Design, development, and in-vitro/in-vivo evaluation of docetaxel-loaded PEGylated solid lipid nanoparticles in prostate cancer therapy

Abstract

Docetaxel (DOC) is a potent anticancer molecule widely used to treat various cancers. However, its therapeutic efficacy as a potential anticancer agent has been limited owing to poor aqueous solubility, short circulation time, rapid reticuloendothelial system uptake, and high renal clearance, which consecutively showed poor bioavailability. In the present investigation, we developed polyethylene glycol (PEG) decorated solid lipid nanoparticles (SLN) using the solvent diffusion method to increase the biopharmaceutical properties of DOC. PEG monostearate (SA-PEG2000) was initially synthesized and characterized using various analytical techniques. Afterwards, DOC-loaded SLN was synthesized with and without SA-PEG2000and systematically characterized for in-vitro and in-vivo properties. Spherical-shaped SA-PEG2000-DOC SLN showed hydrodynamic diameter and zeta potential of 177 nm and −13 mV, respectively. During the in-vitro release study DOC-loaded SLN showed a controlledrelease of approximately 54.35 % ± 5.46 within 12 h with Higuchi release kinetics in the tumor microenvironment (pH 5.5).In an in-vitro cytotoxicity study,SA-PEG2000-DOC SLN showedsignificantlylower IC50values(p < 0.001)compared to DOC-SLN and DOC aloneagainst prostate cancer cell lines (PC-3). Similarly, an in-vitro cellular uptake study showed a significant increase in intracellular DOC concentration for SA-PEG2000-DOC SLN. Additionally, inin-vivostudies,PEGylated SLN of DOC showed around 2- and 15-fold increase in the maximum concentration of drug (Cmax) and area under the curve (AUC), respectively, as compared to plain DOC solution due to the uniquehydrophilicity and hydrophobicity balance and electrical neutrality of specially designed PEG architect. The biological half-life (t1/2) and mean residence time (MRT) was found to increase from 8.55 and 11.43 to 34.96 and 47.68 h, respectively, with SA-PEG2000-DOC SLN. Moreover, the bio-distribution study indicates high DOC concentration in the plasma which signifies the more pronounced blood residence time of SA-PEG2000-DOC SLN. In a nutshell, SA-PEG2000-DOC SLNwasfound to bea promising and efficient drug delivery platform for the management of Metastatic Prostate cancer.