"Photo-responsive nanotechnology solutions to address cancer drug resistance" with Huang Chiao Huang, University of Maryland (In-Person Seminar)
Title: Photo-responsive nanotechnology solutions to address cancer drug resistance
Speaker: Huang Chiao Huang, University of Maryland
Hosted by: Jeffery Klauda & Arpita Upadhyaya
Abstract: Efforts to overcome cancer multidrug resistance through the inhibition of adenosine triphosphate-binding cassette (ABC) drug transporters, ABCB1 and ABCG2, have largely failed in the clinic. Challenges faced during the development of non-toxic modulators suggest a need for a conceptual shift to new strategies for inhibition of ABC drug transporters. Here, we developed several bioengineering approaches and revealed the fundamental mechanisms by which photodynamic therapy (PDT) can be exploited to manipulate the function and integrity of ABC drug transporters. PDT is a clinically relevant, photochemistry-based tool that involves light activation of photosensitizers to generate reactive oxygen species. To bypass ABC transporters-mediated efflux of photosensitizers, we first introduce a lipidation strategy to create photosensitizers derivatives that are no longer ABC transporters substrates. ATPase activity and in silico molecular docking analyses show that the benzoporphyrin derivative (BPD) photosensitizer binds to ABCB1 and ABCG2 at micromolar half-maximal inhibitory concentrations in the absence of light. Light activation of BPD generates singlet oxygen to further reduce the ATPase activity of ABCB1 and ABCG2 by up to 12-fold in an optical dose-dependent manner. Gel electrophoresis and Western blotting revealed that light-activated BPD induces aggregation of these transporters by covalent crosslinking. This study provides a proof of principle that PDT affects the function of ABCB1 and ABCG2 by modulating the ATPase activity and protein integrity of these transporters. Finally, we combined nanotechnology and PDT to simultaneously damage ABC transporters and enhance drug accumulation in tumor cells. Insights gained from this study concerning the photodynamic manipulation of ABC drug transporters could aid in the development and application of new optical tools to overcome the multidrug resistance that often develops after cancer chemotherapy.
Biography: Dr. Huang is an Assistant Professor in the Fischell Department of Bioengineering at the University of Maryland College Park, and a member of the Program in Oncology at the University of Maryland Marlene and Stewart Greenebaum Cancer Center. His research efforts focus on designing nanomedicine and light-based therapy for cancer, and has published close to 50 peer-reviewed articles. His preclinical discoveries in photodynamic therapy (PDT)-based combination treatment have set the foundation for an ongoing NIH-funded clinical trial. Since starting his lab at UMD in 2018, Dr. Huang has raised $6.5M of research funding from NIH, NSF and other agencies, won the NIH NIBIB Trailblazer Award, and is currently running a lab of 10+ phd students and post doc. In 2020, he was elected to the American Society for Photobiology Council.