title: iRGD-targeted delivery of a pro-apoptotic peptide activated by cathepsin B inhibits tumor growth and metastasis in mice.
abstract: The use of cytolytic peptides with potential therapeutic properties is a promising approach to cancer therapy due to their convenient automated synthesis and their capacity for modifications. However, the use of cytolytic peptides is limited due to their nonspecific cytolytic activity. In this study, we designed a tumor-targeting proapoptotic system based on an amphipathic D-amino acid-modified apoptotic peptide, KLA, a variant of (KLAKLAK)2, which is fused with a linear tumor-penetrating homing peptide iRGD through specific cathepsin B (CTSB) cleavage sequences that are overexpressed in many types of tumor tissues. Our data show that the procytotoxic peptide D(KLAKLAKKLAKLA)K-GG-iRGD (m(KLA)-iRGD) is internalized into cultured tumor cells through a neuropilin-1 (NRP1)-activated pathway by iRGD delivery. Once inside the cells, the peptide triggers rapid apoptosis through both the mitochondrial-induced apoptotic pathway and the death receptor pathway in NRP1+/αvβ3/CTSB+ tumor cells. Furthermore, m(KLA)-iRGD spread extensively within the tumor tissue when it was injected into 4T1 tumor-bearing mice. The m(KLA)-iRGD peptide inhibited tumor growth to a certain degree, resulting in a significant reduction in tumor volume (P < 0.05) and the total inhibition of metastasis at the end of the treatment. These results suggest that m(KLA)-iRGD has the potential for development as a new antitumor drug.
authors: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, No.132 Wai huan dong Road, University Town, Guangzhou, 510006, China.
authors: Wang
authors: W
authors: Qifan
authors: Guangzhou Institute of Pediatrics, Department of Obstetrics, Guangzhou Women and Children's Medical Center, Guangzhou, China.
authors: Ning
authors: N
authors: Fen
authors: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, No.132 Wai huan dong Road, University Town, Guangzhou, 510006, China.
authors: Xue
authors: X
authors: Ying
authors: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, No.132 Wai huan dong Road, University Town, Guangzhou, 510006, China.
authors: Feng
authors: F
authors: Xinwei
authors: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, No.132 Wai huan dong Road, University Town, Guangzhou, 510006, China.
authors: Du
authors: D
authors: Jun
authors: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, No.132 Wai huan dong Road, University Town, Guangzhou, 510006, China. zhangge@mail.sysu.edu.cn.
authors: Zhang
authors: Z
authors: Ge
mesh_terms: D065767:Activation, Metabolic; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology; D002401:Cathepsin B / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004337:Drug Carriers / Q000008:administration & dosage; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects; D009362:Neoplasm Metastasis; D039942:Neuropilin-1 / Q000502:physiology; D009842:Oligopeptides / Q000008:administration & dosage*; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019014:fas Receptor / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; C569656:N-end cysteine peptide tumor-homing peptide; D009842:Oligopeptides; D011355:Prodrugs; D019014:fas Receptor; C000614276:m(KLA)-iRGD peptide; D039942:Neuropilin-1; D002401:Cathepsin B; C533915:Ctsb protein, mouse
keywords: Cathepsin B; Metastasis; Tumor growth; iRGD