Fibrin Targeted Cancer Therapy

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DESCRIPTION (provided by applicant): We propose to improve efficacy of liposomal drugs by active targeting to tumoral fibrin deposits so as to significantly increase biodistribution of drugto the tumor, thus inducing more effective tumor cell killing. Liposomal encapsulated drugs achieve extended circulation times in plasma and some non-specific targeting to tumors via an enhanced permeation and retention effect. Liposomal doxorubicin formulation (Doxil(R)) is approved as a treatment for metastatic breast and ovarian cancer, and improves survival. Second-generation liposomes seek to improve upon this passive targeting mechanism by decorating liposomes with ligands directed to tumor-associated targets, thus further enhancing the local tumor concentration. We propose to exploit a highly specific fibrin binding peptide, Tn6-Fbn, developed in our lab to target liposomes to the prominent fibrin deposits that are common to most growing tumors. Fibrin is an excellent target for tumor targeting: it is present at high concentration at the host-tumor interface and throughout the tumor stroma, and apart from wound healing, is not otherwise promiscuous in normal tissue. It represents a high capacity storage depot for sustained release of liposomal chemotherapy that is effectively tumor selective, general to most (if not all) solid tumor types, and present throughout tumor development. We have performed early validation of this concept demonstrating targeting and retention of a Tn6-Fbn based magnetic resonance imaging probe, EP-2104R, to fibrin in the tumor stroma of a murine breast cancer xenograft. This proposal involves synthesizing and characterizing fibrin targeted liposomes, as well as optimizing key physicochemical and biochemical properties, including liposome stability and fibrin binding. Biodistribution of liposomes to tumors will be evaluated in an orthotopic breast cancer model and compared to non-targeted controls using a combination of in vivo molecular imaging and tumor histology. Finally, the ability of fibrin targeted liposomes to prevent primary tumor growth will be evaluated and compared to non-targeted liposomes and the gold standard Doxil.