Overcoming drug resistance with a docetaxel and disulfiram loaded pH-sensitive nanoparticle.

Previous studies have demonstrated that breast cancer cells deploy a myriad array of strategies to thwart the activity of anticancer drugs like docetaxel (DTX), including acquired drug resistance due to overexpression of drug-efflux pumps like P-glycoprotein (P-gp) and innate drug resistance by cancer stem cells (CSCs). As disulfiram (DSF) can inhibit both P-gp and CSCs, we hypothesized that co-treatment of DTX and DSF could sensitize the drug-resistant breast cancer cells. To deliver a fixed dose ratio of DTX and DSF targeted to the tumor, a tumor extracellular pH-responsive nanoparticle (NP) was developed using a histidine-conjugated star-shaped PLGA with TPGS surface decoration ([DD]NpH-T). By releasing the encapsulated drugs in the tumor microenvironment, pH-sensitive NPs can overcome the tumor stroma-based resistance against nanomedicines. In in-vitro studies, [DD]NpH-T exhibited increased drug release at pH 6.8, improved penetration in a 3D tumor spheroid, reduced serum protein adsorption, and enhanced cytotoxic efficacy against both innate and acquired DTX-resistant breast cancer cells. In in-vivo studies, a significant increase in plasma AUC and tumor drug delivery was observed with [DD]NpH-T, which resulted in an enhanced in-vivo anti-tumor efficacy against a mouse orthotopic breast cancer, with a significantly increased intratumoral ROS and apoptosis, while decreasing P-gp expression and prevention of lung metastasis. Altogether, the current study demonstrated that the DTX and DSF combination could effectively target multiple drug-resistance pathways in-vitro, and the in-vivo delivery of this drug combination using TPGS-decorated pH-sensitive NPs could increase tumor accumulation, resulting in improved anti-tumor efficacy.

Breaking the niche: multidimensional nanotherapeutics for tumor microenvironment modulation.

Most of the current antitumor therapeutics were developed targeting the cancer cells only. Unfortunately, in the majority of tumors, this single-dimensional therapy is found to be ineffective. Advanced research has shown that cancer is a multicellular disorder. The tumor microenvironment (TME), which is made by a complex network of the bulk tumor cells and other supporting cells, plays a crucial role in tumor progression. Understanding the importance of the TME in tumor growth, different treatment modalities have been developed targeting these supporting cells. Recent clinical results suggest that simultaneously targeting multiple components of the tumor ecosystem with drug combinations can be highly effective. This type of "multidimensional" therapy has a high potential for cancer treatment. However, tumor-specific delivery of such multi-drug combinations remains a challenge. Nanomedicine could be utilized for the tumor-targeted delivery of such multidimensional therapeutics. In this review, we first give a brief overview of the major components of TME. We then highlight the latest developments in nanoparticle-based combination therapies, where one drug targets cancer cells and other drug targets tumor-supporting components in the TME for a synergistic effect. We include the latest preclinical and clinical studies and discuss innovative nanoparticle-mediated targeting strategies.

pH-Responsive Nanoparticles for Multidimensional Combined Chemo-Immunotherapy of Cancer.

Current research has demonstrated that tumor development and progression are dependent on a multi-cellular interactome, which forms the tumor microenvironment. Multiple components of this multi-cellular ecosystem need to be targeted simultaneously for successful cancer therapy. The objective of this study was to develop a multidimensional combined chemo-immunotherapeutic modality for effective breast cancer treatment. TLR 7/8 agonist resiquimod was identified as a potent macrophage stimulant in an initial screening. To deliver paclitaxel as a chemotherapeutic drug and resiquimod as an immune activator in a tumor-targeted fashion, two different pH-sensitive nanoparticles were synthesized using two different polymers, a linear PLGA and a multi-arm, star-shaped PLGA. The star-PLGA pH-responsive nanoparticles exhibited improved pH-dependent drug release and increased penetration in a complex breast cancer spheroid model (breast cancer cell + macrophage cell). Treatment with paclitaxel and resiquimod encapsulated in the pH-responsive nanoparticles resulted in increased cancer cell death and macrophage activation, as tested in an in-vitro breast cancer spheroid model. Altogether, the current study suggests that the paclitaxel and resiquimod combination has potent chemo-immunotherapeutic activity, and delivery using a pH-sensitive nanoparticle further improves its efficacy.

Disulfiram potentiates docetaxel cytotoxicity in breast cancer cells through enhanced ROS and autophagy.

BACKGROUND: Recent studies have demonstrated that autophagy plays a critical role in reducing the drug sensitivity of docetaxel (DTX) therapy. Disulfiram (DSF) has exhibited potent autophagy inducing activity in multiple studies. We hypothesized that DSF co-treatment could sensitize breast cancer cells to DTX therapy via autophagy modulation. METHODS: Breast cancer cells, MCF7, and 4T1, were treated with DTX and DSF, alone and in combination. The effects were analyzed by evaluating cytotoxicity, induction of apoptosis, induction of autophagy, and reactive oxygen species (ROS) generation. In addition, the consequence of autophagy and ROS inhibition on the DTX + DSF mediated cytotoxicity was also evaluated. RESULTS: Significant synergism in cytotoxicity was observed with DTX + DSF combination in breast cancer cells, MCF7, and 4T1. Hyper induction of ROS and autophagy was also found with the combination treatment. ROS inhibition by N-Acetyl Cysteine (NAC), as well as autophagy inhibition by ATG5 silencing significantly reduced the autophagy level as well as cytotoxicity of the DTX + DSF combination, indicating that the induction of autophagy mediated by high ROS generation played a critical role behind the synergistic cytotoxicity. CONCLUSIONS: This study indicates that DTX + DSF combination therapy can effectively sensitize cancer cells by hyper inducing autophagy through ROS generation and can be developed as a therapeutic strategy for cancer treatment in the future.

Chitosan-Chondroitin sulfate based polyelectrolyte complex for effective management of chronic wounds.

Acute and chronic wound remain an unresolved clinical problem among various demographic groups. Traditional marketed products focus mainly on inhibition of bacterial growth at the wound site neglecting the tissue repair, which significantly affect the healing rate. It would be highly beneficial if a wound healing material can be developed which has both antibacterial as well as tissue regenerating potential. We have prepared a polyelectrolyte complex (PEC) using chitosan (CH) and chondroitin sulfate (CS) which can form an in-situ scaffold by spontaneous mixing. The fabrication of CH-CS PEC was optimized using Quality-By-Design (QbD) approach. The prepared PEC showed very high swelling and porosity property. It was found to be non-hemolytic with good blood compatibility and low blood clotting index. It also exhibited good antibacterial activity against both gram-positive and gram-negative bacteria. The cell proliferation study exhibited good cytocompatibility and almost four-fold increase in cell density when treated with CH-CS PEC compared to control. In summary, we demonstrated that the prepared CH-CS PEC showed good blood compatibility, high antibacterial effect, and promoted wound healing potentially by stimulating fibroblast growth, making it an ideal wound dressing material.

Tumor heterogeneity and nanoparticle-mediated tumor targeting: the importance of delivery system personalization.

After the discovery of the enhanced permeability and retention effect in 1986, it was envisioned that nanoparticle-mediated tumor-targeted delivery of chemotherapeutics would make a radical change in cancer therapy. However, after three decades of extensive research, only a few nanotherapeutics have been approved for clinical use. Although significant advantages of nanomedicines have been demonstrated in pre-clinical studies, clinical outcome was found to be variable. Advanced research has revealed that significant biochemical and structural variations exist between (and among) different tumors. These variations can considerably affect the tumor delivery and efficacy of nanomedicines. Tumor penetration is an important determining factor for positive therapeutic outcome and same nanomedicine can show diverse efficacy against different tumors depending on the extent of tumor accumulation and penetration. Recent research has started shading light on how the tumor variations can influence nanoparticle tumor delivery. These findings indicate that there is no "ideal" design of nanoparticles for exhibiting equally high efficacy against a broad spectrum of tumors. For achieving maximum benefit of the nanotherapeutics, it is necessary to analyze the tumor microenvironment for understanding the biological and structural characteristics of the tumor. Designing of the nanomedicine should be done according to the tumor characteristics. In this comprehensive review, we have first given a brief overview of the design characteristics of nanomedicine which impact their tumor delivery. Then we discussed about the variability in the tumor architecture and how it influences nanomedicine delivery. Finally, we have discussed the possibility of delivery system personalization based on the tumor characteristics.