The overall goal is to develop a method to treat prostate cancer by inducing hemostasis in tumor capillaries. It is known that arrest and activation of platelets is integral to hemostasis and that the endothelium bears unique molecular markers at sites of angiogenesis. We hypothesize that molecular conjugates of dextran and receptor antagonist peptides can be used to arrest and activate platelets on endothelial cells at sites of prostate cancer angiogenesis. Our strategy is to construct a dextran-peptide conjugate (dextran-P) that binds to the platelet GPIIbIIIa integrin. A second conjugate (dextran-E) is used to target tumor sites of angiogenesis and carry a platelet activator peptide. The cross coupling of the conjugates causes arrest and activation of platelets in tumor capillaries. The R21 phase of this proposal will address biochemical, mechanical, toxicological and functional aspects of the strategy. We will evaluate dextran-E,P peptide conjugates under high shear rate (300-1600 sec(-1) flow conditions to determine loading concentration to achieve platelet arrest and activation on endothelial cell monolayers. We will assess effect of dextran-E,P conjugates on platelet function and biodistribution in-vivo in SCID mice and assess histopathologic features of normal and prostate tumor tissues after therapy with dextran-E,P conjugates in SCID mouse DU-145 and PC- 3M xenograft models of human prostate cancer. The R33 phase develops the method of dextran-E image guidance to tailor the amount of administered platelet therapy and will explore the value of follow-up dextranE imaging to assess therapeutic endpoints. This will develop an image guided therapeutic technology for eventual use in patients with prostate cancer. Finally, a phase I trial will be carried out in volunteers to assess the human biodistribution and safety of dextran-E. Successful completion of these aims will enhance detection of local and systemic disease and provide a angiogenesis marker of tumor aggressiveness. It should provide an effective therapy with low systemic toxicity with broad applicability to prostate and other cancers.
| Mitra, Amitava; Nan, Anjan; Papadimitriou, John C et al. (2006) Polymer-peptide conjugates for angiogenesis targeted tumor radiotherapy. Nucl Med Biol 33:43-52 |
| Mitra, Amitava; Nan, Anjan; Line, Bruce R et al. (2006) Nanocarriers for nuclear imaging and radiotherapy of cancer. Curr Pharm Des 12:4729-49 |
