مقاله انگلیسی پیش داروی پلیمری حساس به GSH
Abstract
Graphical abstract
Keywords
1. Introduction
2. Materials and methods
3. Results and discussion
4. Conclusions
Author contributions
Declaration of Competing Interest
Acknowledgments
Appendix A. Supplementary data
References
Abstract
Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug (MW: 93.5 kDa) was produced by reversible addition-fragmentation chain transfer (RAFT) polymerization. The amphiphilic block polymer-doxorubicin (DOX) prodrug was employed to deliver a hydrophobic photosensitizer (PS), chlorin e6 (Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione (GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 kDa in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition (TGI, 58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent.
1. Introduction
Chemotherapy is generally considered to be one of the most efficient methods for antitumor therapy, while photodynamic therapy (PDT), which uses light to excite photosensitizers (PSs) to generate reactive oxygen species (ROS) for oxidizing intracellular biomacromolecules to induce the death of tumor cells, offers minimal invasive treatment for assisting in chemotherapy1,2. However, a low antitumor efficiency and severe systemic toxic effects of chemotherapeutics and poor water solubility and insufficient tumor accumulation of PDT agents have hampered their application3. To overcome these challenges, nanomedicines derived from liposomes, micelles, nanoparticles, dendrimers and other polymers have been applied as drug delivery systems (DDSs) for anti-tumor agents4, 5, 6, 7, 8, 9, 10. These nanomedicines have improved their accumulation owing to the enhanced permeability and retention (EPR) effect, which can decrease side effects and enhance therapeutic efficacies11, 12, 13, 14. Among these reported systems, functional polymers in response to the tumor microenvironment have been designed as smart DDSs with great potential for cancer diagnosis and therapy.