Abstract
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 (IFNα) 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 IFNα from ELP and thus to recover the bioactivity of IFNα. Consequently, it exhibits dramatically enhanced tumor accumulation, tumor penetration, and antitumor efficacy as compared to free IFNα 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.
Highlights
IFNα (0.8 h), whereas the bioactivity of PEGASYS is 51.3-fold lower than that of free IFNα.[11]
We further studied the effect of the matrix metalloproteinase (MMP)-cleavable function of IFNα-MMP substrate (MMPS)-ELP(A) on its in vivo properties in a mouse model of C8161 melanoma (Figure 2)
All the results indicated that the introduction of the MMPS linker into IFNα-ELP(A) did not change the pharmacokinetics and biodistribution but improved the tumor penetration and antitumor efficacy
Summary
IFNα (0.8 h), whereas the bioactivity of PEGASYS is 51.3-fold lower than that of free IFNα.[11]. Penetration limits the antitumor efficacy of protein-polymer conjugates To address this dilemma, we introduce stimuli-responsive functions into protein-polymer conjugates to design body temperature-responsive and matrix metalloproteinase (MMP)cleavable protein-polymer conjugates with spatiotemporally-programed two-step release kinetics for enhanced tumor therapy. In two mouse models of melanoma and ovarian tumor, the conjugate showed remarkably increased tumor accumulation, tumor penetration, and antitumor efficacy as well as dramatically enhanced pharmacokinetics as compared to free IFNα
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