Nitroreductase-responsive polymeric micelles based on 4-nitrobenzyl and AIE moieties for intracellular doxorubicin release

Enzyme-responsive drug delivery systems (DDSs) have shown great potential in the diagnosis and treatment of cancer. Nitroreductase (NTR) that plays an essential role in the reduction of nitro compounds has been found to be overexpressed in tumor cells than in normal cells. Here, we present an amphiphilic polymer TNP that is flanked by an NTR responsive 4-nitrobenzyl group, hydrophobic AIE tetraphenylethylene (TPE), and polyethylene glycol hydrophilic moieties, which can be self-assembled into micelles to efficiently encapsulate the hydrophobic drug doxorubicin (DOX) in aqueous solution. In the presence of NADH, the 4-nitrobenzyl unit of TNP is reduced by NTR, leading to the decomposition of the TNP micelles and DOX release with the detection limit as low as 2.6 ng mL −1 . MTT assays showed that TNP @DOX micelles possess an obvious toxicity against cancer cells, while negligible toxicity towards normal cells was observed. With the advantage of the AIE properties of TNP , the TNP @DOX micelles were able to be efficiently endocytosed by HeLa cells, and release DOX in a selective manner as determined by confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) analyses. This work provides a promising nanoplatform for cancer diagnosis and treatment with controlled drug release. An amphiphilic polymer TNP demonstrated the formation of a nitroreductase-responsive DOX delivery nanoplatform with high sensitivity and selectivity.