The long term goal of the proposed research is the development of a strategy for simultaneously targeting a pro- cytotoxin to angiogenesis and metastatic tumor cells. Angiogenesis is an important target for cancer therapy because vascular endothelial cells are genetically stable and do not become resistant with treatment. Anti-angiogenic therapy should inhibit the progression of cancer, but the combination of anti- angiogenic and cytotoxic therapy may effect cures. The proposed design will delay release of the cytotoxin with a triggering group until the targeting group has had an opportunity to locate its cell surface receptor. The cytotoxin will be an activated form of doxorubicin which is 10- to 100-fold more toxic to resistant tumor cells and to non-confluent epithelial cells than doxorubicin. For proof of concept, the targeting groups will be small peptides which home to receptors expressed by endothelial cells at the site of angiogenesis but not by endothelial cells of mature vasculature. One of the peptides will also home to the same receptor expressed by metastatic breast and prostate cancer cells.
Specific aims 1 and 2 are to synthesize and characterize preactivated doxorubicin, protected by a triggering group which is tethered to peptides which target two different receptors on the surface of endothelial cells at the site of angiogenesis.
Specific aim 3 is to evaluate targeted pro-cytotoxins in breast and prostate cancer cell models and in an endothelial cell model.
Specific aim 4 is to evaluate the targeted pro-cytotoxins in nude mouse models for metastatic breast and prostate cancer. The targeted, activated pro-cytotoxin should be effective against metastatic disease with substantially less side effects than observed with Doxorubicin. Less side effects will result from the lower dose required through targeting and preactivation. Further, once released at the site of angiogenesis, preactivated doxorubicin has a short half-life with respect to conversion to doxorubicin which is 10-fold less toxic. Hence, tissues remote from the metastatic lesion will only be exposed to low levels of doxorubicin.
