PTPS-10REPURPOSING CHEMOTHERAPY DRUGS FOR NEW APPLICATIONS IN CHILDREN'S BRAIN TUMOURS: PRECLINICAL SCREENING WITH AN IN VITRO 3D MODEL

Abstract

BACKGROUND: While novel targeted therapeutics hold great promise in precisely eliminating sensitive subsets of tumour cells, their selectivity may lead to the proliferation of resistant clones and tumour recurrence. In this respect enhancing the distribution of less-selective, older-generation chemotherapeutics may result in improved tumour control and more favourable side effects profile. To this end we are exploring strategies relying on nanoparticle transport of drugs, intra-cavitary and metronomic intra-CSF drug delivery in order to maximise the cytotoxic effect and minimize the toxicity of chemotherapy in paediatric brain tumours. Human-based 3D in vitro models showing both safety and efficacy were established and a number of drug delivery strategies were tested for improved selectivity against medulloblastoma compared to normal human foetal brain tissue. METHODS: The topoisomerase inhibitors etoposide and teniposide were encapsulated in Poly(ethylene glycol)-block-poly(ɛ-caprolactone) (PEG-PCL 5kDa-5kDa) nanoparticles using the solvent-emulsification method. Comparative toxicity towards normal and tumour human cells was determined by treating normal and tumour spheroids with empty nanoparticles, drug-loaded nanoparticles or free drug. Spheroid volume and metabolism dose-response curves were compared between the different formulations. RESULTS: The more lipophilic drug, teniposide, showed higher drug loading (8%w/w) compared to etoposide (0.4%w/w) in the purified nanoparticles. Whereas both drugs exhibited toxicity towards proliferating cells regardless of whether those were normal or tumour, etoposide had a narrow therapeutic window of 3-10 µM where normal brain tissue showed higher viability compared to medulloblastoma cells. In addition, the teniposide-loaded nanoparticles were 1.5 times less toxic to normal tissue and equally cytotoxic to tumour cells compared to free teniposide. CONCLUSIONS: The tumour-selective therapeutic levels of 3-10 µM identified for etoposide can be useful for intra-CSF prophylaxis against distant metastasis. Although the teniposide-loaded nanoparticles offered an incremental improvement in the therapeutic index of teniposide future formulations with optimised release profile or covalently linked drug may yield better results.