The long-term goal of the project is development of superior anti-breast cancer drugs that are delivered to the tumor cells by specifically targeted nanoparticles. We propose a new approach which relies on the use of the stripped landscape phage-the composition of the phage coat proteins-as the targeting ligands of he drug-loaded liposomes and micelles. In our approach the phage specific for the target organ, tissue or cell is selected from the multibillion landscape phage libraries and converted to the liposome and micelles exploring intrinsic amphiphilic properties of the phage proteins. As a result, the targeting probe-the tumor- specific peptide fused to the major coat protein-is exposed on the shell of the drug-loaded vesicle. In contrast to sophisticated and poorly controllable conjugation procedures currently used for coupling of antibodies to the targeted vesicles, the proposed phage-based approach relies on the powerful and extremely precise mechanisms of selection, biosynthesis and self assemblage. As a proof of the concept, we will select filamentous phages specifically binding surface receptors of human and mouse breast cancer cells and/or penetrating into these cells. The selected landscape phages displaying breast cancer cell- Dinding peptides will be stripped and recombinant major coat protein pVIII will be introduced into the doxorubicin- or paclitaxel-loaded vesicles. Bioselective binding properties of the phage protein-targeted drug carriers will be studied by optical, electron and fluorescent microscopy, flow cytometry and protein microarrays, and their cytotoxic effects on the target tumor cells will be evaluated in comparison with nontargeted drug-loaded vesicles using healthy cells as control. Potential therapeutic efficiencies of the targeted drug-loaded vesicles will be determined using immunosupressed mice with ingrafted human breast tumor xenografts. We believe that accomplishment of this program would allow to futher enhance performance of existing anticancer preparations by their targeting to the specific surface markers of the patient's tumor cells and tumor-surrounding vasculature. We believe that the accomplishment of this project would create strong basis for expansion of the landscape phage technology for preparation of the drug carriers targeted to the breast tumors and other pathologies. In contrast to antibodies, the phage technology may be adapted for developing of targeted drugs against any pathology requiring a fast turnaround time. . ? ? ?
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