期刊
ADVANCED SCIENCE
卷 6, 期 16, 页码 -出版社
WILEY
DOI: 10.1002/advs.201900586
关键词
elastin-like polypeptides; interferon; matrix metalloproteinases; protein-polymer conjugates; tumor microenvironment
资金
- National Natural Science Foundation of China [21534006]
Protein-polymer conjugates show improved pharmacokinetics but reduced bioactivity and tumor penetration as compared to native proteins, resulting in limited antitumor efficacy. To address this dilemma, genetic engineering of a body temperature-responsive and matrix metalloproteinase (MMP)-cleavable conjugate of interferon alpha (IFN alpha) and elastin-like polypeptide (ELP) is reported with spatiotemporally programmed two-step release kinetics for tumor therapy. Notably, the conjugate could phase separate to form a depot postsubcutaneous injection, leading to 1-month zero-order release kinetics. Furthermore, it could selectively be cleaved by MMPs that are overexpressed in tumors to release IFN alpha from ELP and thus to recover the bioactivity of IFN alpha. Consequently, it exhibits dramatically enhanced tumor accumulation, tumor penetration, and antitumor efficacy as compared to free IFN alpha in two mouse models of melanoma and ovarian tumor. These findings may provide an intelligent technology of thermoresponsive and protease-cleavable protein-polymer conjugates with spatiotemporally programmed two-step release kinetics for tumor treatment.
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