An intramolecular photoswitch can significantly promote photoactivation of Pt(iv) prodrugs. Issue 19 (13th April 2021)

• Record Type: Journal Article
• Authors: Deng, Zhiqin; Li, Cai; Chen, Shu; Zhou, Qiyuan; Xu, Zoufeng; Wang, Zhigang; Yao, Houzong; Hirao, Hajime; Zhu, Guangyu
• Is Part Of: Chemical science. Volume 12:Issue 19(2021)
• Page Start: 6536
• Page End: 6542
• Publication Date: 2021-04-13
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d0sc06839j
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : The newly developed Pt(iv ) prodrugs, rhodaplatins, contain an internal photoswitch and present up to 4.8 × 10 4 -fold increased photoconversion efficiency compared to the conventional "photocatalyst plus Pt(iv ) prodrug" photocatalysis platform. Abstract : Selective activation of prodrugs at diseased tissue through bioorthogonal catalysis represents an attractive strategy for precision cancer treatment. Achieving efficient prodrug photoactivation in cancer cells, however, remains challenging. Herein, we report two Pt(iv ) complexes, designated as rhodaplatins {rhodaplatin 1, [Pt(CBDCA- O, O ′)(NH3 )2 (RhB)OH]; rhodaplatin 2, [Pt(DACH)ox(RhB)(OH)], where CBDCA is cyclobutane-1, 1-dicarboxylate, RhB is rhodamine B, DACH is (1 R, 2 R )-1, 2-diaminocyclohexane, and ox is oxalate}, that bear an internal photoswitch to realize efficient accumulation, significant co-localization, and subsequent effective photoactivation in cancer cells. Compared with the conventional platform of "external photocatalyst plus substrate", rhodaplatins presented up to 4.8 × 10 4 -fold increased photoconversion efficiency in converting inert Pt(iv ) prodrugs to active Pt(ii ) species under physiological conditions, due to the increased proximity and covalent bond between the photoswitch and Pt(iv ) substrate. As a result, rhodaplatins displayed increased photocytotoxicity compared with a mixture of RhB and conventional Pt(iv ) compound in cancer cells including Pt-resistant ones. Intriguingly, rhodaplatin 2 efficiently accumulated in the mitochondria and induced apoptosis without causing genomic DNA damage to overcome drug resistance. This work presents a new approach to develop highly effective prodrugs containing intramolecular photoswitches for potential medical applications.