the interactions between ciliated protozoan species. When exposed to the highest CeO₂ NPs (200?mg/L), the intrinsic growth rates of Loxocephalus and Paramecium were significantly decreased by 18.87% and 88.27%, respectively, while their carrying capacities declined by more than 90%. However, CeO₂ NP exposure made it difficult to predict outcomes of interspecific competition between species. At higher NP exposure (100 and 200?mg/L), competition led to the extinction of both species in the Loxocephalus and Paramecium microcosms that survived in the absence of competitors or CeO₂ NPs. Further, the presence of potential competitors improved the survival of Loxocephalus to hundreds of individuals per milliliter in microcosms with Tetrahymena where Loxocephalus would otherwise not be able to tolerate high levels of NP exposure. This result could be attributed to weakened NP adsorption on the cell surface due to competitor-caused reduction of NP surface charge (from ?18.52 to ?25.17?mV) and intensified NP aggregation via phagocytosis of NPs by ciliate cells. Our results emphasize the need to explicitly consider species interactions for a more comprehensive understanding of the ecological consequences of NP exposure.     

Nanoparticle-mediated co-delivery of chemotherapeutic agent and siRNA for combination cancer therapy

Introduction: Cancer is the leading cause of death worldwide. Current cancer treatments in the clinic mainly include chemotherapy, radiotherapy and surgery, with chemotherapy being the most common.

Areas covered: Cancer treatments based on the single ‘magic-bullet’ concept are often associated with limited therapeutic efficacy, unwanted adverse effects, and drug resistance. The combination of multiple drugs is a promising strategy for effective cancer treatment due to the synergistic or additive effects. Small interfering RNA (siRNA) has the ability to knock down the expression of carcinogenic genes or drug efflux transporter genes, paving the way for cancer treatment. Treatment with both a chemotherapeutic agent and siRNA based on nanoparticle (NP)-mediated co-delivery is a promising approach for combination cancer therapy.

Expert opinion: The combination of chemotherapeutic agents and siRNAs for cancer treatment offers the potential to enhance therapeutic efficacy, decrease side effects, and overcome drug resistance. Co-delivery of chemical drug and siRNA in the same NP would be much more effective in cancer therapy than application of chemical agent or siRNA alone. With the development of material science, NPs have come to be the most widely used platform for co-delivery of chemotherapeutic drugs and siRNAs.     

TRAIL receptor signaling and therapeutics

Importance of the field: TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptotic cell death in a variety of tumor cells by engaging specific death receptors, TRAIL-R1 and TRAIL-R2, while having low toxicity towards normal cells. There is interest in cancer therapy inducing cell death by activation of the death-receptor-mediated apoptotic pathway while avoiding decoy-receptor-mediated neutralization of the signal. This has led to the development of a number of receptor-specific TRAIL-variants and agonistic antibodies. Some of these soluble recombinant TRAIL and agonist antibodies targeting TRAIL-R1 and/or TRAIL-R2 are progressing in clinical trials. In addition, TRAIL-resistant tumors can be sensitized to TRAIL by a combination of TRAIL or agonistic antibodies with chemotherapeutic agents, targeted small molecules or irradiation.

Areas covered in this review: Recent advances in developing TRAIL or its agonist receptor antibodies in cancer therapy. We also discuss combination therapies in overcoming TRAIL resistance in cancer cells.

What the reader will gain: Knowledge of current clinical trials, the promise and obstacles in the future development of therapies affecting TRAIL signaling pathways.

Take home message: Cancer therapeutics targeting the TRAIL/TRAIL receptor signaling pathway hold great promise for molecularly targeted pro-apoptotic anti-cancer therapy.