Cardiolipin-Targeted NIR-II Fluorophore Causes “Avalanche Effects” for Re-Engaging Cancer Apoptosis and Inhibiting Metastasis,Journal of the American Chemical Society

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Cardiolipin-Targeted NIR-II Fluorophore Causes “Avalanche Effects” for Re-Engaging Cancer Apoptosis and Inhibiting Metastasis
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2022-11-29 , DOI: 10.1021/jacs.2c08602
Hui Bian ₁ , Dandan Ma ₁ , Fei Pan ₂ , Xiaodong Zhang ₃ , Kai Xin ₃ , Xinfu Zhang ₁ , Youjun Yang ₃ , Xiaojun Peng ₁ , Yi Xiao ₁

Affiliation

Restoring innate apoptosis and simultaneously inhibiting metastasis by a molecular drug is an effective cancer therapeutic approach. Herein, a large rigid and V-shaped NIR-II dye, DUT850, is rationally designed for potential cardiolipin (CL)-targeted chemo-phototheranostic application. DUT850 displays moderate NIR-II fluorescence, excellent photodynamic therapy (PDT) and photothermal therapy (PTT) performance, and ultra-high photostability. More importantly, the unique rigid V-shaped backbone, positive charge, and lipophilicity of DUT850 afford its specific recognition and efficient binding to CL; such an interaction of DUT850–CL induced a spectrum of physiological disruptions, including translocation of cytochrome c, Ca²⁺ overload, reactive oxygen species burst, and ATP depletion, which not only activated cancer cell apoptosis but also inhibited tumor metastasis both in vitro and in vivo. Furthermore, the tight binding of DUT850–CL improves the phototoxicity of DUT850 toward cancer cells (IC₅₀ as low as 90 nM) under safe 808 nm laser irradiation (330 mW cm^–2). Upon encapsulation into bovine serum albumin (BSA), DUT850@BSA exerted a synergetic chemo-PDT–PTT effect on the 4T1 tumor mouse model, eventually leading to solid tumor annihilation and metastasis inhibition, which could be followed in real time with the NIR-II fluorescence of DUT850. This work contributed a promising approach for simultaneously re-engaging cancer cell apoptotic networks and activating the anti-metastasis pathway by targeting a pivotal upstream effector, which will bring a medical boon for inhibition of tumor proliferation and metastasis.

中文翻译：

心磷脂靶向 NIR-II 荧光团引起“雪崩效应”以重新参与癌症细胞凋亡和抑制转移

通过分子药物恢复先天细胞凋亡并同时抑制转移是一种有效的癌症治疗方法。在此，一种大型刚性 V 形 NIR-II 染料DUT850被合理设计用于潜在的心磷脂 (CL) 靶向化学光疗应用。DUT850显示出中等的 NIR-II 荧光、出色的光动力疗法 (PDT) 和光热疗法 (PTT) 性能以及超高的光稳定性。更重要的是， DUT850独特的刚性 V 型主链、正电荷和亲脂性为其提供了与 CL 的特异性识别和高效结合；DUT850 –CL的这种相互作用引起了一系列生理学破坏，包括细胞色素c的易位、Ca ²⁺超载、活性氧爆发和 ATP 耗竭，不仅激活癌细胞凋亡，而且在体外和体内抑制肿瘤转移。此外，DUT850 –CL 的紧密结合提高了DUT850在安全的 808 nm 激光照射 (330 mW cm ^–2 ) 下对癌细胞的光毒性（IC ₅₀低至 90 nM ）。在封装到牛血清白蛋白 (BSA) 中后，DUT850@BSA对 4T1 肿瘤小鼠模型发挥协同化学-PDT-PTT 作用，最终导致实体瘤消灭和转移抑制，这可以通过 NIR- DUT850的II荧光. 这项工作为通过靶向关键的上游效应器同时重新参与癌细胞凋亡网络和激活抗转移途径提供了一种有前途的方法，这将为抑制肿瘤增殖和转移带来医学上的福音。

更新日期：2022-11-29

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