Optimized rapamycin-loaded PEGylated PLGA nanoparticles: Preparation, characterization and pharmacokinetics study

Abstract

Rapamycin (RAP), an inhibitor of mTOR signaling pathway, has been widely used for its immunosuppressive activity over its anti-tumor and anti-inflammatory properties. The objective of this study was to encapsulate RAP into appropriately sized PEGylated nanoparticles, using biodegradable polyethylene glycol-poly (D, l-lactide-co-glycolide) copolymer (PEG-PLGA), for preferential tumor delivery through the enhanced permeability and retention (EPR) effect. Taguchi experimental design was used to determine the optimum preparation conditions for desirable sized nanoparticles and particle size was set as characteristic response. Nanoprecipitation method was used to prepare nanoparticles and the effects of stirring time, Tween 80 concentration, and RAP/PEG-PLGA ratio on nanoparticles size were investigated. The particle size of RAP-loaded PEGylated PLGA nanoparticles (RPP NPs) prepared using optimum conditions was about 118.8 nm. The release of RAP from optimized RPP NPs followed a non-Fickian sustained release pattern over a period of 7 days. In addition, the in vitro cytotoxicity of RPP NPs was investigated on various cell lines, and human leukemic Jurkat T cells revealed the lowest IC50 value. RPP NPs showed a good stability when stored for one month at 4 °C. The in vivo study on mice model showed enhanced pharmacokinetic profile of loaded RAP compared to its free form. Therefore, RPP NPs could be a potential therapeutic system for cancer and inflammatory disorder therapies.