PT  - JOURNAL ARTICLE
AU  - Tommaso Di Ianni
AU  - Rajendran J.C. Bose
AU  - Uday K. Sukumar
AU  - Sunitha Bachawal
AU  - Huaijun Wang
AU  - Arsenii Telichko
AU  - Carl D. Herickhoff
AU  - Elise Robinson
AU  - Sam Baker
AU  - José G. Vilches-Moure
AU  - Stephen A. Felt
AU  - Sanjiv S. Gambhir
AU  - Ramasamy Paulmurugan
AU  - Jeremy D. Dahl
TI  - Ultrasound- and microbubble-mediated targeted delivery of therapeutic microRNA-loaded nanocarriers to deep liver and kidney tissues in pigs
AID  - 10.1101/592931
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 592931
4099  - http://biorxiv.org/content/early/2019/03/30/592931.short
4100  - http://biorxiv.org/content/early/2019/03/30/592931.full
AB  - In this study, we designed and validated a platform for ultrasound (US) and microbubble (MB)-mediated delivery of FDA-approved pegylated poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) loaded with anticancer microRNAs (miRNAs) to deep tissues in a pig model. Small RNAs have the ability to reprogram tumor cells and sensitize them to clinically used chemotherapy. However, to overcome their short intravascular circulation half-life and achieve controlled and sustained release into tumor cells, anticancer miRNAs need to be encapsulated into NPs. Moreover, focused US combined with gas-filled MBs provides a safe and noninvasive way to improve the permeability of tumor vasculature and increase the delivery efficiency of drug-loaded nanocarriers. A single handheld, curvilinear US array was used in this study for image-guidance and therapy with clinical-grade SonoVue MBs. First, we validated the platform on phantoms to optimize the MB 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-NPs co-loaded with antisense-miRNA-21 and antisense-miRNA-10b in pig liver and kidney. Enhanced miRNA delivery was observed (1.9- to 3.7-fold increase) as a result of the US-MB treatment compared to untreated control regions. Additionally, we used highly fluorescent semiconducting polymer nanoparticles (SPNs) co-delivered with miRNA-loaded PLGA-NPs to visually assess NP delivery. Fluorescent microscopy of SPNs confirmed NP extravasation and showed the presence of particles in the extravascular compartment. Hematoxylin and eosin staining of treated tissues did not reveal tissue damage. The results presented in this manuscript suggest that enhanced delivery of miRNA-loaded NPs to target regions in deep organs is feasible in large animal models using the proposed platform.