Drug carriers can alter pharmacology and confer novel mechanisms of action upon agents having properties that compliment the characteristics of the carrier. Doxorubicin encapsulated within long-circulating liposomes by means of a """"""""remote loading"""""""" method (L-DXR) represents the first in a new class of anticancer agents, and was recently approved by the FDA. However, its full spectrum of action and mechanisms remain to be defined. Previously we demonstrated substantial extension of lifespan for rats bearing an orthotopically-implanted drug-resistant brain tumor when administered L-DXR, but not free DXR. We have recently observed that repetitive doses of L-DXR (but not equivalent doses of free DXR) increase tumor vascular permeability and mediate vascular barrier breakdown. Normal vasculature appears to be unaffected. This effect, unprecedented in the literature, has important clinical and basic implications. The objectives of this proposal are (a) to understand the mechanistic basis by which this drug carrier system confers upon DXR the property of compromising vascular permeability, and (b) to determine the functional consequences of this effect. In particular, we will (c) explore the potential to enhance therapy through rational application of tumor vascular barrier breakdown, not only to optimize tumor deposition and therapeutic effect of L-DXR itself, but also to promote the therapeutic effects of other agents. Selective tumor vascular barrier breakdown could improve the penetration and effects of gene-carrier systems, and could increase the sensitivity of tumors to drugs having complimentary mechanisms of action, such as antiangiogenic agents. Vascular permeability changes resulting from repetitive L-DXR treatment will be investigated using a series of permeability probes and immunohistological approaches. Free DXR will be used as a control. Functional Magnetic Resonance (fMR) imaging will enable dynamic observation of tumor perfusion and vascular permeability changes. Effects of the vascular permeability compromise on the activity of potentially complementary agents will be investigated using TNP-470 and paclitaxel; the former is a well-characterized antiangiogenic agent, while the latter is an active chemotherapeutic agent having some antiangiogenic properties. The effect of vascular permeability changes on delivery by other macromolecular carriers will be probed using viral vectors carrying model genes.
