Development of new PLGA-based nanocarriers for triple negative breast cancer: Fabrication, characterization, and pharmacological evaluation

Abstract

Triple negative breast cancer (TNBC) is a subtype of breast cancer that is characterised by aggressive nature, high metastasis, onset at young age, high recurrence rate and limited availability of targeted therapies. Paclitaxel (PTX) and docetaxel (DTX) belong to the family of taxanes and they are currently being used clinically for TNBC treatment. Curcumin has also shown activity against TNBC in vitro and in vivo. These compounds have extremely poor water solubility which either limits the clinical use (curcumin) or require specific solvent system for clinical use (PTX and DTX) and that solvent system may cause significant side effects. Despite the availability of different reported nano-formulations loaded with poorly-water soluble agents such as PTX, DTX or Cur, none of those formulations have reached the clinic so far with only a few are in clinical trials (such as NK 105 for PTX and ATI-1123 for DTX). A primary factor contributing to this issue is the inability to attain an optimal combination of physicochemical and biological properties.

The first objective of this PhD project was optimising and developing a new poly (lactic-co-glycolic acid) (PLGA)-based drug delivery systems that can efficiently delivery different poorly water-soluble anticancer agents using PTX, DTX or curcumin as model drugs. Several optimised methods employing the nanoprecipitation approach were trialed, resulting in the successful production of water-dispersible PLGA nanoparticles loaded with the model drugs. The second objective of this PhD project aimed to enhance the previously developed PLGA-based technology by improving its physicochemical characteristics. This was followed by a third objective, which focused on achieving active tumour targeting through the implementation of a dual-targeted approach.