title: In vivo anti-tumor activity of polypeptide HM-3 modified by different polyethylene glycols (PEG).
abstract: HM-3, designed by our laboratory, is a polypeptide composed of 18 amino acids. Pharmacodynamic studies in vivo and in vitro indicated that HM-3 could inhibit endothelial cell migration and angiogenesis, thereby inhibiting tumor growth. However, the half-life of HM-3 is short. In this study, we modified HM-3 with different polyethylene glycols (PEG) in order to reduce the plasma clearance rate, extend the half-life in the body, maintain a high concentration of HM-3 in the blood and increase the therapeutic efficiency. HM-3 was modified with four different types of PEG with different molecular weights (ALD-mPEG(5k), ALD-mPEG(10k), SC-mPEG(10k) and SC-mPEG(20k)), resulting in four modified products (ALD-mPEG(5k)-HM-3, ALD-mPEG(10k)-HM-3, SC-mPEG(10k)-HM-3 and SC-mPEG(20k)-HM-3, respectively). Anti-tumor activity of these four modified HM-3 was determined in BALB/c mice with Taxol as a positive control and normal saline as a negative control. Tumor weight inhibition rates of mice treated with Taxol, HM-3, ALD-mPEG(5k)-HM-3, ALD-mPEG(10k)-HM-3, SC-mPEG(10k)-HM-3 and SC-mPEG(20k)-HM-3 were 44.50%, 43.92%, 37.95%, 31.64%, 20.27% and 50.23%, respectively. Tumor inhibition rates in the Taxol, HM-3 and SC-mPEG(20k)-HM-3 groups were significantly higher than that in the negative control group. The efficiency of tumor inhibition in the SC-mPEG(20k)-HM-3 group (drug treatment frequency: once per two days) was better than that in the HM-3 group (drug treatment frequency: twice per day). In addition, tumor inhibition rate in the SC-mPEG(20k)-HM-3 group was higher than that in the taxol group. We conclude that SC-mPEG(20k)-HM-3 had a low plasma clearance rate and long half-life, resulting in high anti-tumor therapeutic efficacy in vivo. Therefore, SC-mPEG(20k)-HM-3 could be potentially developed as new anti-tumor drugs.
authors: Department of Marine Pharmacy, College of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China; E-Mails: liuzhendong0403@163.com (Z.L.); renyinling123@126.com (Y.R.); panli0225@163.com (L.P.).
authors: Zhendong
authors: Z
authors: Liu
authors: Yinling
authors: Y
authors: Ren
authors: Li
authors: L
authors: Pan
authors: Han-Mei
authors: HM
authors: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D010455:Peptides / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; C099846:succinimidyl carbonate poly(ethylene glycol) monomethyl ether; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D017239:Paclitaxel