Delivery of thymoquinone through hyaluronic acid-decorated mixed Pluronic® nanoparticles to attenuate angiogenesis and metastasis of triple-negative breast cancer
Delivery of thymoquinone through hyaluronic acid-decorated mixed Pluronic® nanoparticles to attenuate angiogenesis and metastasis of triple-negative breast cancer
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DOI：
10.1016/j.jconrel.2020.03.033
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发表时间：
2020-06-10
影响因子：
10.8
通讯作者：
Adhikary, Arghya
中科院分区：
文献类型：
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作者：
Bhattacharya, Saurav;Ghosh, Avijit;Adhikary, Arghya
三阴性乳腺癌(TNBC)是一种高度侵袭性和转移性的乳腺癌亚型，对大多数可用治疗方案无反应。因此，需要智能的治疗方法来选择性地运输和靶向TNBCs。在此，我们开发了负载胸腺醌(TQ)、透明质酸(HA)偶联的Pluronic(R)P123和F127共聚纳米粒(HA-TQ-NPS)作为选择性载药载体，将抗癌植物化学物质TQ输送到TNBC细胞。纳米粒子的平均尺寸约为19.3+/-3.2 nm。它们在室温下的稳定性可达4个月。HA-TQ-NPS对TNBC细胞有极强的细胞毒作用，而对正常细胞无明显毒性作用。详细的研究也证明了它的促凋亡、抗转移和抗血管生成活性。深入的机制研究表明，HA-TQ-NPS通过上调microRNA-361来抑制TNBC细胞的迁移，而microRNA-361又下调了rac1和RhoA介导的细胞迁移，并在VEGF-A的自分泌效应的影响下扰乱了癌细胞的迁移。此外，HA-TQ-NP治疗还通过减少血管内皮生长因子-A的分泌而干扰肿瘤诱导的血管生成。HA-TQNps的抗转移和抗血管生成活性在MDAMB-231异种移植鸡胚胎和同基因小鼠4T1乳腺实体瘤模型中均明显。因此，一种创新的靶向纳米治疗方法正在建立，以减少肿瘤负担，同时抑制转移和血管生成，以更好地管理TNBC。
Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic subtype of breast cancer showing nonresponsiveness to most available therapeutic options. Therefore, smart therapeutic approaches to selectively transport and target TNBCs are required. Herein, we developed thymoquinone (TQ)-loaded, hyaluronic acid (HA)-conjugated Pluronic (R) P123 and F127 copolymer nanoparticles (HA-TQ-Nps) as a selective drug-carrying vehicle to deliver anticancer phytochemical TQ to TNBC cells. The mean size of nanoparticles was around 19.3 +/- 3.2 nm. and they were stable at room temperature up to 4 months. HA-TQ-Nps were immensely cytotoxic towards TNBC cells but did not show the toxic effect on normal cells. Detailed investigations also demonstrated its pro-apoptotic, anti-metastatic and anti-angiogenic activity. In-depth mechanistic studies highlighted that HA-TQ-Nps retarded cell migration of TNBC cells through up-regulation of microRNA-361 which in turn down-regulated Rac1 and RhoA mediated cell migration and also perturbed the cancer cell migration under the influence of the autocrine effect of VEGF-A. Moreover, HA-TQ-Np-treatment also perturbed tumor-induced vascularization by reducing the secretion of VEGF-A. The anti-metastatic and anti-angiogenic activity of HA-TQNps was found to be evident in both MDA-MB-231 xenograft chick embryos and 4T1-mammary solid tumor model in syngeneic mice. Thus, an innovative targeted nano-therapeutic approach is being established to reduce the tumor burden and inhibit metastasis and angiogenesis simultaneously for better management of TNBC.