TY - JOUR
T1 - Overcoming the Limits of Hypoxia in Photodynamic Therapy
T2 - A Carbonic Anhydrase IX-Targeted Approach
AU - Jung, Hyo Sung
AU - Han, Jiyou
AU - Shi, Hu
AU - Koo, Seyoung
AU - Singh, Hardev
AU - Kim, Hyo Jin
AU - Sessler, Jonathan L.
AU - Lee, Jin Yong
AU - Kim, Jong-Hoon
AU - Kim, Jong Seung
N1 - Funding Information:
The work in Austin was supported by the National Institutes of Health (CA68682, J.L.S.) and the Robert A. Welch Foundation.
Publisher Copyright:
© 2017 American Chemical Society.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2017/6/7
Y1 - 2017/6/7
N2 - A major challenge in photodynamic cancer therapy (PDT) is avoiding PDT-induced hypoxia, which can lead to cancer recurrence and progression through activation of various angiogenic factors and significantly reduce treatment outcomes. Reported here is an acetazolamide (AZ)-conjugated BODIPY photosensitizer (AZ-BPS) designed to mitigate the effects of PDT-based hypoxia by combining the benefits of anti-angiogenesis therapy with PDT. AZ-BPS showed specific affinity to aggressive cancer cells (MDA-MB-231 cells) that overexpress carbonic anhydrase IX (CAIX). It displayed enhanced photocytotoxicity compared to a reference compound, BPS, which is an analogous PDT agent that lacks an acetazolamide unit. AZ-BPS also displayed an enhanced in vivo efficacy in a xenograft mouse tumor regrowth model relative to BPS, an effect attributed to inhibition of tumor angiogenesis by both PDT-induced ROS generation and CAIX knockdown. AZ-BPS was evaluated successfully in clinical samples collected from breast cancer patients. We thus believe that the combined approach described here represents an attractive therapeutic approach to targeting CAIX-overexpressing tumors.
AB - A major challenge in photodynamic cancer therapy (PDT) is avoiding PDT-induced hypoxia, which can lead to cancer recurrence and progression through activation of various angiogenic factors and significantly reduce treatment outcomes. Reported here is an acetazolamide (AZ)-conjugated BODIPY photosensitizer (AZ-BPS) designed to mitigate the effects of PDT-based hypoxia by combining the benefits of anti-angiogenesis therapy with PDT. AZ-BPS showed specific affinity to aggressive cancer cells (MDA-MB-231 cells) that overexpress carbonic anhydrase IX (CAIX). It displayed enhanced photocytotoxicity compared to a reference compound, BPS, which is an analogous PDT agent that lacks an acetazolamide unit. AZ-BPS also displayed an enhanced in vivo efficacy in a xenograft mouse tumor regrowth model relative to BPS, an effect attributed to inhibition of tumor angiogenesis by both PDT-induced ROS generation and CAIX knockdown. AZ-BPS was evaluated successfully in clinical samples collected from breast cancer patients. We thus believe that the combined approach described here represents an attractive therapeutic approach to targeting CAIX-overexpressing tumors.
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U2 - 10.1021/jacs.7b02396
DO - 10.1021/jacs.7b02396
M3 - Article
C2 - 28459562
AN - SCOPUS:85020382009
VL - 139
SP - 7595
EP - 7602
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 22
ER -
