Synergistic enzymatic and bioorthogonal reactions for selective prodrug activation in living systems

Qingxin Yao,Ye Liu,Yuan Gao,Yanpu Wang,Xinyuan Fan,Xingyu Jiang,Peng R Chen,Feng Lin,Zhaofei Liu

doi:10.1038/s41467-018-07490-6

Abstract

Adverse drug reactions (ADRs) restrict the maximum doses applicable in chemotherapy, which leads to failure in cancer treatment. Various approaches, including nano-drug and prodrug strategies aimed at reducing ADRs, have been developed, but these strategies have their own pitfalls. A renovated strategy for ADR reduction is urgently needed. Here, we employ an enzymatic supramolecular self-assembly process to accumulate a bioorthogonal decaging reaction trigger inside targeted cancer cells, enabling spatiotemporally controlled, synergistic prodrug activation. The bioorthogonally activated prodrug exhibits significantly enhanced potency against cancer cells compared with normal cells. This prodrug activation strategy further demonstrates high tumour inhibition efficacy with satisfactory biocompatibility, pharmacokinetics, and safety in vivo. We envision that integration of enzymatic and bioorthogonal reactions will serve as a general small-molecule-based strategy for alleviation of ADRs in chemotherapy.

Highlights

Adverse drug reactions (ADRs) restrict the maximum doses applicable in chemotherapy, which leads to failure in cancer treatment
Upon the addition of alkaline phosphatase (ALP) (10 U mL−1) into the solution of 2, a transparent purple hydrogel was formed within 1 h (Fig. 2b inset), and the critical hydrogelation concentration was 1.0 mg mL−1 (Supplementary Fig. 3)
As shown in this study, intracellular self-assembly led to high levels of accumulation of Tz in cancer cells, which guaranteed rapid and specific activation of TCO-Dox and facilitated target engagement of the activated Dox inside the nucleus

Summary

Introduction

Adverse drug reactions (ADRs) restrict the maximum doses applicable in chemotherapy, which leads to failure in cancer treatment. We employ an enzymatic supramolecular self-assembly process to accumulate a bioorthogonal decaging reaction trigger inside targeted cancer cells, enabling spatiotemporally controlled, synergistic prodrug activation. For cells that have very high phosphatase levels, such as Saos-2 cells, EISA may have direct and strong inhibitory effects via necroptosis[21] By systemic administration, these small molecules may diffuse deeply into the tumour and may overcome the disadvantages of insufficient penetration, which is often observed with mAbs[22]. We use a combination of EISA and Tz/TCO bioorthogonal decaging reaction which simultaneously leads to spatiotemporal targeting and selective activation of prodrugs inside cancer cells, achieving the urgently needed selectivity of chemodrugs for cancer cells over normal cells (Fig. 1). Our strategy enables spatiotemporally controlled, synergistic prodrug activation with superior selectivity for cancer over non-cancer cells, which leads to effective and safe tumour inhibition, as demonstrated in a xenografted cervical cancer model (HeLa cells) in mice

Methods

Results

Conclusion