State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
Int J Nanomedicine. 2022 May 13;17:2165-2187. doi: 10.2147/IJN.S360161. eCollection 2022.
Triple negative breast cancer (TNBC) is challenging for effective remission due to its very aggressive, extremely metastatic and resistant to conventional chemotherapy. Herein, a multifunctional theranostic nanoparticle was fabricated to enhance tumor targeted imaging and promote focused ultrasound (FUS) ablation and chemotherapy and sonodynamic therapy (SDT). A multi-modal synergistic therapy can improve the therapeutic efficacy and prognosis of TNBC.
AS1411 aptamer modified PEG@PLGA nanoparticles encapsulated with perfluorohexane (PFH) and anti-cancer drug doxorubicin (DOX) were constructed (AS1411-DOX/PFH-PEG@PLGA) to enhance tumor targeted imaging to guide ablation and synergistic effect of FUS/chemotherapy. FUS was utilized to trigger the co-release of doxorubicin and simultaneously PFH phase transition and activate DOX for SDT effect. The physicochemical, phase-changeable imaging capability, biosafety of nanoparticles and multi-mode synergistic effects on growth of TNBC were thoroughly evaluated in vivo and in vitro.
The synthesized AS1411-DOX/PFH-PEG@PLGA (A-DPPs) nanoparticles are uniformly round with an average diameter of 306.03 ± 5.35 nm and the zeta potential of -4.05 ± 0.13 mV, displaying high biosafety and FUS-responsive drug release in vitro and in vivo. AS1411 modified NPs specifically bind to 4T1 cells and elevate the ultrasound contrast agent (UCA) image contrast intensity via PFH phase-transition after FUS exposure. Moreover, the combined treatment of A-DPPs nanoparticles with FUS exhibited significantly higher apoptosis rate, stronger inhibitory effect on 4T1 cell invasion in vitro, induced more reactive oxygen species (ROS), and enhanced anti-tumor effect compared to a single therapy (p < 0.05). Additionally, the joint strategy resulted in more intense cavitation effect and larger ablated areas and reduced energy efficiency factor (EEF) both in vitro and in vivo.
The multifunctional AS1411-DOX/PFH-PEG@PLGA nanoparticles can perform as a marvelous synergistic agent for enhanced FUS/chemotherapy, promote real-time contrast enhanced US imaging and improve the therapeutic efficacy and prognosis of TNBC.
三阴性乳腺癌（TNBC）由于其侵袭性强、转移性极高且对常规化疗耐药，因此有效缓解极具挑战性。在此，构建了一种多功能治疗诊断纳米粒子，以增强肿瘤靶向成像并促进聚焦超声（FUS）消融以及化学疗法和声动力学疗法（SDT）。多模态协同治疗可以提高 TNBC 的治疗效果和预后。
构建了载有全氟己烷（PFH）和抗癌药物阿霉素（DOX）的 AS1411 适体修饰的聚乙二醇（PEG）@PLGA 纳米粒子（AS1411-DOX/PFH-PEG@PLGA），以增强肿瘤靶向成像，指导消融和 FUS/化学疗法的协同作用。利用 FUS 触发阿霉素的共释放，同时 PFH 相变并激活 DOX 以产生 SDT 效应。在体内和体外彻底评估了纳米粒子的理化性质、相变性成像能力、生物安全性以及对 TNBC 生长的多模式协同作用。
合成的 AS1411-DOX/PFH-PEG@PLGA（A-DPPs）纳米粒子为均匀的圆形，平均直径为 306.03±5.35nm，zeta 电位为-4.05±0.13mV，表现出高生物安全性和体外、体内 FUS 响应性药物释放。AS1411 修饰的 NPs 特异性结合到 4T1 细胞上，并在 FUS 暴露后通过 PFH 相变提高了超声造影剂（UCA）的图像对比度强度。此外，与单一疗法相比，A-DPPs 纳米粒子与 FUS 的联合治疗在体外表现出更高的细胞凋亡率、更强的抑制 4T1 细胞侵袭能力、诱导更多的活性氧（ROS）以及增强的抗肿瘤作用（p<0.05）。此外，在体外和体内，联合策略均导致更强的空化效应、更大的消融区域以及更低的能量效率因子（EEF）。
多功能 AS1411-DOX/PFH-PEG@PLGA 纳米粒子可用作增强 FUS/化学疗法的协同剂，促进实时对比增强超声成像，并提高 TNBC 的治疗效果和预后。
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