Tumor Responsive and Tunable Polymeric Platform for Optimized Delivery of Paclitaxel to Treat Glioblastoma.

Current interstitial therapies for glioblastoma can overcome the blood-brain barrier, but fail to optimally release therapy at a rate which stalls cancer reoccurrence. To address this lapse, acetalated dextran (Ace-DEX) nanofibrous scaffolds were used for their unique degradation rates that translate to a broad range of drug release kinetics. A distinctive range of drug release rates was illustrated via electrospun Ace-DEX or poly(lactic acid) (PLA) scaffolds. Scaffold comprised of fast, medium, and slow degrading Ace-DEX resulted in 14.1, 2.9, and 1.3 percent paclitaxel released per day. To better understand the impact of paclitaxel release rate on interstitial therapy, two clinically relevant orthotopic glioblastoma mouse models were explored: 1) a surgical model of resection and recurrence (resection model) and 2) a distant metastasis model. The effect of unique drug release was illustrated in the resection model when a 78% long term survival was observed with combined fast and slow release scaffolds, in comparison to a survival of 20% when the same dose is delivered at a medium release rate. In contrast, only the fast release rate scaffold displayed treatment efficacy in the distant metastasis model. Additionally, the acid-sensitive Ace-DEX scaffolds were shown to respond to the lower pH conditions associated with GBM tumors, releasing more paclitaxel in vivo when a tumor was present in contrast to non-acid sensitive PLA scaffolds. The unique range of tunable degradation and stimuli-responsive nature makes Ace-DEX a promising drug delivery platform to improve interstitial therapy for glioblastoma.