Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People's Republic of China.
Int J Nanomedicine. 2023 Apr 19;18:2037-2052. doi: 10.2147/IJN.S400495. eCollection 2023.
Triple-negative breast cancer (TNBC) is known to be the most aggressive form of breast cancer. Due to its high recurrence and mortality rates, the treatment of TNBC is a significant challenge for the medical community. Besides, ferroptosis is an emerging regulatory cell death that may provide new insights into the treatment of TNBC. As a central inhibitor of the ferroptosis process, the selenoenzyme glutathione peroxidase 4 (GPX4) is its classical therapeutic target. However, inhibition of GPX4 expression is quite detrimental to normal tissues. Ultrasound contrast agents, as an emerging visualization precision treatment, may provide a solution to the existing problem.
In this study, nanodroplets (NDs) carrying simvastatin (SIM) were constructed using the homogeneous/emulsification method. Then, the characterization of SIM-NDs was systematically evaluated. Meanwhile, in this study, the ability of SIM-NDs combined with ultrasound-targeted microbubble disruption (UTMD) to initiate ferroptosis and its respective mechanisms of ferroptosis induction were verified. Finally, the antitumor activity of SIM-NDs was investigated in vitro and in vivo using MDA-MB-231 cells and TNBC animal models.
SIM-NDs exhibited excellent pH- and ultrasound-responsive drug release and noticeable ultrasonographic imaging ability, also showing good biocompatibility and biosafety. UTMD could promote increased intracellular reactive oxygen species and consume intracellular glutathione. However, SIM-NDs were efficiently internalized into cells under ultrasound irradiation, followed by the rapid release of SIM, which inhibited intracellular mevalonate production, and synergistically downregulated GPX4 expression, thereby promoting ferroptosis. Moreover, this combined treatment demonstrated strong antitumor ability in vitro and in vivo.
The combination of UTMD and SIM-NDs presents a promising avenue for harnessing ferroptosis in the treatment of malignant tumors.
三阴性乳腺癌（TNBC）是已知最具侵袭性的乳腺癌。由于其高复发率和死亡率，TNBC 的治疗对医学界来说是一个重大挑战。此外，铁死亡是一种新兴的调节性细胞死亡，可能为 TNBC 的治疗提供新的思路。作为铁死亡过程的中央抑制剂，硒酶谷胱甘肽过氧化物酶 4（GPX4）是其经典的治疗靶点。然而，抑制 GPX4 的表达对正常组织相当不利。超声对比剂作为一种新兴的可视化精准治疗方法，可能为解决现有问题提供一种解决方案。
在这项研究中，使用均相/乳化法构建了载有辛伐他汀（SIM）的纳米液滴（NDs）。然后，系统地评估了 SIM-NDs 的特性。同时，在这项研究中，验证了 SIM-NDs 与超声靶向微泡破坏（UTMD）联合诱导铁死亡的能力及其各自的铁死亡诱导机制。最后，使用 MDA-MB-231 细胞和 TNBC 动物模型在体外和体内研究了 SIM-NDs 的抗肿瘤活性。
SIM-NDs 表现出优异的 pH 和超声响应性药物释放以及明显的超声成像能力，同时表现出良好的生物相容性和生物安全性。UTMD 可以促进细胞内活性氧的增加和细胞内谷胱甘肽的消耗。然而，在超声照射下，SIM-NDs 可以有效地被细胞内化，随后 SIM 迅速释放，抑制细胞内甲羟戊酸的产生，并协同地下调 GPX4 的表达，从而促进铁死亡。此外，这种联合治疗在体外和体内均显示出强大的抗肿瘤能力。
UTMD 和 SIM-NDs 的联合应用为利用铁死亡治疗恶性肿瘤提供了一种有前途的方法。
