Paclitaxel (PTX) is the first-line chemotherapeutic agent for various types of cancers including breast cancer (BCa), prostate cancer (PCa), lung cancer and others. However, the effectiveness of PTX is limited by untolerated systemic toxicity, which limits the amount of drug that can be given to kill most if not all cancer cells. This will lead to selective survival of tumor subpopulations with newly acquired drug-resistance. Development of effective delivery systems represents an important strategy to improve the therapeutic index of chemotherapeutic drugs. Abraxane(R) is a human albumin-stabilized nanoformulation of PTX that has been approved for clinical use and demonstrated improvements in both toxicity and efficacy of PTX therapy. However, the size of these particles (~130 nm) is not sufficiently small to achieve effective penetration into poorly vascularized tumor tissues. Micelles-based formulations can effectively deliver drugs to tumors due to their small sizes and various types of polymeric systems have been developed. Most of the polymeric systems use """"""""inert"""""""" excipients that lack therapeutic activity. The presence of large amounts of carrier materials not only adds to the cost but also imposes additional safety issue. We have developed a PEG-derivatized embelin- based delivery system that simultaneously enhances targeted delivery and sensitizes the cancer cells to PTX via targeting X-linked inhibitor of apoptosis protein (XIAP). PTX formulated in our novel system shows superior maximal tolerated dose (MTD, 100~120 PTX mg/kg) and antitumor activity over Taxol, a clinically used PTX formulation. This application is focused on improving the delivery system through systematic study on structure-activity relationship (SAR). Their efficiency in synergistic action with PTX is then examined both in vitro and in vivo. Finally, the mechanism of action will be investigated. BCa will be used as a model system to address these issues.
Four specific aims will be pursued to achieve our goals:
Aim 1 will define the optimal structure of PEG-embelin conjugates through systematic SAR study;
Aim 2 will study the mechanism by which PEG-embelin synergizes with co-delivered drug in antitumor activity;
Aim 3 will define the efficiency of in vivo tumor targeting and pharmacokinetics in a mouse model of human BCa;
Aim 4 will evaluate the synergistic antitumor activity of PEG-embelin-targeted PTX in a mouse model of human BCa xenograft. Completion of the proposed studies in this proposal is likely to lead to the development of a new strategy of targeted combination therapy for the treatment of various types of cancers including BCa.
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