DESIGN AND SYNTHESIS OF SELECTIVE POLYMERIC NANO-CARRIERS FOR DRUG DELIVERY AND COMBINATION THERAPY

We combined emerging technologies to tackle an unsolved problem of selective targeting of anti-angiogenic drugs to tumor blood vessels. We designed, synthesized and characterized a water-soluble conjugate of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer, cathepsin-cleavable linker and TNP-470, a very potent agent but highly toxic in clinical trials. This conjugate accumulated selectively in tumor vessels due to the enhanced permeability and retention (EPR) effect. It substantially enhanced and prolonged the anticancer activity of TNP-470. Polymer conjugation prevented TNP-470 from crossing the blood-brain barrier and decreased its accumulation in normal organs, thereby avoiding drug-related toxicities. This new approach for targeting angiogenesis inhibitors specifically to the tumor vasculature provided a new strategy for the rational design of cancer therapies. This work was published in Nature Medicine in 2004. This is the first anti-angiogenic nanomedicine. Prior to this work, polymer therapeutics were targeted to cancer cells whereas the stromal compartment was neglected. Several patents were filed on this anti-angiogenic nanomedicine and it was licensed to a pharmaceutical company.

A second project focused on the hyperpermeability associated with angiogenic blood vessels compared to that of normal vessels. We found that several anti-angiogenic agents decrease vascular hyperpermeability of tumor blood vessels, reduce delayed-type hypersensitivity, and pulmonary edema induced by IL-2. We found that the mechanism was via inhibition of VEGF-induced phosphorylation of VEGFR-2, calcium influx, and RhoA activation in endothelial cells. These findings were published in Cancer Cell in 2005. This was the first time to identify the inhibition of VEGF-induced vessel hyperpermeability as the mechanism of action of many angiogenesis inhibitors. It suggests that this activity likely contributes to their anti-angiogenic effect, thus they can be used in the treatment of cancer, inflammation and other angiogenesis-dependent diseases.