Evidence is provided that Photodynamic Therapy (PDT) can affect vascular permeability to macromolecules and macromolecular complexes in a way that allows enhanced tumor uptake of therapeutic agents in human tumor xenografts or in transplantable murine tumors. This can lead to significantly enhanced tumor control, as shown with liposome-encapsulated doxorubicin. The PDT protocol, termed """"""""permeabilizing"""""""" (P)-PDT, differs from conventional PDT in that it by itself has no or minimal anti-tumor effects. At present, this protocol involves the interaction of two photosensitizers, an anionic pyropheophorbide derivative (HPPH) and the cationic dye Victoria Blue-BO (VBBO). Understanding and exploiting the mechanisms by which P-PDT lowers the vascular barrier encountered by large molecular therapeutic agents may provide an additional approach in the treatment of solid tumors. The preliminary data have led to the hypothesis that P-PDT affects the microvasculature by opening endothelial gaps that allow macromolecules to egress from the vasculature and enter the interstitial tumor space. The applicant further hypothesizes that this mechanism will facilitate the egress of liposomes and microspheres carrying chemotherapeutic drugs or immunomodulating cytokines, thus enhancing cytotoxicity or stimulating anti-tumor immune responses, or of viral gene vectors enhancing transfection efficiencies. The overall goal of this application is to conduct a series of experiments that will test these possibilities.
In Aim 1 the applicant proposes to optimize treatment parameters by exploring additional treatment regimes and photosensitizers. These experiments will not only improve the treatment, but also provide important hints as to the mechanisms involved.
In Aim 2 she proposes to expand the application of this treatment from the delivery of liposomally carried chemotherapeutic drugs to microspheres carrying the cytokine GM-CSF and a viral gene vector expressing the beta-galactosidase (beta-gal) gene.
Aim 3 will focus on the mechanisms of macromolecular egress by determining the size of vascular gaps produced, by monitoring changes in perfusion and permeability in real time by functional MRI, and by administering a number of inhibitors to physiological vasoactive mediators Finally, in Aim 4 she proposes to add a therapeutic PDT component by activating the present photosensitizers with therapeutic light doses that cause photodynamic tumor destruction. She hypothesizes that this added cytoreduction by PDT after maximal chemotherapeutic drug uptake will be beneficial for tumor control. Similarly, PDT destroyed tumor cells may provide tumor antigen to differentiating dendritic cells generated by preceding delivery of GM-CSF.
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