A General Strategy for Macrotheranostic Prodrug Activation: Synergy between the Acidic Tumor Microenvironment and Bioorthogonal Chemistry.

Abstract

Prodrugs activated by endogenous stimuli face the problem of tumor heterogeneity. Bioorthogonal prodrug activation that utilizes an exogenous click reaction has the potential to solve this problem, but most of the strategies currently used rely on the presence of endogenous receptors or overexpressed enzymes. We herein integrate the acidic, extracellular microenvironment of a tumor and a click reaction as a general strategy for prodrug activation. This was achieved by using a tumor pH-responsive polymer containing tetrazine groups, which formed unreactive micelles in the blood but disassembled in response to tumor pH. The vinyl ether group on the macrotheranostic prodrug (CyPVE) is activated by the tetrazine groups, which was confirmed by tumor-specific fluorescence activation and phototoxicity restoration. Therefore, the bioorthogonal reactions in the context of the ubiquitous acidic tumor microenvironment can provide a general strategy for bioorthogonal prodrug activation.

• Authors: Yansong Dong, Yalan Tu, Kewei Wang, Congfei Xu, Youyong Yuan, Jun Wang
• Journal: Angewandte Chemie (International ed. in English) (Angew Chem Int Ed Engl) Vol. 59 Issue 18 Pg. 7168-7172 (04 27 2020) ISSN: 1521-3773 [Electronic] Germany
• PMID: 32003112 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Micelles
• Polymers
• Prodrugs
• Tetrazoles

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Breast Neoplasms (diagnostic imaging, drug therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Click Chemistry
• Drug Screening Assays, Antitumor
• Female
• Hydrogen-Ion Concentration
• Mammary Neoplasms, Experimental (diagnostic imaging, drug therapy)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Micelles
• Molecular Structure
• Nanoparticles (chemistry)
• Optical Imaging
• Polymers (chemical synthesis, chemistry, pharmacology)
• Prodrugs (chemical synthesis, chemistry, pharmacology)
• Tetrazoles (chemistry, pharmacology)
• Theranostic Nanomedicine
• Tumor Microenvironment (drug effects)