One Change, Many Benefits: A Glycine-Modified Bacteriochlorin with NIR Absorption and a Type I Photochemical Mechanism for Versatile Photodynamic Therapy.

Difluorinated sulfonamide porphyrin (FPGly) and bacteriochlorin (FBGly), modified by glycine residues, were synthesized and evaluated for photodynamic therapy (PDT). F₂PGly exhibits superior stability and singlet oxygen generation efficiency but features a low-intensity band in the red range (λ = 639 nm). In contrast, FBGly shows a favorable, red-shifted absorption spectrum (λ = 746 nm) that aligns well with phototherapeutic window, facilitating deeper tissue penetration. Moreover, it demonstrates reasonable photostability, necessary for the efficient generation of both singlet oxygen (type II) and oxygen-centered radicals (type I mechanism) which contributes to enhanced therapeutic efficacy. Importantly, the glycine modifications in FBGly enhance its uptake in MCF-7 cells, known for their resistance to PDT due to efflux transport proteins like LAT1, showing great potential in the cancer cell-targeted PDT. The glycine groups potentially enable FBGly to bypass these barriers, resulting in increased intracellular accumulation and more effective Reactive Oxygen Species (ROS) generation under illumination. In vivo studies indicated promising vascular-targeted PDT results, with real-time fluorescence imaging used to monitor photosensitizer distribution prior to irradiation. These findings suggest that FBGly is a promising photosensitizer candidate with enhanced cancer cell selectivity and photodynamic efficiency, meriting further exploration in targeted PDT applications for multiple types of cancers.