Effect of peripheral shell cross-linking on the efficacy of a hydrophobic vascular disrupting agent physically loaded in core-shell polymeric micelle

The recruitment of blood vessels from existing vasculature (angiogenesis) is a critical factor in the metastasis and growth of solid tumors such as breast cancer. Thus, considering that metastasis from the primary tumor is responsible for the majority of cancer-related deaths, the disruption of tumor angiogenesis and tumor vasculature has significant potential in the therapy of metastatic breast cancer. A promising low molecular weight (MW) VDA, Combretastatin A4 (CA4), alters the morphology of activated tumor microvascular endothelial cells to collapse existing tumor vasculature and block tumor angiogenesis. This drug, however, has very poor aqueous solubility and suffers from dose-limiting toxicity. Its water soluble prodrug form, Combretastatin A4 phosphate (CA4-P) also suffers from cardiotoxicity. Physical loading in core-shell polymer micelles (PM) is limited by the possible premature release of loaded drug in the blood. Cross-linking the PM shell through functional groups within the shell block (internal shell cross-linking) to decrease premature drug release can increase the bioavailability and subsequent potency of physically loaded drugs against solid tumors after IV administration. Alternatively, cross-linking the PM shell through peripheral end-groups on the surface of the micelle (peripheral shell cross-linking) may have similar effects but with less effect on drug loading, rate of drug release at the target cell, and functionality of the PM shell. The feasibility and potential of this approach, however, has not been fully explored. Individual Pluronic F127 PM which were peripherally cross-linked with ethylenediamine at 76% of total PEO blocks (X-F127 PM) and physically loaded with Combretastatin A4 (CA4), showed promising results as compared to uncross-linked F127 PM and free drug, both in vitro and in vivo. Thus, peripherally cross-linking the shell of core-shell polymer micelles may be a simple approach to decrease premature release of physically loaded CA4 in the blood and increase the potency in solid tumors.