title: In vivo pharmacokinetics, immunogenicity and mechanism of PEGylated antitumor polypeptide.
abstract: HM-3, An RGD (Arg-Gly-Asp)-modified polypeptide derived from endostatin, is a potent angiogenesis inhibitor. Its robust inhibitory effects on endothelial cell migration and tumor growth have been demonstrated by activity assay both in vitro and in vivo. However, HM-3 has relatively short half-life in vivo. In order to prolong its half-life and retain its safety and efficacy, previous studies modified HM-3 with four types of PEG (site-specific N-terminal modification), and the results showed that mPEG-SC20k-HM-3 was the most ideal modification product via activity evaluation in vivo. In the present study, we determined the pharmacokinetic properties, immunogenicity and binding targets of mPEG-SC20k-HM-3. The results showed that mPEG-SC20k-HM-3 had good linear pharmacokinetic properties in SD rats. The half-life of mPEG-SC20k-HM-3 was 43.76-fold longer than that of unmodified HM-3 after intravenous injection in SD rats. The administration frequency of the modified product (mPEG-SC20k-HM-3) was reduced from twice a day to once every 2 days, while the safety and efficacy were retained. The immunogenicity of mPEG-SC20k-HM-3 was significantly lower than that of HM-3 in BALB/c mice. Histochemical and immunohistochemical results showed that mPEG-SC20k-HM-3 could significantly inhibit angiogenesis and tumor growth, induce continuous necrosis, and reduce vessel density within tumor tissues. Furthermore, mPEG-SC20k-HM-3 could bind multi-target αvβ3 and α5β1 of integrin, and the major binding target was integrin αvβ3. All of these results indicated that PEGylated HM-3 had a good application prospect.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Liu
authors.forename: Weiguang
authors.initials: W
authors.lastname: Li
authors.forename: Han-Mei
authors.initials: HM
authors.lastname: Xu
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Huang
authors.forename: Li
authors.initials: L
authors.lastname: Pan
authors.forename: Yinling
authors.initials: Y
authors.lastname: Ren
authors.forename: Yongjing
authors.initials: Y
authors.lastname: Yang
authors.forename: Yongbing
authors.initials: Y
authors.lastname: Li
authors.forename: Chunyan
authors.initials: C
authors.lastname: Pu
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood / Q000276:immunology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000276:immunology / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D045744:Cell Line, Tumor; D043169:Endostatins / Q000737:chemistry*; D005260:Female; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D009842:Oligopeptides / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D043169:Endostatins; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D010446:Peptide Fragments; C099846:succinimidyl carbonate poly(ethylene glycol) monomethyl ether; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid