Fabrication and Evaluation of Redox Micellar nanocarriers for Intracellular Delivery in Solid Tumor Therapy

Abstract

The current study was designed to develop an innovative means to bring amphiphilic mucopermeating functional micelles to tumors. The Mucopermeating nanocargoes being able to overcome mucosal, as well as extracellular barrier leads to enhance penetration of poorly soluble anticancer drugs at its target site. Papain (Pap) grafted thiolated hyaluronic acid-pluronic F127-lithocholic acid triblock (Pap-THA-g-F127-SS-LCA) was synthesized in this study. As-prepared formulation yielded Pap functionalized thiolated redox micelles (PT-R-Ms). Mucolytic and tumor extracellular matrix-degrading property of Pap enzyme facilitated the diffusion of paclitaxel loaded PT-R-Ms. Moreover, PT-R-Ms exhibited glutathione-triggered release serving as a mimic for the tumor microenvironment yielding enhanced intracellular tumor penetration thereby leading to high tumor cytotoxicity. PTR- Ms exhibited spherical shape with a size of 80 nm, negative zeta potential of -29 ±3.85, and high encapsulation efficiency i.e., 80±3.29% of paclitaxel. Glutathione triggered release as mimic the tumor redox microenvironment indicated 50% drug release within 24hr. In-vitro anticancer activity demonstrated higher cytotoxicity of PT-R-Ms against all HCT-116, Hep-2, and RD cancerous cell lines in comparison to free paclitaxel. PT-R-Ms indicated the highest penetration in tumor tissue in terms of maximum fluorescence. Moreover, the presence of CD44 receptors in the tumor tissue synergistically nurtures the diffusion of PT-R-Ms, due to maximum uptake, and pronounced degradation of ECM. Moreover, PT-R-Ms exhibited the highest apoptosis-mediated cell death in contrast to pure PTX. In vivo study evidenced the highest fluorescence into the intestine, confirmed the mucopermeation of micelles across the intestine. The orally administered PT-R-Ms efficiently overcome intestinal barriers and inhibit P-gp efflux pump resulting in augmented bioavailability of PTX (8 folds) in comparison to pure PTX. Biodistribution and tumor accumulation were determined following the oral administration of fluortagged PT-RMs. Acute oral toxicity evinced the zero toxicity of Ms, R-Ms, P-R-Ms and PT-RMs due to biocompatibility and hemocompatibility. Briefly, this delivery system addresses the existing clinical challenges by enabling as-prepared nanocargoes to release paclitaxel when reaching the site of a target (where it is the most needed), thereby minimizing off-target toxic effects. Targeted delivery of drug using nanocargoes has the potential to propel the field of drug delivery in solving real-world clinical problems.