Ultrasound-Mediated Microbubble Destruction (UMMD) Facilitates the Delivery of CA19-9 Targeted and Paclitaxel Loaded mPEG-PLGA-PLL Nanoparticles in Pancreatic Cancer.
Ultrasound-Mediated Microbubble Destruction (UMMD) Facilitates the Delivery of CA19-9 Targeted and Paclitaxel Loaded mPEG-PLGA-PLL Nanoparticles in Pancreatic Cancer.
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超声介导的微泡破坏 (UMMD) 促进胰腺癌中靶向 CA19-9 和负载紫杉醇的 mPEG-PLGA-PLL 纳米颗粒的递送
作者：
Xing L;Shi Q;Zheng K;Shen M;Ma J;Li F;Liu Y;Lin L;Tu W;Duan Y;Du L
胰腺癌是最致命的人类恶性肿瘤之一，预后不佳，现有的放化疗治疗方式难以治愈。开发有效的方法，特别是针对胰腺癌的药物递送，是一个关键的未满足的需求。靶向和载药纳米颗粒（NPs）结合超声介导的微泡破坏（UMMD）已被证明可以显著增加体外细胞摄取和体内药物保留，这为癌症治疗提供了一种有前景的策略。在本研究中，我们合成了以抗CA19-9抗体和包封紫杉醇（PTX）修饰的靶向胰腺癌的有机NPs。三嵌段共聚物甲氧基聚乙二醇-聚乳酸-乙醇酸-聚赖氨酸（mPEG-PLGA-PLL）构成了NPs的骨架。我们推测PTX- nps -anti CA19-9将在体内长期循环，“主动靶向”胰腺癌细胞，持续释放负载的PTX，而UMMD将“被动靶向”照射后的肿瘤，有效增加细胞膜和毛细血管间隙的通透性。我们的研究结果表明，PTX-NPs-anti CA19-9与UMMD联合在体外获得了较低的IC50，显著的细胞周期阻滞和细胞凋亡。在小鼠胰腺肿瘤异种移植物中，PTX-NP-anti - CA19-9 NPs与UMMD联合应用获得了最高的肿瘤抑制率，通过增加AUC、t1/2和平均停留时间（MRT）来促进药代动力学谱，并降低清除率。结果可延长荷瘤裸鼠的生存期，且无明显毒性。细胞摄取的动态变化、靶向实时成像、血浆和肿瘤中PTX的浓度都与体外和体内的治疗效果密切相关。我们的研究表明，PTX-NP-anti - CA19-9 NPs联合UMMD是治疗胰腺癌的一种很有前景的策略。
Pancreatic cancer, one of the most lethal human malignancies with dismal prognosis, is refractory to existing radio-chemotherapeutic treatment modalities. There is a critical unmet need to develop effective approaches, especially for targeted pancreatic cancer drug delivery. Targeted and drug-loaded nanoparticles (NPs) combined with ultrasound-mediated microbubble destruction (UMMD) have been shown to significantly increase the cellular uptake in vitro and drug retention in vivo, suggesting a promising strategy for cancer therapy. In this study, we synthesized pancreatic cancer-targeting organic NPs that were modified with anti CA19-9 antibody and encapsulated paclitaxol (PTX). The three-block copolymer methoxy polyethylene glycol-polylacticco-glycolic acid-polylysine (mPEG-PLGA-PLL) constituted the skeleton of the NPs. We speculated that the PTX-NPs-anti CA19-9 would circulate long-term in vivo, "actively target" pancreatic cancer cells, and sustainably release the loaded PTX while UMMD would "passively target" the irradiated tumor and effectively increase the permeability of cell membrane and capillary gaps. Our results demonstrated that the combination of PTX-NPs-anti CA19-9 with UMMD achieved a low IC50, significant cell cycle arrest, and cell apoptosis in vitro. In mouse pancreatic tumor xenografts, the combined application of PTX-NP-anti CA19-9 NPs with UMMD attained the highest tumor inhibition rate, promoted the pharmacokinetic profile by increasing AUC, t1/2, and mean residence time (MRT), and decreased clearance. Consequently, the survival of the tumor-bearing nude mice was prolonged without obvious toxicity. The dynamic change in cellular uptake, targeted real-time imaging, and the concentration of PTX in the plasma and tumor were all closely associated with the treatment efficacy both in vitro and in vivo. Our study suggests that PTX-NP-anti CA19-9 NPs combined with UMMD is a promising strategy for the treatment of pancreatic cancer.