Photosensitizers typically rely on a singular photochemical reaction to generate reactive oxygen species, which can then inhibit or eradicate lesions. However, photosensitizers often exhibit limited therapeutic efficiency due to their reliance on a single photochemical effect. Herein, we propose a new strategy that integrates the photochemical effect (type-I photochemical effect) with a biological effect (proton sponge effect). To test our strategy, we designed a series of photosensitizers (ZZ-sers) based on the naphthalimide molecule. ZZ-sers incorporate both a p-toluenesulfonyl moiety and weakly basic groups to activate the proton sponge effect while simultaneously strengthening the type-I photochemical effect, resulting in enhanced apoptosis and programmed cell death. Experiments confirmed near-complete eradication of the tumour burden after 14 days (W_light/W_control ≈ 0.18, W represents the tumour weight). These findings support the notion that the coupling of a type-I photochemical effect with a proton sponge effect can enhance the tumour inhibition by ZZ-sers, even if the basic molecular backbones of the photosensitizers exhibit nearly zero or minimal tumour inhibition ability. We anticipate that this strategy can be generalized to develop additional new photosensitizers with improved therapeutic efficacy while overcoming limitations associated with systems relying solely on single photochemical effects.

中文翻译：

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光化学和生物双重效应增强光敏剂对肿瘤生长的抑制

光敏剂通常依靠单一的光化学反应来产生活性氧，从而抑制或根除病变。然而，光敏剂由于依赖于单一的光化学效应，通常表现出有限的治疗效率。在此，我们提出了一种将光化学效应（I型光化学效应）与生物效应（质子海绵效应）相结合的新策略。为了测试我们的策略，我们设计了一系列基于萘酰亚胺分子的光敏剂（ ZZ-sers ）。 ZZ-sers结合了对甲苯磺酰基部分和弱碱性基团来激活质子海绵效应，同时增强I型光化学效应，从而增强细胞凋亡和程序性细胞死亡。实验证实14天后肿瘤负荷几乎完全消除（W _light / W _control ≈ 0.18，W代表肿瘤重量）。这些发现支持这样的观点：I型光化学效应与质子海绵效应的耦合可以增强ZZ-sers的肿瘤抑制作用，即使光敏剂的基本分子主链表现出几乎为零或最小的肿瘤抑制能力。我们预计这一策略可以推广到开发更多的新型光敏剂，以提高治疗效果，同时克服与仅依赖单一光化学效应的系统相关的局限性。