Acoustically Driven Microbubbles Enable Targeted Delivery of microRNA‐Loaded Nanoparticles to Spontaneous Hepatocellular Neoplasia in Canines

Abstract

Spatially localized microbubble cavitation by ultrasound offers an effective means of altering the permeability of natural barriers (i.e., blood vessels and cell membranes) in favor of nanomaterial accumulation in target sites. In this study, a clinically relevant, minimally invasive ultrasound guided therapeutic approach is investigated for the targeted delivery of anticancer microRNA loaded PLGA-b-PEG nanoparticles to spontaneous hepatocellular neoplasia in a canine model. Quantitative assessment of the delivered microRNAs reveals a prominent and consistent increase in microRNAs levels (1.5-to 2.3-fold increase [p < 0.001]) in ultrasound treated tumor regions compared to untreated control regions. The immunohistology of ultrasound treated tumor tissue presents clear evidence for a higher amount of nanoparticle extravasation from the blood vessels. A distinct pattern of cytokine expression supporting a CD8+ T cells mediated "cold-to-hot" tumor transition is evident in all patients. This proposed platform can enhance delivery of microRNA-loaded nanoparticles to deeply located visceral tumors in large animals to enhance chemotherapy.

Engineered Cell‐Derived Vesicles Displaying Targeting Peptide and Functionalized with Nanocarriers for Therapeutic microRNA Delivery to Triple‐Negative Breast Cancer in Mice

“…Ex Vivo Histology and RT‐PCR Analysis : The ex vivo histology and RT‐PCR quantification were performed for the delivered antisense microRNAs by following the protocols published previously by the authors. [ 24,26,37 ]…”

“…Ex Vivo Histology and RT-PCR Analysis: The ex vivo histology and RT-PCR quantification were performed for the delivered antisense microRNAs by following the protocols published previously by the authors. [24,26,37] Statistical Analyses: All statistical analyses were performed using Student's t test and Prism software (Version 8.4.1, GraphPad, LLC). The results were presented as mean ± standard deviation (SD).…”

“…[ 21 ] Encapsulation of miRNAs within biodegradable polymeric nanocarriers can provide sufficient protection from nucleases and improve the sustained release of miRNAs for long periods to enhance the therapeutic efficacy of miRNAs. We have shown the production and preclinical validation of miRNA‐loaded PLGA‐NPs in rodent, [ 22 ] pig, [ 23 ] and dog [ 24 ] models. We established diverse strategies to enhance the overall therapeutic efficacy of miRNAs in vivo.…”

A 3D printable perfused hydrogel vascular model to assay ultrasound-induced permeability

“…Ultrasound in combination with intraluminal microbubble administration has been shown as a promising route for enhancing the delivery of therapeutics across a cellular barrier. 32,50,51,[59][60][61][62] After achieving an endothelialized vascular model with improved barrier function, the next step was to incorporate the application of ultrasound to study the transport of a fluorescent molecular tracer from the lumen, through the endothelial barrier, and into the surrounding hydrogel matrix. This work involved using a channel endothelialized with GFP HUVECs and perfused with a solution of 70 kDa rhodamine-dextran and microbubbles, as a molecular tracer and an agent for sonoporation, respectively.…”