2022 Thayer Investiture

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Jones Seminar: Light-activatable Nanoconstructs to Overcome Cancer Drug Resistance

Nov

12

Friday
3:30pm - 4:30pm EST

Spanos Auditorium / Zoom

Optional ZOOM LINK
Meeting ID: 946 6366 7807
Passcode: 566147

This talk covers recent work on engineering light-activatable nanoconstructs to overcome adenosine triphosphate-binding cassette (ABC) transporters-mediated cancer drug resistance.

Efforts to overcome cancer multidrug resistance through inhibition of the 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 photosensitizer benzoporphyrin derivative (BPD) binds to ABCB1 and ABCG2 with 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.

About the Speaker(s)

Huang Chiao Huang
Professor of Bioengineering, University of Maryland

Huang Chiao Huang

Huang Chiao (Joe) Huang earned his PhD in chemical engineering from Arizona State University, then completed postdoctoral training at Harvard Medical School. He started The Huang Lab at the University of Maryland, College Park where he is now an assistant professor of bioengineering. Dr. Huang is recognized for his research on cancer nanotechnology and photodynamic therapy, has given many invited talks and received awards from diverse societies and foundations. His research has been funded by the National Cancer Institute (K99/R00; R01), the National Institute of Biomedical Imaging and Bioengineering (R21 Trailblazer), the National Science Foundation, the Industry, and the Foundation for Women's Cancer.

Contact

For more information, contact Ashley Parker at ashley.l.parker@dartmouth.edu.