Hydrogen Sulfide Triggered Charge-Reversal Micelles for Cancer-Targeted Drug Delivery and Imaging

Currently, the development of polymeric micelles combining diagnosis and targeted therapy is theoretically and practically significant in cancer treatment. In addition, it has been reported that cancer cells can produce large amounts of hydrogen sulfide (H2S) and their survival depends on the content of H2S. In this study, a series of N-(2-hydroxyethyl)-4-azide-1,8-naphthalimide ended amphiphilic diblock copolymer poly(2-hydroxyethyl methacrylate)-block-poly(methyl methacrylate) (N-3-Nap-PHEMA-b-PMMA-N-3) micelles were prepared. Around cancer tissues, the N-3-Nap-PHEMA(45)-b-PMMA(42)-N-3 micelles exhibited dual characteristics of monitoring H2S and H2S triggered Cytoplasm charge reversal with the reduction of the azido group. The surface charge of N-3-Nap-PHEMA(45)-b-PMMA(42)-N-3 micelles reversed from negative to positive after monitoring H2S. With H2S triggered charge reversal, the cellular uptake of DOX-loaded N-3-Nap-PHEMA(45)-b-PMMA(42)-N-3 micelles was effectively enhanced through electrostatic attraction mediated targeting, and a fast rate was observed. The MTT assay demonstrated that N-3-Nap-PHEMA(45)-b-PMMA(42)-N-3 micelles were biocompatible to HeLa cells, and DOX-loaded N-3-Nap-PHEMA(45)-b-PMMA(42)-N-3 micelles showed enhanced cytotoxicity in HeLa cells in the presence of H2S. Furthermore, in vivo fluorescence imaging and biodistribution experiments revealed that DOX-loaded N-3-Nap-PHEMA(45)-b-PMMA(42)-N-3 micelles could provide good tumor imaging and accumulate in tumor tissue. Therefore, N-3-Nap-PHEMA(45)-b-PMMA(42)-N-3 micelles can be used as a promising platform for tumor diagnosis and therapy.