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Theranostics 2016; 6(12):2235-2249. doi:10.7150/thno.16425 This issue Cite

Research Paper

Multivalent Targeting Based Delivery of Therapeutic Peptide using AP1-ELP Carrier for Effective Cancer Therapy

Vijaya Sarangthem^1*, Yunjae Kim^1*, Thoudam Debraj Singh^2*, Bo-Yeon Seo¹, Sun-Ha Cheon¹, Young-Jin Lee¹, Byung-Heon Lee¹, Rang-Woon Park^1✉

1. Department of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea.
2. Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea.
* These authors contributed equally to the study.

✉ Corresponding author: Rang-Woon Park, MD, PhD. E-mail: nwparkac.kr, phone No.: +82 53 420 4822, Fax No.: +82 53 422 1466.

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)₂ referred 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)₂ peptide. 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.

Keywords: IL-4 receptor, AP1, multivalent targeting, micelle, apoptosis, drug delivery.

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