RESUMO
Using photodynamic therapy (PDT) to trigger nonconventional cell death pathways has provided a new scheme for highly efficient and non-side effects to drug-resistant cancer therapies. Nonetheless, the unclear targets of available photosensitizers leave the manner of PDT-induced tumor cell death relatively unpredictable. Herein, we developed a novel Ru(II)-based photosensitizer, Ru-Poma. Possessing the E3 ubiquitin ligase CRBN-targeting moiety and high singlet oxygen yield of 0.96, Ru-Poma was demonstrated to specifically photodegrade endogenous CRBN, increase lipid peroxide, downregulate GPX4 and GAPDH expression, and consequently induce ferroptosis in cisplatin-resistant cancerous cells. Furthermore, with the deep penetration of two-photon excitation, Ru-Poma achieved drug-resistant circumvention in a 3D tumor cell model. Thus, we describe the first sample of the CRBN-targeting Ru(II) complex active in PDT.
Assuntos
Antineoplásicos , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Ferroptose , Fotoquimioterapia , Fármacos Fotossensibilizantes , Rutênio , Ubiquitina-Proteína Ligases , Humanos , Ferroptose/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Cisplatino/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/síntese química , Rutênio/química , Rutênio/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Fótons , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
A hetero-bimetallic Ru(II)-Ir(III) photosensitizer was developed. Upon light exposure, contrary to the homogeneous Ru(II)-Ru(II) and Ir(III)-Ir(III) complexes that can only produce singlet oxygen, Ru(II)-Ir(III) can generate multiple reactive oxygen species and kill hypoxic tumors. This study presents the first example of a hetero-bimetallic type-I and type-II dual photosensitizer.