title: Increased antitumor activity of tumor-specific peptide modified thymopentin.
abstract: Thymopoietin pentapeptide (thymopentin, TP5), an immunomodulatory peptide, has been successfully used as an immune system enhancer for treating immune deficiency, cancer, and infectious diseases. However, poor penetration into tumors remains a key limitation to the efficacy and application of TP5. iRGD (CRGDK/RGPD/EC) has been introduced to certain anticancer agents, and increased specific tumor penetrability of drugs and cell internalization have been observed. In the present study, we fused this iRGD fragment with the C-terminal of TP5 to yield a new product, TP5-iRGD. Cell attachment assay showed that TP5-iRGD exhibits more extensive attachment to the melanoma cell line B16F10 than wild-type TP5. Tumor cell viability assay showed that iRGD conjugation with the TP5 C-terminus increases the basal antiproliferative activity of the pentapeptide against the melanoma cell line B16F10, the human lung cancer cell line H460, and the human breast cancer cell line MCF-7. Subsequent injections of TP5-iRGD inhibited in vivo melanoma progression more efficiently than the native TP5. Murine spleen lymphocyte proliferation assay also showed that TP5-iRGD and the parent pentapeptide feature nearly identical spleen lymphocyte proliferation activities. We built an integrin αvβ3 and TP5-iRGD computational binding model to investigate the mechanism by which TP5-iRGD promotes increased activity further. Conjugation with iRGD promotes binding to integrin αvβ3, thereby increasing the tumor-homing efficiency of the resultant peptide. These experimental and computational observations of increased TP5-iRGD activity help broaden the usage of TP5 and reflect the great application potential of the peptide as an anticancer agent.
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Xingzhen
authors.initials: X
authors.lastname: Lao
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Meng
authors.initials: M
authors.lastname: Liu
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Chen
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: xdgao@cpu.edu.cn.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Gao
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: cpu_zhengheng@163.com.
authors.forename: Heng
authors.initials: H
authors.lastname: Zheng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051940:B7-2 Antigen / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000737:chemistry / Q000378:metabolism; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D016305:Thymopentin / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D051940:B7-2 Antigen; D039302:Integrin alphaVbeta3; D016305:Thymopentin
keywords: Anticancer; Integrin; RGD; Tumor penetrating