(584ae) Improved Antitumor Efficacy of Doxorubicin By Lipid Vesicles Integrating Tunable Targeting With Interstitial and Intracellular Release

We hypothesize that the efficacy of chemotherapeutics to vascularized tumors may be improved when delivered by carriers designed to simultaneously address a number of interstitial and intracellular transport barriers.  We evaluate a pH-responsive functionalized lipid membrane in the form of vesicles to deliver doxorubicin; these vesicles integrate triggered unmasking of targeting anti-HER2 peptides upon extravasation in the tumor to selectively enhance cell uptake, interstitial release of doxorubicin to improve intratumoral penetration, and endosomal release of doxorubicin to maximize bioexposure. In vitro, at the lower limit of interstitial pH, unmasking of anti-HER2 peptides on integrated vesicles results in 175% increase in specific uptake of vesicles by HER2-expressing BT474 cells relative to neutral pH. Exposure of BT474 spheroids to targeted integrated vesicles loaded with doxorubicin results in complete cell killing. In vivo, subcutaneous tumor xenografts treated with targeted integrated vesicles are 55% smaller than tumors treated with the non-targeted forms, and 67% smaller than tumors treated with non-targeted vesicles lacking triggered release. Functionalization of the latter improves tumor control, but tumors are 22% larger than these treated with targeted integrated vesicles. This proof-of-concept study supports the significance of designing drug delivery carriers that simultaneously address diverse transport barriers to tumors.