Zou Liang, Liu Xiaowei, Li Jingjing, Li Wei, Zhang Lele, Fu Chaomei, Zhang Jinming, Gu Zhongwei
Key Laboratory of Coarse Cereal Processing of Ministry of Agriculture and Rural Affairs, Chengdu University, Chengdu 610106, People's Republic of China.
State Key Laboratory of Southwestern Chinese Medicine Resources, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, People's Republic of China.
Theranostics. 2021 Feb 20;11(9):4171-4186. doi: 10.7150/thno.42260. eCollection 2021.
Combinations of two or more therapeutic agents targeting different signaling pathways involved in tumor progression can have synergistic anticancer effects. However, combination chemotherapies are greatly limited by the different pharmacokinetics, tumor targeting, and cellular uptake capacities of the combined drugs. We have previously demonstrated the potential synergistic efficacy of paclitaxel (PTX) and the natural anti-angiogenic agent tetramethylpyrazine (TMP) for suppressing ovarian carcinoma growth. An efficient, facile, and smart nanosystem to deliver PTX and TMP simultaneously is greatly desired. We constructed a redox-sensitive nanosystem based on the amphiphilic PTX-ss-TMP conjugate, in which PTX and TMP are linked by a disulfide bond. We characterized the structure of the drug conjugate by H NMR and LC-MS, and then prepared PTX-ss-TMP NPs by a one-step nanoprecipitation method. We investigated the redox sensitivity, tumor-targeting ability, anticancer efficacy, and anti-angiogenesis activity of PTX-ss-TMP NPs and . The amphiphilic PTX-ss-TMP conjugate readily self-assembled into stable nanoparticles in aqueous solution with a low critical association concentration of 1.35 µg/mL, well-defined spherical structure, small particle size (152 nm), high drug loading, redox-responsive drug release, high biocompatibility, and high storage stability. In cancer cells pretreated with GSH-OEt, PTX-ss-TMP NPs exhibited higher cytotoxicity, apoptosis rate, and cell-cycle arrest than monotherapy or combination therapy with free drugs, which was attributed to their improved cellular uptake and rapid intracellular drug release. Additionally, PTX-ss-TMP NPs also had a stronger anti-angiogenesis effect in HUVECs than free drug, which was mediated by VEGFR2-involved downstream signals. Finally, PTX-ss-TMP NPs showed tumor-specific accumulation and excellent antitumor activity in A2780 xenograft mice compared with free drug. These and results provide clear evidence that this redox-responsive carrier-free nanosystem with intrinsic amphiphilicity has great potential for combination cancer chemotherapy.
两种或更多种靶向肿瘤进展中不同信号通路的治疗药物联合使用可产生协同抗癌效果。然而，联合化疗受到联合药物不同的药代动力学、肿瘤靶向性和细胞摄取能力的极大限制。我们之前已证明紫杉醇（PTX）与天然抗血管生成剂川芎嗪（TMP）在抑制卵巢癌生长方面具有潜在的协同疗效。因此，迫切需要一种高效、简便且智能的纳米系统来同时递送PTX和TMP。我们构建了一种基于两亲性PTX-ss-TMP共轭物的氧化还原敏感纳米系统，其中PTX和TMP通过二硫键连接。我们通过氢核磁共振（H NMR）和液相色谱-质谱联用（LC-MS）对药物共轭物的结构进行了表征，然后通过一步纳米沉淀法制备了PTX-ss-TMP纳米颗粒（NPs）。我们研究了PTX-ss-TMP NPs的氧化还原敏感性、肿瘤靶向能力、抗癌疗效和抗血管生成活性。两亲性PTX-ss-TMP共轭物在水溶液中易于自组装成稳定的纳米颗粒，其临界缔合浓度低至1.35 µg/mL，具有明确的球形结构、小粒径（152 nm）、高载药量、氧化还原响应性药物释放、高生物相容性和高储存稳定性。在用谷胱甘肽乙酯（GSH-OEt）预处理的癌细胞中，PTX-ss-TMP NPs表现出比游离药物单药治疗或联合治疗更高的细胞毒性、凋亡率和细胞周期阻滞，这归因于其改善的细胞摄取和快速的细胞内药物释放。此外，PTX-ss-TMP NPs在人脐静脉内皮细胞（HUVECs）中也比游离药物具有更强的抗血管生成作用，这是由涉及血管内皮生长因子受体2（VEGFR2）的下游信号介导的。最后，与游离药物相比，PTX-ss-TMP NPs在A2780异种移植小鼠中表现出肿瘤特异性蓄积和优异的抗肿瘤活性。这些结果提供了明确的证据，表明这种具有固有两亲性的氧化还原响应性无载体纳米系统在联合癌症化疗方面具有巨大潜力。
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