Ultrasound/microbubble-mediated targeted delivery of anticancer microRNA-loaded nanoparticles to deep tissues in pigs

JOURNAL OF CONTROLLED RELEASE

卷:309

Article

Di Ianni, Tommaso¹  Bose, Rajendran J. C.¹  Sukumar, Uday K.¹  Bachawal, Sunitha¹  Wang, Huaijun¹  Telichko, Arsenii¹  Herickhoff, Carl¹  Robinson, Elise¹  Baker, Sam²  Vilches-Moure, Jose G.²  Felt, Stephen A.²  Gambhir, Sanjiv S.^1,3  Paulmurugan, Ramasamy¹  Dahl, Jeremy D.¹ 

[1] Stanford Univ, Sch Med, Dept Radiol, Stanford, CA 94305 USA

[2] Stanford Univ, Sch Med, Dept Comparat Med, Stanford, CA 94305 USA

[3] Stanford Univ, Dept Mat Sci & Engn, Dept Bioengn, Stanford, CA 94305 USA

关键词: Ultrasound;    Microbubbles;    Nanoparticles;    microRNAs;    Cancer treatment;    Targeted drug delivery;   

DOI  :  10.1016/j.jconrel.2019.07.024

来源: Elsevier

【 摘 要 】

In this study, we designed and validated a platform for ultrasound and microbubble-mediated delivery of FDA-approved pegylated poly lactic-co-glycolic acid (PLGA) nanoparticles loaded with anticancer microRNAs (miRNAs) to deep tissues in a pig model. Small RNAs have been shown to reprogram tumor cells and sensitize them to clinically used chemotherapy. To overcome their short intravascular circulation half-life and achieve controlled and sustained release into tumor cells, anticancer miRNAs need to be encapsulated into nanocarriers. Focused ultrasound combined with gas-filled microbubbles provides a noninvasive way to improve the permeability of tumor vasculature and increase the delivery efficiency of drug-loaded particles. A single handheld, curvilinear ultrasound array was used in this study for image-guided therapy with clinical-grade SonoVue contrast agent. First, we validated the platform on phantoms to optimize the microbubble cavitation dose based on acoustic parameters, including peak negative pressure, pulse length, and pulse repetition frequency. We then tested the system in vivo by delivering PLGA nanoparticles co-loaded with antisense-miRNA-21 and antisensemiRNA-10b to pig liver and kidney. Enhanced miRNA delivery was observed (1.9- to 3.7-fold increase) as a result of the ultrasound treatment compared to untreated control regions. Additionally, we used highly fluorescent semiconducting polymer nanoparticles to visually assess nanoparticle extravasation. Fluorescent microscopy suggested the presence of nanoparticles in the extravascular compartment. Hematoxylin and eosin staining of treated tissues did not reveal tissue damage. The results presented in this manuscript suggest that the proposed platform may be used to safely and noninvasively enhance the delivery of miRNA-loaded nanoparticles to target regions in deep organs in large animal models.

【 授权许可】

Free