Development of cholate conjugated hybrid polymeric micelles for FXR receptor mediated effective site-specific delivery of paclitaxel

Abstract

The aim of the present study was to explore the tumor targeting potential of a cholic acid (CA) conjugated polymeric micelle system for the effective delivery of paclitaxel (PTX). CA has a high binding affinity to the farnesoid X receptor (FXR) which is overexpressed in most breast cancer cells. CA grafted poly(bis(carboxyphenoxy)phosphazene)–poly(diallyldimethylammonium chloride) (PCPP–PDADMAC) micelles were prepared by nanoprecipitation in the presence of a surfactant. The polymeric nano micelles (PNMs) exhibited well-defined spherical morphology with a hydrodynamic diameter of around 218 nm. CA incorporated hybrid polymeric micelles form a strong gel at body temperature and exhibit prolonged drug release. In addition, the surface charge of the micelles undergoes positive to negative conversion based on the environmental pH. Positively charged nanomaterials promote faster cellular uptake in the cancer acidic milieu. CA formulation specifically targeted the FXR overexpressed in breast cancer for significant progression of the cytotoxicity of PNM with a 2.69-fold increase in comparison to free PTX. γH2AX and comet assays demonstrate efficient cellular uptake, preferential tumor accumulation, and drug release in the cytoplasmic region. This work suggests that the prepared micelle system has a good tumor-targeting ability with reduced systemic toxicity, proving it to be a promising formulation for breast cancer therapy.