Lutetium Texaphyrin–Celecoxib Conjugate as a Potential Immuno-Photodynamic Therapy Agent

• Published in: Journal of the American Chemical Society 2024-07, Vol.146 (28), p.19434-19448
• Main Authors: An, Jusung, Lv, Kong-Peng, Chau, Calvin V., Lim, Jong Hyeon, Parida, Rakesh, Huang, Xin, Debnath, Snehasish, Xu, Yunjie, Zheng, Siqi, Sedgwick, Adam C., Lee, Jin Yong, Luo, Dixian, Liu, Quan, Sessler, Jonathan L., Kim, Jong Seung
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Celecoxib - chemistry; Celecoxib - pharmacology; Cell Line, Tumor; Female; Humans; Immunotherapy; Lutetium - chemistry; Mice; Photochemotherapy; Photosensitizing Agents - chemistry; Photosensitizing Agents - pharmacology; Porphyrins - chemistry; Porphyrins - pharmacology
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.4c05978

Immuno-photodynamic therapy (IPDT) has emerged as a new modality for cancer treatment. Novel photosensitizers can help achieve the promise inherent in IPDT, namely, the complete eradication of a tumor without recurrence. We report here a small molecule photosensitizer conjugate, LuCXB. This IPDT agent integrates a celecoxib (cyclooxygenase-2 inhibitor) moiety with a near-infrared absorbing lutetium texaphyrin photocatalytic core. In aqueous environments, the two components of LuCXB are self-associated through inferred donor–acceptor interactions. A consequence of this intramolecular association is that upon photoirradiation with 730 nm light, LuCXB produces superoxide radicals (O2 –•) via a type I photodynamic pathway; this provides a first line of defense against the tumor while promoting IPDT. For in vivo therapeutic applications, we prepared a CD133-targeting, aptamer-functionalized exosome-based nanophotosensitizer (Ex-apt@LuCXB) designed to target cancer stem cells. Ex-apt@LuCXB was found to display good photosensitivity, acceptable biocompatibility, and robust tumor targetability. Under conditions of photoirradiation, Ex-apt@LuCXB acts to amplify IPDT while exerting a significant antitumor effect in both liver and breast cancer mouse models. The observed therapeutic effects are attributed to a synergistic mechanism that combines antiangiogenesis and photoinduced cancer immunotherapy.