Coordinating bioorthogonal reactions with two tumor-microenvironment-responsive nanovehicles for spatiotemporally controlled prodrug activation.

Chemical Science
Liping ZuoHai-Yan Xie

Abstract

Precise activation of prodrugs in tumor tissues is critical to ensuring specific antitumor efficacy, meanwhile reducing the serious adverse effects. Here, a spatiotemporally controlled prodrug activation strategy was provided by integrating the inverse electron demand Diels-Alder (IEDDA) reaction with two tumor-microenvironment-responsive nanovehicles. The prodrug (Dox-TCO) and [4-(6-methyl-1,2,4,5-tetrazin-3-yl)phenyl]methanamine (Tz) were separately camouflaged into low pH and matrix metalloproteinase 2 (MMP-2) sensitive micellar nanoparticles. After systemic administration, only in the tumor tissues could both the nanovehicles dissociate via responding to two special tumor microenvironments, with Dox-TCO and Tz released and then immediately triggering the prodrug activation through the IEDDA reaction. The hierarchically regulated and locally confined Dox liberation led to dramatically decreased side-effects that were much lower than those of the clinical Doxorubicin Hydrochloride Liposomal Injection (Doxil), while the antitumor therapeutic effect was potent.

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Citations

Oct 10, 2020·Chemistry, an Asian Journal·Xueqian ChenDongdong Su
Dec 4, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yayue WangPing Feng
Aug 9, 2021·Bioorganic & Medicinal Chemistry·Boris Lozhkin, Thomas R Ward
Dec 11, 2020·Analytical Chemistry·Guobin MaoZhike He

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Methods Mentioned

BETA
Fluorescence
fluorescence imaging

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