PO12TENIPOSIDE-LOADED NANOPARTICLES FOR LOCAL DRUG DELIVERY IN MEDULLOBLASTOMA

Abstract

INTRODUCTION: Current medulloblastoma (MB) therapy involving chemo-radiotherapy is moderately effective but causes severe acute haematological toxicity and serious long term neuro-toxicity affecting patients' quality of life. Delivering drugs to the post-surgical tumour bed, using drug-loaded nanoparticles (NP), offers a way of treating residual tumour with minimal systemic toxicity. Previous work demonstrated NP being taken up preferentially by tumour cells compared to the normal brain. Teniposide was chosen for NP encapsulation due to reported MB activity without neurotoxicity. METHOD: Teniposide was incorporated in Poly(ethylene glycol)-block-poly(ɛ-caprolactone) (5kDa-5kDa) NPs using solvent-emulsification and purified by gel-filtration. Drug loading was determined using UV-spectrophotometry, and drug release by dialysis and ultra-centrifugation. Comparative toxicity towards foetal brain and tumour cells was assessed in 3D in vitro MB spheroid models. Spheroid volume and metabolism dose-response curves were obtained comparing empty NP, drug-loaded NPs and free drug. RESULTS: Teniposide drug loading in the NPs was 8%w/w, but the delivery system showed rapid drug release. While the IC50 for teniposide in proliferating normal neurospheres was 20nM, the IC50 for UW228-3 tumours was 18 times higher. The drug-loaded NPs were 1.5 times less toxic to normal tissue and equally cytotoxic to tumour cells compared to the free drug. CONCLUSION: The difference in toxicity between drug-loaded NPs and free drug was not large enough to offset the drug's toxicity towards foetal cells. Nanoparticle delivery may therefore enhance the therapeutic index of drugs, but improved drug retention in the NPs will be required for confirmation.