No abstract

Organ specific drug targeting was explored in mice as a possible alternative to surgery to treat prostate diseases. Peptides that specifically recognize the vasculature in the prostate were identified from phage-displayed peptide libraries by selecting for phage capable of homing into the prostate after an i.v. injection. One of the phage selected in this manner homed to the prostate 10 -15 times more than to other organs. Unselected phage did not show this preference. The phage bound also to vasculature in the human prostate. The peptide displayed by the prostate-homing phage, SMSIARL (single letter code), was synthesized and shown to inhibit the homing of the phage when co-injected into mice with the phage. Systemic treatment of mice with a chimeric peptide consisting of the SMSIARL homing peptide, linked to a proapoptotic peptide that disrupts mitochondrial membranes, caused tissue destruction in the prostate, but not in other organs. The chimeric peptide delayed the development of the cancers in prostate cancerprone transgenic mice (TRAMP mice). These results suggest that it may be possible to develop an alternative to surgical prostate resection and that such a treatment may also reduce future cancer risk. Diseases affecting the prostate have gained major significance clinically and economically, primarily because of the increasing average age of the male population in the industrialized countries. Benign prostate hyperplasia affects to some degree most elderly men. Even more serious, the prostate is a frequent site of cancer. Some autopsy studies find that most men older than 70 have occult or overt cancer in the prostate (1). The surgical therapies of prostate hypertrophy and prostate cancer are associated with serious side effects, such as incontinence and impotence.We have sought to develop a strategy that would provide a less traumatic treatment for prostate disease than is currently available. Our strategy is based on identification of peptides that home to specific sites in the vasculature by in vivo screening of intravenously injected phage libraries. These studies have revealed a surprising degree of specialization in the endothelia of various normal tissues (2, 3). Screening phage libraries for tumor homing has yielded a collection of peptides that home to tumor vasculature (4). We and others have used these tumor-homing peptides to direct therapies into tumors in mice (4, 5). We report here the identification of peptides that home to the vasculature of the prostate and the use of one of these homing peptides to deliver a proapoptotic peptide to the prostate. Materials and MethodsMaterials. Peptides were synthesized to our specifications by AnaSpec (San Jose, CA) or by our Peptide Synthesis Facility. The peptides were purified by HPLC and their identity was confirmed with mass spectrometry.Apotag Kit for TUNEL staining was purchased from Intergen (Purchase, NY). Testosterone pellets (12.5 mg) and control pellets were from Innovative Research of America (Sarasota, FL), and controlled release pumps ...

The vasculature in the angiogenic stages of a mouse model of pancreatic islet carcinogenesis was profiled in vivo with phage libraries that display short peptides. We characterized seven peptides distinguished by their differential homing to angiogenic progenitors, solid tumors, or both. None homed appreciably to normal pancreatic islets or other organs. Five peptides selectively homed to neoplastic lesions in the pancreas and not to islet beta cell tumors growing subcutaneously, xenotransplant tumors from a human cancer cell line, or an endogenously arising squamous cell tumor of the skin. Three peptides with distinctive homing to angiogenic islets, tumors, or both colocalized with markers that identify endothelial cells or pericytes. One peptide is homologous with pro-PDGF-B, which is expressed in endothelial cells, while its receptor is expressed in pericytes.