Rational Design of Biocompatible Heavy-Atom-Free Thionaphthalimide-Based Nanophotosensitizers for Photodynamic Cancer Therapy.

Abstract

Heavy-atom-free photosensitizers, particularly those containing thiocarbonyl groups, hold significant promise for photodynamic therapy, yet their full potential remains untapped. The unique photophysical and photochemical properties of sulfur-modified carbonyl fluorophores are not fully understood. Additionally, challenges such as limited aqueous solubility, aggregation-induced quenching, and inadequate tumor-targeting efficiency hinder their effectiveness in biomedical applications. In this study, we designed and synthesized two thionated naphthalimides and evaluated their potential for photodynamic therapy. Our results showed that transforming carbonyl groups into thiocarbonyl moieties within the naphthalimide structure caused a significant red shift in the absorption profile. This modification also resulted in increased molar absorptivity and a marked improvement in singlet oxygen generation efficiency. Interestingly, substituting at the imide nitrogen of the naphthalimide core had little effect on absorption characteristics and singlet oxygen generation. In contrast, replacing the dimethylamino group with a triphenylamine moiety at the para position of the naphthalimide led to a hypsochromic shift in the absorption spectrum, along with lower molar absorptivity and reduced singlet oxygen yield. Additionally, we successfully prepared biocompatible MANIH-S nanoparticles (MANIH-S NPs) by encapsulating MANIH-S in DSPE-PEG(2000)-biotin to enhance the system's biomedical potential. Upon red light irradiation, MANIH-S NPs effectively generated reactive oxygen species via both type I and type II photodynamic mechanisms. Additionally, these nanoparticles exhibited strong phototoxic effects against HeLa cells when exposed to red light while showing minimal toxicity in the dark. This work highlights the potential of sulfur-substituted naphthalimide derivatives, combined with DSPE-PEG(2000)-biotin nanoencapsulation, as a versatile platform for advanced photodynamic cancer therapy.