Temperature-triggered micellization of interferon alpha-diblock copolypeptide conjugate with enhanced stability and pharmacology

Zhuoran Wang; Jianwen Guo; Xinyu Liu; Jiawei Sun; Weiping Gao

doi:10.1016/j.jconrel.2020.08.065

Temperature-triggered micellization of interferon alpha-diblock copolypeptide conjugate with enhanced stability and pharmacology

J Control Release. 2020 Dec 10:328:444-453. doi: 10.1016/j.jconrel.2020.08.065. Epub 2020 Sep 6.

Authors

Zhuoran Wang¹, Jianwen Guo², Xinyu Liu³, Jiawei Sun², Weiping Gao⁴

Affiliations

¹ Department of Geriatric Dentistry, Beijing Laboratory of Biomedical Materials, Peking University School and Hospital of Stomatology, Beijing 100081, PR China; Biomedical Engineering Department, Peking University, Beijing 100191, PR China; CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, PR China.
² Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, PR China.
³ Department of Geriatric Dentistry, Beijing Laboratory of Biomedical Materials, Peking University School and Hospital of Stomatology, Beijing 100081, PR China; Biomedical Engineering Department, Peking University, Beijing 100191, PR China.
⁴ Department of Geriatric Dentistry, Beijing Laboratory of Biomedical Materials, Peking University School and Hospital of Stomatology, Beijing 100081, PR China; Biomedical Engineering Department, Peking University, Beijing 100191, PR China. Electronic address: [email protected].

PMID: 32898593
DOI: 10.1016/j.jconrel.2020.08.065

Abstract

Polypeptides are useful in designing protein-polypeptide conjugates for therapeutic applications; however, they are not satisfactory in improving the stability of therapeutic proteins and extending their in vivo half-life. Here we show that thermally-induced self-assembly (TISA) of elastin-like polypeptide diblock copolymer fused interferon alpha (IFNα-ELP_diblock) into a spherical micelle can dramatically enhance the proteolytic stability of IFNα. Notably, the circulation half-life of IFNα-ELP_diblock micelle (54.7 h) is 124.3-, 5.7-, and 1.4-time longer than those of free IFNα (0.44 h), freely soluble IFNα-ELP (9.6 h), and PEGylated IFNα (39.0 h), respectively. Importantly, in a mouse model of ovarian tumor, IFNα-ELP_diblock micelle exhibited significantly enhanced tumor retention and antitumor efficacy over free IFNα, freely soluble IFNα-ELP, and even PEGylated IFNα. These findings provide a thermoresponsive supramolecular strategy of TISA to design protein-diblock copolypeptide conjugate micelles with enhanced stability and pharmacology.

Keywords: Polypeptide; Protein delivery; Protein-polymer conjugate; Self-assembly; Thermosensitivity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Elastin*
Interferon-alpha*
Mice
Micelles
Peptides
Temperature

Substances

Interferon-alpha
Micelles
Peptides
Elastin