RESUMEN
The dimerization of boron dipyrromethene (BODIPY) moieties is an appealing molecular design approach for developing heavy-atom-free triplet photosensitizers (PSs). However, BODIPY dimer-based PSs generally lack target specificity, which limits their clinical use for photodynamic therapy. This study reports the synthesis of two mitochondria-targeting triphenylphosphonium (TPP)-functionalized meso-ß directly linked BODIPY dimers (BTPP and BeTPP). Both BODIPY dimers exhibited solvent-polarity-dependent singlet oxygen (1O2) quantum yields, with maximum values of 0.84 and 0.55 for BTPP and BeTPP, respectively, in tetrahydrofuran. The compact orthogonal geometry of the BODIPY dimers facilitated the generation of triplet excited states via photoinduced charge separation (CS) and subsequent spin-orbit charge-transfer intersystem crossing (SOCT-ISC) processes and their rates were dependent on the energetic configuration between the frontier molecular orbitals of the two BODIPY subunits. The as-synthesized compounds were amphiphilic and hence formed stable nanoparticles (â¼36 nm in diameter) in aqueous solutions, with a zeta potential of â¼33 mV beneficial for mitochondrial targeting. In vitro experiments with MCF-7 and HeLa cancer cells indicated the effective localization of BTPP and BeTPP within cancer-cell mitochondria. Under light irradiation, BTPP and BeTPP exhibited robust photo-induced therapeutic effects in both cell lines, with half-maximal inhibitory concentration (IC50) values of â¼30 and â¼55 nM, respectively.
Asunto(s)
Compuestos de Boro , Mitocondrias , Nanopartículas , Compuestos Organofosforados , Fotoquimioterapia , Fármacos Fotosensibilizantes , Oxígeno Singlete , Humanos , Compuestos de Boro/química , Compuestos de Boro/farmacología , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacología , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Nanopartículas/química , Oxígeno Singlete/metabolismo , Oxígeno Singlete/química , Células MCF-7 , Supervivencia Celular/efectos de los fármacos , Células HeLa , DimerizaciónRESUMEN
Imaging-guided diagnosis and treatment of cancer hold potential to significantly improve therapeutic accuracies and efficacies. Central to this theragnostic approach has been the use of multicomponent-based multimodal nanoparticles (NPs). Apart from this conventional approach, here we propose a design strategy for the simple and straightforward formulation of NPs based on boron dipyrromethene (BODIPY) derivatives, LaB-X (X = H, Et, and Br). Specifically, the conjugation of lactose to the inherently hydrophobic BODIPY promoted the formation of LaB-X NPs in water. Furthermore, the BODIPY backbone was subjected to distyrylation, dibromination, and diethylation to tailor the optical window and the balance between fluorescence and singlet oxygen generation capabilities. We demonstrate that while the photoinduced anticancer activities of LaB-H and LaB-Et NPs were trivial, LaB-Br NPs effectively induced the apoptotic death of hepatocellular carcinoma cells under red light irradiation while allowing fluorescence cell imaging in the phototherapeutic window. This dual fluorescence photosensitizing activity of LaB-Br NPs could be switched off and on, so that both fluorescence and singlet oxygen generation were paused during NP formation in an aqueous solution, while both processes resumed after cellular uptake, likely due to NP disassembly.