Abstract 3682: Characterization of PolyDots, a novel nanomicelle drug delivery system, for targeted therapy of neurological malignancies

Abstract

Abstract Background: Conventional chemotherapy strategies against malignant primary brain tumors such as glioblastoma have limited success in improving clinical outcome. There is a need for novel anti-glioma treatment strategies that efficiently transgress the blood brain barrier (BBB), specifically target the tumor, provide sustained drug release, allow combination strategies to overcome resistance, and provide imaging correlates for drug delivery. We hypothesized that nanoparticle delivery systems, which can bypass the BBB and specifically access tumor cells, can deliver combinations and have several unique advantages for neuro-oncological drug delivery compared to conventional agents. Methods: We tested the efficacy of a novel nanodelivery vehicle called PolyDots that combines features of two drug delivery systems, micelles and polymer (i.e. poly(lactic-co-glycolic acid), PLGA) nanoparticles against gliomas in vitro. Using glioma cell lines, glioma stem cell lines (GSC), organotypic slice cultures and a zebrafish intracranial brain tumor model, we examined the in vivo and in vitro effects of PolyDot delivery both as empty particles and loaded with either fluorescent markers (Coumarin 6), HDAC inhibitor (vorinostat) as single agent or in combination with a cytotoxic agent (temozolomide). Results: Both glioma cells and GSC tumor spheres showed robust uptake of fluorescent PolyDots with initial appearance of punctate vesicles consistent with endosomal uptake followed by diffusion of signal suggesting release from endosomes, indicating that PolyDots can access both monolayer and three-dimensional tumor cell aggregates. Upon treatment with empty PolyDots (PD-C6) or those loaded with vorinostat (PD-V), PD-V treated LN229 and U373 cells showed increased Acetyl-Histone 3 and Acetyl-tubulin levels suggesting uptake of drug loaded PolyDots by glioma cells with subsequent drug release and induction of biological effect. Lastly, fluorescent PolyDots injected into intracranial glioma xenografts in zebrafish showed discrete green punctae throughout the brain after 30 minutes and throughout the nueraxis at 24 hours, signifying neuraxis retention and wide-spread distribution of PolyDots in vivo after intracranial injection. Conclusions: Our results suggest that PolyDots can serve as a robust and tunable drug delivery platform that can encapsulate both drugs and imageable markers compared to micelles alone for drug delivery to the brain. Of particular relevance to treatment of neurological malignancies, they exhibit tunable release characteristics with the potential for co-release of multiple agents with different release rates, and have the potential for enhanced BBB penetration and diffusion in brain. PolyDots hence constitute a novel therapeutic delivery system that has the potential to overcome several critical roadblocks in drug delivery for nervous system cancers. Citation Format: Jihong Xu, Alessandra Welker, Brandon Miller, Mark Calhoun, Jose Otero, Catherine Czeisler, J. Brad Elder, Christine E. Beattie, Metin N. Gurcan, Jessica O. Winter, Vinay K. Puduvalli. Characterization of PolyDots, a novel nanomicelle drug delivery system, for targeted therapy of neurological malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3682. doi:10.1158/1538-7445.AM2015-3682