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

Difluorinated sulfonamide porphyrin (F₂PGly) and bacteriochlorin (F₂BGly), 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_max = 639 nm). In contrast, F₂BGly shows a favorable, red-shifted absorption spectrum (λ_max = 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 F₂BGly 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 F₂BGly 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 F₂BGly 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.