Biopanning, identification and application of peptides targeting the vasculature of orthotopic colorectal cancer based on in vivo phage display technology.

• Other Authors: Li, Zhijie
• Format: Others
• Language: English; Chinese
• Published: 2010
• Subjects: Colon (Anatomy) > Cancer > Chemotherapy; Drug targeting; Peptides > Therapeutic use; Rectum > Cancer > Chemotherapy; Colorectal Neoplasms > drug therapy; Drug Administration Routes; Drug Delivery Systems; Peptides > therapeutic use
• Online Access: http://library.cuhk.edu.hk/record=b6074858; http://repository.lib.cuhk.edu.hk/en/item/cuhk-344491

Colorectal cancer (CRC) is one of the most common malignancies worldwide. However, adjuvant chemotherapeutic agents exhibit poor accumulation in the tumor mass and frequently result in serious side effects due to nonspecific damage to normal organs. Therefore, the development of more selective anticancer drugs with targeted delivery to tumor sites is the current trend in cancer therapies. Among these sites, tumor neovasculature is an attractive target for anticancer agents. It is because tumor growth is largely limited by blood supply which is dependent on the extent of angiogenesis in the tumor. === Experimental analysis suggested that TCP-1 phage and synthetic TCP-1 peptide specifically homed to colorectal cancer tissues and co-localized with the tumor vasculature. Moreover, TCP-1 peptide also recognized the vasculature of human colorectal cancer specimens. Subsequently, the homing abilities of TCP-1 phage were extensively tested in other cancer models. Results showed that TCP-1 peptide could also target the vasculature of orthotopic gastric cancer induced by human colon cancer cell line (MKN45) in BALB/c nude mice. Meanwhile, TCP-1 phage exhibited binding activity to colorectal cancer cells such as colon 26 and SW1116. TCP-1 peptide could carry a pro-apoptotic peptide into these cells and markedly enhanced its pro-apoptotic action. === In summary, we have used the phage display technology to isolate two unique peptides TCP-1 and TCP-2, which targeted the vasculature of orthotopic colorectal cancer and also recognized the vasculature of human colorectal cancer. Moreover, they could deliver fluorescein or pro-apoptotic peptide only to the tumor vasculature but not to other normal tissues, for imaging detection and targeted therapy. In conclusion, both TCP-1 and TCP-2 may have significant clinical applications as carriers in diagnostic imaging and ligand-mediated targeted therapy for human colorectal cancer. === Similarly, TCP-2 phage or its peptide also targeted specifically the orthotopic colorectal cancer, and co-localized with the tumor vasculature in mice. Meanwhile, TCP-2 peptide recognized the vasculature of human colorectal cancer specimens. FITC-labeled TCP-2 peptide could also be used to detect cancer tissues in tumor-bearing mice. === To identify specific ligands targeting the tumor neovasculature, in vivo phage display technology has been extensively used. Several dozens of peptides homing to normal or diseased vasculature have been identified through this technology. However, these peptides target mainly the tumors growing at distant sites but not at the primary organ, thus limiting their clinical application. To obtain specific peptides targeting the neovasculature of colorectal cancer growing in situ, we established an orthotopic colorectal cancer model in normal BALB/c mice by using syngeneic colon cancer cells (colon 26). Subsequently, in vivo phage display technology was utilized to isolate peptides which specifically recognized the vasculature of the cancer. Four peptides (termed TCP-1, 2, 3, 4) were enriched more than once after four-round selections. Further investigation disclosed that TCP-1 and TCP-2 phages had relatively stronger binding abilities to cancer tissues among the four phage clones. They were chosen for further study. === We further demonstrated that TCP-1 could serve as a carrier for image detection and drug delivery. FITC-labeled TCP-1 could specifically produce a strong fluorescence signal in the tumors after intravenous injection into the orthotopic tumor-bearing mice. Moreover TCP-1, when conjugated with a pro-apoptotic peptide, could also specifically induce apoptosis of tumor vasculature in vivo. === Li, Zhijie. === Adviser: Cho Chiltin. === Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . === Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. === Includes bibliographical references (leaves 194-221). === Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. === Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. === Abstract also in Chinese.