Fibrin Targeted Cancer Therapy

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 Tn 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 Tn Fbn based magnetic resonance imaging probe EP R 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 PUBLIC HEALTH RELEVANCE Cancer nanobiology is a promising platform for improved delivery of chemotherapeutics to a wide range of cancers This application proposes to improve efficacy of liposomal drugs by active targeting to tumoral fibrin deposits so as to significantly increase biodistribution of drug to the tumor thus inducing more effective tumor cell killing