Quaternary ammonium cations conjugated 5,15-diaryltetranaphtho[2,3]porphyrins as photosensitizers for photodynamic therapy

Abstract

In quest for new photosensitizers (PSs) with remarkable antitumor photodynamic efficacy, a series of fifteen quaternary ammonium (QA) cations conjugated 5,15-diaryltetranaphtho[2,3]porphyrins (Ar₂TNPs) was synthesized and evaluated in vitro and in vivo to understand how variations in the length of the alkoxy group and the kind of QA cations on meso-phenyl influence the photodynamic antitumor activity. All final compounds (I_1-5, II_1-5, and III_1-5) exhibited robust absorption at 729 nm with significant bathochromic shift and high molar extinction coefficients (1.16 × 10⁵-1.41 × 10⁵ M^-1 cm^-1), as well as other absorptions at 445, 475, 651, and 714 nm for tumors and other diseases of diverse sizes and depths. Upon exposure to 474 nm light, they displayed intense fluorescence emission with fluorescence quantum yields ranging from 0.32 to 0.43. The ability to generate reactive oxygen species (ROS) was also quantified, attaining a maximum rate of up to 0.0961 s^-1. The IC₅₀ values of all the compounds regarding phototoxicity and dark toxicity were determined using KYSE-150 cells, and the phototoxicity indices were calculated. Among these compounds, III₁ demonstrated the highest phototoxic index with minimal dark toxicity, and suppressed successfully the growth of esophageal carcinoma xenograft with favorable tolerance in vivo. Furthermore, the histological results showed III₁-mediated PDT had a significant cytotoxic effect on the tumor. These outcomes underscore the potential of III₁ as a highly effective antitumor photosensitizer drug in photodynamic therapy (PDT).

Keywords: Antitumor; Photodynamic therapy; Photosensitizer; Quaternary ammonium; Tetranaphtho[2,3]porphyrin.