ATPS-69POLYDOTS, A NOVEL NANOMICELLE DRUG DELIVERY SYSTEM, FOR TARGETED THERAPY OF BRAIN TUMORS

Standard therapies have limited success against malignant primary brain tumors such as glioblastoma (GB) raising the need for novel therapies that can efficiently transgress the blood brain barrier (BBB), target tumor and provide sustained drug release. Nanoparticle delivery systems which can bypass the BBB and target nervous system tumor cells allowing combined delivery of therapeutic agents with unique advantages compared to conventional agents. We have developed a novel nanodelivery vehicle called PolyDots that combines features of nanomicelles and polymer (poly[lactic-co-glycolic acid]) nanoparticles. We examined the in vivo and in vitro effects of PolyDot delivery both as empty particles and loaded with either fluorescent markers (Coumarin 6) or a therapeutic agent, vorinostat (HDAC inhibitor). Both glioma cells and GSC tumor spheres showed robust uptake of fluorescent PolyDots with initial endosomal uptake (punctate foci) followed by release from endosomes (diffuse fluorescence) indicating entry into both monolayer and 3-D tumor cell aggregates. Treatment of LN229 and U373 cells with fluorescent empty (PDC6) or vorinostat-loaded (PDV) PolyDots showed PDV-specific increase in acetyl-Histone 3 and acetyl-tubulin levels indicating uptake and biological effect of drug-loaded PolyDots in glioma cells. Lastly, fluorescent PolyDots injected into intracranial glioma xenografts in zebrafish showed discrete green punctae in the brain after 30 min and throughout the neuraxis at 24 hours, indicating neuraxis retention and wide-spread distribution of PolyDots in vivo after intracranial injection. Our results suggest that PolyDots can serve as a robust drug delivery platform that can encapsulate both drugs and imageable markers for nervous system delivery. Of particular relevance, they exhibit tunable release characteristics with potential for co-release of multiple agents with different release rates along with enhanced BBB penetration and diffusion in brain. PolyDots hence constitute a novel therapeutic delivery system that has the potential to overcome critical roadblocks in drug delivery for nervous system malignancies.