Abstract 4439: A reversibly self-crosslinking nano-carrier system for efficient anticancer drug delivery

Abstract

Abstract It is known that the intracellular concentration of glutathione (GSH) is substantially higher than that in the cellular exterior (∼10 mM vs ∼2 μM) and many types of tumor cells have an elevated GSH level compared to normal cells. This dramatic variation of the GSH concentration provides an opportunity for designing tumor specific drug delivery systems. Most of the chemotherapeutic drugs used in clinic suffer from severe dose-limiting side effects. In order to enhance the therapeutic efficacy and minimum the side effect of these drugs, we developed a stable and efficient nano-carrier drug delivery system based on the disulfide crosslinked micelles comprise of poly (ethylene glycol) (PEG) and dendritic oligmers of cholic acids and cysteines. Various poorly water-soluble anticancer drugs can be efficiently incorporated inside these polymeric nano-carriers. The nano-carriers are stabilized by disulfide bridges in the core to avoid premature release of the loaded drugs during circulation. After reaching the tumor sites via enhanced permeability and retention (EPR) effect, the nano-carriers will disassemble to release the core-loaded drugs upon the cleavage of disulfide bridges under reductive conditions following the intracellular uptake or triggered by additional reducing agents. The crosslinked nano-carriers were spherical with a uniform size of 30 ± 5 nm, and can load paclitaxel (PTX) in the core with drug loading content up to 35% (w/w). Cross-linking of the nano-carriers within the core reduced their critical aggregate concentration and greatly enhanced their stability in non-reductive physiological conditions. The release of PTX from the crosslinked nano-carriers was significantly slower than that from non-crosslinked nano-carriers and can be gradually facilitated in a reducing environment. The fluorescence intensity of BODIPY 650/665 (near infrared dye) labeled disulfide crosslinked nano-carriers sustained up to 24 hours within the blood stream of nude mice while that of non-crosslinked nano-carriers decreased faster and fell into the background level within 8 hours post injection. Targeted drug delivery to tumor site with these crosslinked nano-carriers was demonstrated by near infrared fluorescence imaging in nude mice bearing ovarian cancer xenograft. The nano-formulation of PTX was found to be less toxic than its free drug form in nude mice. We further demonstrated the crosslinked nano-formulation of PTX was more efficacious than both free drug and non-crosslinked nano-formulation of PTX in ovarian cancer xenograft model. This new class of nano-therapeutics shows great promise in the future cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4439. doi:10.1158/1538-7445.AM2011-4439