Polymeric nanoparticles for intraperitoneal cancer treatment: Development and characterisation of a novel drug delivery platform

Abstract

The emerging field of nanomedicine allows development of drug delivery systems that improve the efficiency and bioavailability of therapeutics. Poly(alkyl cyanoacrylate) (PACA) nanoparticles have been widely studied as drug delivery vehicles due to their biodegradable and biocompatible properties, facile synthesis and high drug loading capacity. This PhD work aimed to increase the therapeutic applicability of PACA nanoparticles in drug delivery, especially in the treatment of intraperitoneal metastases – a cancer form with a high unmet clinical need. This nanoparticle-based strategy was hypothesised to improve the therapeutic ratio of intraperitoneal chemotherapy, by extending intraperitoneal drug residence time and reducing toxic side effects.

In this work, drug-loaded poly(ethylbutyl cyanoacrylate) (PEBCA) nanoparticles were synthesised, physicochemically characterised and evaluated based on their cytotoxic effects towards liver, kidney and mesothelial cells. In vivo studies explored nanoparticle toxicity, pharmacokinetics, biodistribution and therapeutic potential in rodents. Therapeutic efficacy was evaluated in relevant peritoneal metastasis models in mice, including two orthotopic mucinous patient-derived xenograft models and an ovarian cancer model.

This preclinical evaluation demonstrated that nanoencapsulation improved peritoneal retention, toxicity profile and tumour accumulation of the cytostatic drug cabazitaxel. These promising effects were further explored by encapsulating cabazitaxel-loaded nanoparticles in alginate microspheres. The alginate was non-toxic to healthy peritoneal cells and reduced the toxicity of nanoparticles, while maintaining the therapeutic effect of the drug. Hence, alginate encapsulation could improve the therapeutic ratio of cabazitaxel in intraperitoneal applications.

Altogether, the presented work shows that drug encapsulation in PACA nanoparticles can improve drug accumulation in the peritoneal cavity, reduce toxic side effects and enable nanoparticle-specific tumour interactions and consequently improve the therapeutic response of intraperitoneal drug treatment. This demonstrates the potential of PACA drug encapsulation as a novel strategy for treatment of intraperitoneal metastases.