HOCl响应型舒林酸前药及微针递送系统在乳腺癌治疗中的应用

HOCl-activated sulindac prodrug and its microneedle delivery system for breast cancer therapy

摘要

舒林酸(Sulindac)是一种经典的非甾体抗炎药,在肿瘤治疗中展现出良好的抗癌潜力。然而,其在肿瘤治疗中的非特异性分布及系统毒副作用限制了临床应用。为提高其肿瘤靶向性与治疗效率,本研究设计合成了一种基于舒林酸结构的次氯酸(HOCl)激活型前药,并构建了相应的微针递药系统用于乳腺癌局部治疗。该前药在肿瘤微环境中被 HOCl特异性激活,精准释放出具有化疗活性的舒林酸与具备成像和光敏性能的亚甲蓝(MB)。在光照条件下,MB不仅可用于成像示踪,还能产生光动力治疗(PDT)效应,实现化疗与 PDT 的协同。微针贴片的构建则实现了前药的局部、无创递送,增强前药在肿瘤部位的富集。在体外试验中,前药与 HOCl响应较好,并在活体试验中呈现出较好的治疗效果。该研究为 HOCl响应型前药的设计及其微针局部递药在乳腺癌精准治疗中的应用提供了新思路与试验依据。

Abstract

Sulindac, a classic nonsteroidal anti-inflammatory drug (NSAID), has shown promising antitumor potential. However, its clinical application in cancer therapy is limited by poor tumor specificity and systemic toxicity. Here, we report the design of a hypochlorous acid (HOCl)-responsive prodrug probe based on sulindac, which is integrated into a microneedle patch for localized breast cancer treatment. In the tumor microenvironment, the prodrug undergoes HOCl-triggered cleavage, enabling the precise release of sulindac and the photosensitizer methylene blue (MB), which has imaging and photosensitive properties. Upon light irradiation, MB generates reactive oxygen species to induce photodynamic therapy (PDT), synergizing with sulindac’s chemotherapeutic effect. The microneedle system ensures minimally invasive, site-specific drug delivery and enhances local drug retention. In vitro and in vivo studies confirm efficient activation, controlled release, and potent therapeutic outcomes. This work provides a promising strategy for designing HOCl-activated prodrugs and demonstrates the translational potential of microneedle-mediated combination therapy in breast cancer.

关键词

舒林酸 / 次氯酸 / 亚甲基蓝 / 乳腺癌 / 联合治疗

Key words

sulindac / hypochlorous acid / methylene blue / breast cancer / combination therapy

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基金资助

国家自然科学基金(22177019)