title: Enhancing the circulating half-life and the antitumor effects of a tumor-selective cytotoxic peptide by exploiting endogenous serum albumin as a drug carrier.
abstract: The elevated expression of bombesin receptors in many of the deadliest cancers has attracted special interest in developing bombesin-directed agents for tumor imaging and therapy. Previously, we constructed the chimeric peptide BB28 by fusing bombesin to a mitochondria-disrupting peptide. BB28 selectively induced the apoptosis of various tumor cells in vitro and showed promising in vivo antitumor effects. In general, a short circulating half-life limits the in vivo effect of peptides. To prolong the half-life of BB28, here, we generated the novel peptide ABB28 by fusing an albumin-binding domain (ABD) to the N-terminus of BB28. ABB28 exhibited much higher binding affinity for albumin than BB28, and this modification extended the peptide half-life from several minutes to 2 h. Optical imaging revealed that ABB28 accumulated in xenografted tumors within 1h post-injection and persisted at an evident level for up to 24 h. ABB28 exerted stronger tumor-suppressive effects than BB28. Significant differences in the tumor volumes (P<0.001) and the tumor weights (P=0.002) were observed between ABB28- and BB28-treated mice. Moreover, ABB28 exhibited tumor suppression comparable to that of PEGylated 5K-BB28 in vivo. These results suggest that half-life extension via ABD fusion represents a useful strategy for optimizing bombesin-directed pharmaceuticals for cancer-targeted therapy.
authors.affiliation: Key Lab of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Su
authors.affiliation: Key Lab of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Yang
authors.affiliation: Key Lab of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Fan
authors.affiliation: Key Lab of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Dianlong
authors.initials: D
authors.lastname: Jia
authors.affiliation: Key Lab of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Ze
authors.initials: Z
authors.lastname: Tao
authors.affiliation: Key Lab of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wan
authors.affiliation: Key Lab of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: xiaofenglu@scu.edu.cn.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Lu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001839:Bombesin / Q000737:chemistry*; D004337:Drug Carriers / Q000378:metabolism; D005260:Female; D006207:Half-Life; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry; D018004:Receptors, Bombesin / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism*; D013997:Time Factors; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D010455:Peptides; D018004:Receptors, Bombesin; D012709:Serum Albumin; D011092:Polyethylene Glycols; D001839:Bombesin
keywords: Albumin; Albumin-binding domain; Bombesin; Drug carrier; Tumor-homing peptide