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Charge-reversal-functionalized PLGA nanobubbles as theranostic agents for ultrasonic-imaging-guided combination therapy†
Biomaterials Science ( IF 6.6 ) Pub Date : 2018-07-12 00:00:00 , DOI: 10.1039/c8bm00419f
Hong Yang 1, 2, 3, 4, 5 , Xue Shen 1, 2, 3, 4 , Jie Yan 1, 2, 3, 4 , Xiaoxue Xie 1, 2, 3, 4 , Zhongyuan Chen 1, 2, 3, 4 , Tingting Li 1, 2, 3, 4 , Shun Li 1, 2, 3, 4, 5 , Xiang Qin 1, 2, 3, 4, 5 , Chunhui Wu 1, 2, 3, 4, 5 , Yiyao Liu 1, 2, 3, 4, 6
Affiliation  

The efficacy of cancer chemotherapy can be generally restrained by the multiple drug resistance (MDR) of tumors, which is typically attributed to the upregulation of ATP-binding cassette (ABC) transporter proteins, such as P-glycoprotein (P-gp). There is an urgent need to present innovative strategies to reverse MDR and enhance the therapeutic efficacy of chemotherapeutic agents in biomedical applications. Here, we report a novel nanosystem of charge-reversal-functionalized PLGA nanobubbles (denoted as Dox-NBs/PPP/P-gp shRNA) for the co-delivery of Dox and P-gp shRNA for the reversal of drug resistance and for ultrasonic-imaging-guided tumor therapy. 1H NMR, FT-IR, SEM, DLS, and UV-vis spectroscopy characterizations were conducted to determine the structure, morphology, and composition of the as-prepared nanobubbles. Dox-NBs/PPP/P-gp shRNA exhibited an average diameter of about 300 nm with good dispersity, biocompatibility, and pH-responsive release properties through the charge-reversal process. The in vitro experiments showed that Dox-NBs/PPP/P-gp shRNA nanobubbles could co-deliver Dox and P-gp shRNA into tumor cells and could effectively suppress P-gp expression, leading to enhanced overall therapeutic effects against MCF-7/MDR cells by restraining the drug efflux. An in vivo antitumor assay revealed an approximately 65% inhibition rate of Dox-NBs/PPP/P-gp shRNA against MCF-7/ADR tumors in tumor-bearing nude mice. Both the in vitro and in vivo toxicity results indicated the Dox-NBs/PPP/P-gp shRNA are highly biocompatible with reducing side-effects and have negligible systemic toxicity in the in vivo therapy of resistant cancers by combining with a chemotherapeutic agent and P-gp knockdown. Furthermore, the in vivo imaging data substantiated that the functionalized nanobubbles could be used as an efficient contrast agent for the ultrasonic imaging of solid tumors. This works highlights the great potential of Dox-NBs/PPP/P-gp shRNA nanobubbles for enhanced imaging-guided combination therapy for overcoming MDR.

中文翻译:

电荷逆转功能化PLGA纳米气泡作为超声成像引导联合治疗的治疗治疗药物

癌症化学疗法的功效通常可以被肿瘤的多重耐药性(MDR)所束缚,这通常归因于ATP结合盒(ABC)转运蛋白,例如P-糖蛋白(P-gp)的上调。迫切需要提出创新策略来逆转MDR并增强生物医学应用中化学治疗剂的治疗功效。在这里,我们报告了一种新型的电荷逆转功能化PLGA纳米气泡纳米系统(称为Dox-NBs / PPP / P-gp shRNA),用于Dox和P-gp shRNA的共递送,以逆转耐药性和超声波成像引导的肿瘤治疗。1个进行1 H NMR,FT-IR,SEM,DLS和UV-vis光谱表征,以确定所制备的纳米气泡的结构,形态和组成。Dox-NBs / PPP / P-gp shRNA通过电荷逆转过程显示出约300 nm的平均直径,具有良好的分散性,生物相容性和pH响应释放特性。的体外实验表明,阿霉素-NBS / PPP / P-gp的shRNA的纳米气泡可以共同递送Dox和P-gp的shRNA的进入肿瘤细胞,并可能有效地抑制P-gp表达,导致增强的抗MCF-7的整体治疗效果/ MDR细胞通过抑制药物外排。的体内抗肿瘤试验显示在荷瘤裸鼠中的Dox-NBS / PPP / P-gp的shRNA的的大约65%的抑制率对MCF-7 / ADR肿瘤。这俩体外体内毒性结果表明,Dox-NBs / PPP / P-gp shRNA通过与化学治疗剂和P-gp结合,降低耐药性方面具有高度的生物相容性,并且在体内抗癌治疗中的全身毒性可忽略不计击倒。此外,体内成像数据证实了功能化的纳米气泡可以用作实体瘤超声成像的有效造影剂。这项工作凸显了Dox-NBs / PPP / P-gp shRNA纳米气泡在克服MDR的增强的影像引导联合疗法方面的巨大潜力。
更新日期:2018-07-12
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