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J Am Chem Soc. 2017 Jun 7;139(22):7595-7602. doi: 10.1021/jacs.7b02396. Epub 2017 May 10.

Overcoming the Limits of Hypoxia in Photodynamic Therapy: A Carbonic Anhydrase IX-Targeted Approach.

Author information

1
Department of Chemistry, The University of Texas at Austin , Austin, Texas 78712-1224, United States.
2
Department of Biological Sciences, Laboratory of Stem Cell Research and Biotechnology, Hyupsung University , Hwasung-si 18330, Korea.
3
Department of Chemistry, Sungkyunkwan University , Suwon 440-746, Korea.

Abstract

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.

PMID:
28459562
PMCID:
PMC5772932
DOI:
10.1021/jacs.7b02396
[Indexed for MEDLINE]
Free PMC Article

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