(676f) ROS-Responsive Doxorubicin Prodrug for Effective Breast Cancer Treatment
AIChE Annual Meeting
2019
2019 AIChE Annual Meeting
Nanoscale Science and Engineering Forum
Bionanotechnology for Gene and Drug Delivery II
Thursday, November 14, 2019 - 2:00pm to 2:18pm
The development of nano-scaled carriers as a drug delivery platform has made a tremendous progress in the fight against cancer. Despite the progress, premature leakage and off-target activity remains major hurdles for effective nanoparticle (NP)-based cancer therapy. Sustained release during systemic circulation and controlled release at the tumor sites remains a challenging concept for NPs. Among the different internal and external stimulus-response mechanism, reactive oxygen species (ROS) could be utilized to trigger drugs at the tumor site. High levels of ROS present in breast cancer cells can be used to trigger cancer-targeted prodrugs from reduced cytotoxic drug form to more potent drug form. A ROS-responsive thioketal-based doxorubicin (TK-Dox) conjugate was synthesized using a stable amide bond. The ROS-responsive TK-Dox prodrug was conjugated to an amino polymer of poly(aspartic acid) or poly(l-lysine), which was then encapsulated into biodegradable, biocompatible PLA-PEG with a high drug loading. The NPs formed using nanoprecipitation showed a size of ~100 nm. The prodrug showed significantly reduced cytotoxicity compared to free Dox against breast cancer MDA-MB-231 cell line. The TK-Dox prodrug was tested and found to respond to different concentrations of H2O2. The release kinetics of the prodrug encapsulated in NPs was determined under different conditions of pH, H2O2 concentrations, and fluid sink. The release was comparatively faster at pH 5 than at pH 7, and responded to H2O2 concentrations. The results for NP characterization, drug release kinetics, ROS responsiveness, and in vitro cell viability will be presented.