Ultrasound-guided delivery of microRNA loaded nanoparticles into cancer

Abstract

Ultrasound induced microbubble cavitation can cause enhanced permeability across natural barriers of tumors such as vessel walls or cellular membranes, allowing for enhanced therapeutic delivery into the target tissues. While enhanced delivery of small (<1 nm) molecules has been shown at acoustic pressures below 1MPa both in vitro and in vivo, the delivery efficiency of larger (>100 nm) therapeutic carriers into cancer remains unclear and may require a higher pressure for sufficient delivery. Enhanced delivery of larger therapeutic carriers such as FDA approved pegylated poly(lactic-co-glycolic acid) nanoparticles (PLGA-PEG-NP) has significant clinical value because these nanoparticles have been shown to protect encapsulated drugs from degradation in the blood circulation and allow for slow and prolonged release of encapsulated drugs at the target location. In this study, various acoustic parameters were investigated to facilitate the successful delivery of two nanocarriers, a fluorescent semiconducting polymer model drug nanoparticle as well as PLGA-PEG-NP into human colon cancer xenografts in mice. We first measured the cavitation dose produced by various acoustic parameters (pressure, pulse length, and pulse repetition frequency) and microbubble concentration in a tissue mimicking phantom. Next, in vivo studies were performed to evaluate the penetration depth of nanocarriers using various acoustic pressures, ranging between 1.7 and 6.9 MPa. Finally, a therapeutic microRNA, miR-122, was loaded into PLGA-PEG-NP and the amount of delivered miR-122 was assessed using quantitative RT-PCR. Our results show that acoustic pressures had the strongest effect on cavitation. An increase of the pressure from 0.8 to 6.9 MPa resulted in a nearly 50-fold increase in cavitation in phantom experiments. In vivo, as the pressures increased from 1.7 to 6.9 MPa, the amount of nanoparticles deposited in cancer xenografts was increased from 4- to 14-fold, and the median penetration depth of extravasated nanoparticles was increased from 1.3-fold to 3-fold, compared to control conditions without ultrasound, as examined on 3D confocal microscopy. When delivering miR-122 loaded PLGA-PEG-NP using optimal acoustic settings with minimum tissue damage, miR-122 delivery into tumors with ultrasound and microbubbles was 7.9-fold higher compared to treatment without ultrasound. This study demonstrates that ultrasound induced microbubble cavitation can be a useful tool for delivery of therapeutic miR loaded nanocarriers into cancer in vivo.

Ultrasound-guided therapeutic modulation of hepatocellular carcinoma using complementary microRNAs

“…PLGA-NP were synthesized and loaded with both miRNAs as described previously [22,35](see details in Supplementary section). …”

“…The endogenous expression levels of miRNA-122 and miRNA-21 in doxorubicin-resistant and non-resistant HepG2 cells were analyzed using qRT-PCR as described [22,35](see details in Supplementary section). …”

“…Ultrasound-mediated drug delivery has shown to be markedly potentiated in the presence of contrast microbubbles [33, 34]. Recently, our group has optimized the acoustic parameters to maximize PLGA-NP delivery in human cancer xenografts in mice [35]. …”

Dual tumor-targeted poly(lactic-<em>co</em>-glycolic acid)&ndash;polyethylene glycol&ndash;folic acid nanoparticles: a novel biodegradable nanocarrier for secure and efficient antitumor drug delivery

“…[28][29][30][31][32] Additionally, polyethylene glycolated (PEGylated) PLGA nanoparticles have been developed to improve bioavailability and antitumor targeting further. 28,33,34 In other words, besides the hydrophobic region of PLGA being efficient in hydrophobic drug encapsulation, the hydration on the hydrophilic PEG corona can further prevent nanocarriers from aspecific protein adsorption and reticuloendothelial system clearance for prolonging blood circulation in vivo. [35][36][37][38][39] Therefore, PEGylated PLGA nanoparticles are advanced platforms to enhance targeted antitumor drug delivery.…”

Ultrasound reverses adriamycin-resistance in non-small cell lung cancer via positive regulation of BRAF-activated non-coding RNA (BANCR) expression

“…Consequently, there is still an urgent need to explore viable strategies to overcome MDR. Ultrasound, a form of energy, has been applied to the ablation and reversal of tumor cells [4] . In addition, ultrasound is reported to be a safer and more effective method for reversal of MDR in tumor cells [5,6] .…”