Cui Lishan, Perini Giordano, Minopoli Antonio, Augello Alberto, De Spirito Marco, Palmieri Valentina, Papi Massimiliano
Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, Rome 00168, Italy.
Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, Rome 00168, Italy; Fondazione Policlinico Universitario A. Gemelli IRCSS, Rome 00168, Italy.
Biomed Pharmacother. 2024 Dec;181:117637. doi: 10.1016/j.biopha.2024.117637. Epub 2024 Oct 30.
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer, lacking targeted therapeutic options. Hydrogels, particularly gelatin methacrylate (GelMA), have emerged as promising materials for localized drug delivery due to their biocompatibility and tunable properties. This study investigates a dual-delivery system for enhancing the treatment efficacy of triple-negative breast cancer (TNBC) using a combination of extracellular vesicles (EVs) derived from Citrus limon L. and the chemotherapeutic drug doxorubicin (DOX). We fabricated 3D bioprinted GelMA scaffolds to achieve localized and controlled release of EVs and evaluated their synergistic effects with systemic DOX delivery on both primary and metastatic 3D TNBC models. The GelMA scaffolds, especially those with 95 % methacrylation, exhibited higher stiffness, which enhanced their sustained release. Following 48-h incubation, the combination of EVs and DOX significantly increased cytotoxicity in the primary 3D TNBC model, reducing cell viability to approximately 30 % compared to controls. This was notably more effective than treatments with DOX or EVs alone. During the extended 7-day incubation period, the combination treatment continued to show superior efficacy, with persistently high levels of ROS generation and further reduction in cell viability. In a metastatic 3D TNBC model, a significant sensitivity to the combined treatment was observed, which notably inhibited aggregate formation and migration. Importantly, EVs-embedded scaffolds promoted the proliferation of human fibroblasts, highlighting their non-toxic nature, while concurrently inhibiting TNBC cell growth. This approach provides a promising strategy to improve the treatment outcomes of TNBC by exploiting the synergistic effects of local EVs release and systemic chemotherapy.
三阴性乳腺癌（TNBC）是一种侵袭性很强的乳腺癌亚型，缺乏靶向治疗选择。水凝胶，特别是甲基丙烯酸明胶（GelMA），由于其生物相容性和可调节特性，已成为局部给药的有前景的材料。本研究调查了一种双递送系统，该系统使用源自柠檬（Citrus limon L.）的细胞外囊泡（EVs）和化疗药物阿霉素（DOX）的组合来提高三阴性乳腺癌（TNBC）的治疗效果。我们制造了3D生物打印的GelMA支架，以实现EVs的局部和控释，并评估它们与全身DOX递送对原发性和转移性3D TNBC模型的协同作用。GelMA支架，尤其是甲基丙烯酰化率为95%的支架，表现出更高的硬度，这增强了它们的持续释放。在孵育48小时后，EVs和DOX的组合在原发性3D TNBC模型中显著增加了细胞毒性，与对照组相比，细胞活力降低至约30%。这明显比单独使用DOX或EVs治疗更有效。在延长的7天孵育期内，联合治疗继续显示出卓越的疗效，活性氧生成水平持续较高，细胞活力进一步降低。在转移性3D TNBC模型中，观察到对联合治疗有显著敏感性，这明显抑制了聚集体形成和迁移。重要的是，嵌入EVs的支架促进了人成纤维细胞的增殖，突出了它们的无毒性质，同时抑制了TNBC细胞的生长。这种方法通过利用局部EVs释放和全身化疗的协同作用，为改善TNBC的治疗结果提供了一种有前景的策略。
