Codelivery of anti-cancer agents via double-walled polymeric microparticles/injectable hydrogel: A promising approach for treatment of triple negative breast cancer.

Abstract

Triple negative breast cancer (TNBC) is an aggressive sub-type of breast cancer that rarely responds to conventional chemotherapy. Therefore, novel agents or new routes need to be developed to improve treatment efficacy and diminish severe side-effects of anti-cancer agents in TNBC patients. This study explores a novel localized co-delivery platform with potential application against TNBC. Uniform core-shell microparticles encapsulating cisplatin (Cis-DDP) and paclitaxel (PTX) are fabricated using coaxial electrohydrodynamic atomization technique and subsequently are embedded into an injectable hydrogel. The hydrogel provides an additional diffusion barrier against Cis-DDP and confines premature release of drugs. In addition, the hydrogel can provide a versatile tool for retaining particles in the tumor resected cavity during the injection following debulking surgery and prevent surgical site infection due to its inherent antibacterial properties. The combination of Cis-DDP and PTX demonstrates a synergistic effect against MDA-MB-231 cell line assigned to three different mechanisms of action, including denaturation of DNA strands, stabilization of microtubules, and amplification of intracellular reactive oxygen species (ROS) and activation of caspase-3 pathways. The results show a significant accumulation of mitochondrial ROS insults in cells upon treatment that consequently causes programmed cells death. The performance of microparticles/hydrogel carrier is evaluated against three-dimensional MDA-MB-231 (breast cancer) 3D spheroids, where a superior efficacy and a greater reduction in spheroid growth are observed over 14 days, as compared with free-drug treatment. Overall, drug-loaded core-shell microparticles embedded into injectable hydrogel provides a promising strategy to treat aggressive cancers and a modular platform for a broad range of localized multidrug therapies customizable to the cancer type.