title: Multivalent Targeting Based Delivery of Therapeutic Peptide using AP1-ELP Carrier for Effective Cancer Therapy.
abstract: Elastin-like polypeptide (ELP)-based drug delivery has been utilized for various applications including cancer therapies for many years. Genetic incorporation of internalization ligands and cell-targeting peptides along with ELP polymer enhanced tumor accumulation and retention time as well as stability and activities of the drug conjugates. Herein, we described a unique delivery system comprised of genetically engineered ELP incorporated with multiple copies of IL-4 receptor targeting peptide (AP1) periodically and proapoptotic peptide (KLAKLAK)2referred to as AP1-ELP-KLAK. It triggered thermal-responsive self-assembly into a nanoparticle-like structure at physiological body temperature and stabilized its helical conformation, which is critical for its membrane-disrupting activities. Increased IL-4 receptor specific cellular internalization was associated with the enhanced cytotoxic effect of (KLAKLAK)2peptide. Additionally, multivalent presentation of targeting ligands by AP1-ELP-KLAK significantly enhanced intratumoral localization and prolonged the retention time compared to ELP-KLAK, non-targeted control. Systemic administration of AP1-ELP-KLAK significantly inhibited tumor growth by provoking cell apoptosis in various tumor xenograft models without any specific organ toxicity. Thus, our newly designed AP1-ELP-KLAK polymer nanoparticle is a promising candidate for effective cancer therapy and due to the simple preparative procedures of ELPs, this platform can be used as a good carrier for tumor-specific delivery of other therapeutics.
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea.
authors.forename: Vijaya
authors.initials: V
authors.lastname: Sarangthem
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea.
authors.forename: Yunjae
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea.
authors.forename: Thoudam Debraj
authors.initials: TD
authors.lastname: Singh
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea.
authors.forename: Bo-Yeon
authors.initials: BY
authors.lastname: Seo
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea.
authors.forename: Sun-Ha
authors.initials: SH
authors.lastname: Cheon
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea.
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea.
authors.forename: Byung-Heon
authors.initials: BH
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea.
authors.forename: Rang-Woon
authors.initials: RW
authors.lastname: Park
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage*; D004549:Elastin / Q000008:administration & dosage* / Q000378:metabolism; D005260:Female; D064593:Heterografts; D006801:Humans; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage*; D009369:Neoplasms / Q000628:therapy*; D010455:Peptides / Q000008:administration & dosage* / Q000378:metabolism; D055503:Protein Multimerization; D016896:Treatment Outcome
chemical_list: C513345:AP1 peptide; D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; D004337:Drug Carriers; D010455:Peptides; D004549:Elastin
keywords: AP1; IL-4 receptor; apoptosis; drug delivery.; micelle; multivalent targeting