Tuning Paclitaxel Release Behavior Using Dually-Responsive Nanomicellar Assemblies with Multiple Diselenide/Disulfide Linkages

Abstract

Background: There are many reasons that lead to the failure of cancer chemotherapy, such as uncontrolled drug release, low drug utilization, and severe side effects. Methods: To overcome these obstacles, we designed two kinds of copolymers with thermal and redox-responsive properties containing multiple diselenide/disulfide bonds polyethylene glycol -alt- diselenodipropionate/disulfhydryldipropionate-b-poly(N-isopropylacrylamide) (abbreviated as PEG-alt-DSeDP-b-PNIPAM and PEG-alt-DSDP-b-PNIPAM) by alternative esterification and following atom transfer radical polymerization. Afterward, these prepared copolymers were mixed with the mass ratio of 8:0, 5:3, 3:5, 0:8 (denoted as S1, S2, S3, and S4, respectively), and self-assembled with paclitaxel (PTX) to obtain PTX-loaded S1, S2, S3, and S4 nanomicellar assemblies, aiming to realize PTX controlled and on-demand release. Results: The chemical structures of these two copolymers were characterized by gel permeation chromatography (GPC), indicating eight diselenide/disulfide linkages and eight PEG units were contained in these copolymers. Moreover, the thermal-responsive property was detected by UV-vis spectroscopy, meanwhile, the redox-responsive property was observed by TEM in the presence of 10 mM glutathione (GSH). We found that 76.90% of PTX was released from S1 nanomicelles within 23 h. In contrast, this percentage decreased to 64.53% for S4 nanomicelles even the incubation time prolonged to 82 h, indicating explosive and slow release behaviors of S1 and S4 nanomicelles, respectively. In addition, gradually decreased fluorescence intensity around the cellular nucleus was occurred from S1 to S4 orderly, which was consistent with cellular uptake and in vivo anti-tumor experiments. Conclusion: This work not only provides a strategy for the controlled and effective release of PTX, but also improves drug bioavailability in cancer treatment.