Oxaliplatin and Gedatolisib (PKI-587) Co-Loaded Hollow Polydopamine Nano-Shells with Simultaneous Upstream and Downstream Action to Re-Sensitize Drugs-Resistant Hepatocellular Carcinoma to Chemotherapy
Oxaliplatin and Gedatolisib (PKI-587) Co-Loaded Hollow Polydopamine Nano-Shells with Simultaneous Upstream and Downstream Action to Re-Sensitize Drugs-Resistant Hepatocellular Carcinoma to Chemotherapy
复制标题
奥沙利铂和 Gedatolisib (PKI-587) 共载空心聚多巴胺纳米壳，同时发挥上游和下游作用，使耐药性肝细胞癌对化疗重新敏感
DOI：
10.1166/jbn.2021.3014
复制
发表时间：
2021
影响因子：
2.9
通讯作者：
Tang Xiao-Long
中科院分区：
文献类型：
--
作者：
Zhang Yin-Ci;Wu Cheng-Guang;Li A-Min;Liang Yong;Ma Dong;Tang Xiao-Long
多药耐药性（MDR）是肝细胞癌（HCC）化疗无效的关键。奥沙利铂（OXA）作为肝癌一线化疗药物之一，异常激活PI3K/AKT/mTOR信号通路和DNA损伤修复通路（NHEJ和HR），导致耐药性，进而影响疗效。在此，我们开发了一种基于空心聚多巴胺纳米颗粒（H-PDA）的纳米递送系统（O/P-HP），其中含有OXA和双重PI3K/mTOR抑制剂PKI-587，在对抗癌症化疗中的耐药性方面具有互补作用。 H-PDA的中空结构赋予O/P-HP较高的OXA和PKI-587负载效率，分别高达49.6%和7.0%。此外，得益于H-PDA的细胞内递送以及其中高浓度的药物，O/P-HP抑制了OXA耐药HR细胞的增殖，导致细胞活力仅为17.63%。这些值显着优于 OXA 单药治疗和游离 OXA 与 PKI-587 联合治疗。我们研究了联合疗法的内在机制：O/PHP 通过同时上下游作用使 HR 细胞对化疗重新敏感，具有优异的抗癌作用； OXA通过铂对DNA分子的直接损伤诱导强烈的细胞凋亡，而PKI-587使异常激活的PI3K/AKT/mTOR信号通路和DNA损伤修复通路（NHEJ和HR）正常化，从而减弱OXA的有效性，从而抑制细胞增殖、迁移和DNA修复酶活性，增强细胞凋亡效应。这种同时具有上游和下游作用的联合疗法可能是最大程度地减少抗癌治疗耐药性的策略。
Multidrug resistance (MDR) is a key to the ineffectiveness of hepatocellular carcinoma (HCC) chemotherapy. Oxaliplatin (OXA), as one of the first-line chemotherapeutic drugs for HCC, abnormally activates the PI3K/AKT/mTOR signaling pathway and DNA damage repair pathway (NHEJ and HR), causing drug resistance and consequnet compromised efficacy. Herein, we developed a hollow polydopamine nanoparticle (H-PDA)-based nano-delivery system (O/P-HP) that contained OXA and a dual PI3K/mTOR inhibitor PKI-587 with complementary effects for combating drug resistance in cancer chemotherapy. The hollow structure of H-PDA endowed O/P-HP with high loading efficiencies of OXA and PKI-587–up to 49.6% and 7.0%, respectively. In addition, benefiting from the intracellular delivery of H-PDA as well as the highly concentrated drugs therein, O/P-HP inhibited the proliferation of OXA-resistant HR cells, resulting in a cell viability of only 17.63%. These values were significantly superior to those with OXA single-agent treatment and treatment with free OXA in combination with PKI-587. We examined the intrinsic mechanisms of the combination therapy: O/PHP had excellent anti-cancer effects via the simultaneous upstream and downstream action to re-sensitize HR cells to chemotherapy; OXA induced strong apoptosis via the direct platinum lesions on DNA molecules, while PKI-587 normalized the abnormally activated PI3K/AKT/mTOR signaling pathway and DNA damage repair pathway (NHEJ and HR) that could attenuate the effectiveness of OXA, thus resulting in inhibition of cell proliferation, migration and DNA repair enzyme activity and the augment of apoptotic effects. Such combination therapy, with simultaneous upstream and downstream action, may be a strategy for minimizing resistance for anti-cancer treatments.