Department of Biotechnology, School of Bioengineering, Dalian Polytechnic University, Dalian 116034, Liaoning Province, P. R. China.
School of Chemical Engineering and Energy Technology, Dongguan University of Technology, Dongguan 523808, Guangzhou Province, P. R. China.
Mol Pharm. 2022 Jul 4;19(7):2518-2534. doi: 10.1021/acs.molpharmaceut.2c00150. Epub 2022 May 13.
Limited chemotherapeutic efficiency, drug resistance, and side effects are primary obstacles for cancer treatment. The development of co-delivery systems with synergistic treatment modes should be a promising strategy. Here, we fabricated a multifunctionalized nanocarrier with a combination of chemotherapeutic agents and gold nanoparticles (AuNPs), which could integrate chemo-photothermal therapy, thus enhancing overall anticancer efficacy, sensitizing drug-resistant cancer cells, and diminishing cancer stem cells (CSCs). To be specific, camptothecin nanocrystals (CPT NCs) were prepared as a platform, on the surface of which AuNPs were decorated and a hyaluronic acid layer acted as capping, stabilizing, targeting, and hydrophilic agents for CPT NCs, and reducing agents for AuNPs, providing a bridge connecting AuNPs to CPT. These AuNP-decorated CPT NCs exhibited good physico-chemical properties such as optimal sizes, payload, stability, and photothermal efficiency. Compared to other CPT formulations, they displayed considerably improved biocompatibility, selectivity, intracellular uptake, cytotoxicity, apoptosis induction activity, Pgp inhibitory capability, and anti-CSC activity, owing to a synergistic/cooperative effect from AuNPs, CPT, near-infrared treatment, pH/photothermal-triggered drug release, and nanoscaled structure. A mitochondrial-mediated signaling pathway is the underlying mechanism for cytotoxic and apoptotic effects from AuNP-decorated CPT NCs, in terms of mitochondrial dysfunction, intensified oxidative stress, DNA fragmentation, caspase 3 activation, upregulation of proapoptotic genes such as , , and , and lower levels of antiapoptotic .
有限的化疗效率、耐药性和副作用是癌症治疗的主要障碍。开发具有协同治疗模式的共递药系统应该是一种有前途的策略。在这里，我们构建了一种多功能纳米载体，将化疗药物与金纳米颗粒（AuNPs）结合，整合化疗-光热治疗，从而提高整体抗癌疗效，使耐药癌细胞敏感，并减少癌症干细胞（CSCs）。具体来说，制备喜树碱纳米晶体（CPT NCs）作为平台，在其表面修饰 AuNPs，透明质酸层作为 CPT NCs 的封端、稳定、靶向和亲水试剂，以及 AuNPs 的还原剂，提供连接 AuNPs 和 CPT 的桥梁。这些 AuNP 修饰的 CPT NCs 表现出良好的物理化学性质，如最佳尺寸、载药量、稳定性和光热效率。与其他 CPT 制剂相比，由于 AuNPs、CPT、近红外治疗、pH/光热触发药物释放和纳米结构的协同/协同作用，它们表现出相当改善的生物相容性、选择性、细胞内摄取、细胞毒性、凋亡诱导活性、Pgp 抑制能力和抗 CSC 活性。AuNP 修饰的 CPT NCs 的细胞毒性和凋亡作用的潜在机制是线粒体介导的信号通路，涉及线粒体功能障碍、氧化应激加剧、DNA 片段化、caspase 3 激活、促凋亡基因如 、 、 和 的上调，以及抗凋亡基因 的下调 。
