RGD-coated polymeric microbubbles promote ultrasound-mediated drug delivery in an inflamed endothelium-pericyte co-culture model of the blood-brain barrier.

Drug delivery to central nervous pathologies is compromised by the blood-brain barrier (BBB). A clinically explored strategy to promote drug delivery across the BBB is sonopermeation, which relies on the combined use of ultrasound (US) and microbubbles (MB) to induce temporally and spatially controlled opening of the BBB. We developed an advanced in vitro BBB model to study the impact of sonopermeation on the delivery of the prototypic polymeric drug carrier pHPMA as a larger molecule and the small molecule antiviral drug ribavirin. This was done under standard and under inflammatory conditions, employing both untargeted and RGD peptide-coated MB. The BBB model is based on human cerebral capillary endothelial cells and human placental pericytes, which are co-cultivated in transwell inserts and which present with proper transendothelial electrical resistance (TEER). Sonopermeation induced a significant decrease in TEER values and facilitated the trans-BBB delivery of fluorescently labeled pHPMA (Atto488-pHPMA). To study drug delivery under inflamed endothelial conditions, which are typical for e.g. tumors, neurodegenerative diseases and CNS infections, tumor necrosis factor (TNF) was employed to induce inflammation in the BBB model. RGD-coated MB bound to and permeabilized the inflamed endothelium-pericyte co-culture model, and potently improved Atto488-pHPMA and ribavirin delivery. Taken together, our work combines in vitro BBB bioengineering with MB-mediated drug delivery enhancement, thereby providing a framework for future studies on optimization of US-mediated drug delivery to the brain.

mRNA Sonotransfection of Tumors with Polymeric Microbubbles: Co-Formulation versus Co-Administration.

Despite its high potential, non-viral gene therapy of cancer remains challenging due to inefficient nucleic acid delivery. Ultrasound (US) with microbubbles (MB) can open biological barriers and thus improve DNA and mRNA passage. Polymeric MB are an interesting alternative to clinically used lipid-coated MB because of their high stability, narrow size distribution, and easy functionalization. However, besides choosing the ideal MB, it remains unclear whether nanocarrier-encapsulated mRNA should be administered separately (co-administration) or conjugated to MB (co-formulation). Therefore, the impact of poly(n-butyl cyanoacrylate) MB co-administration with mRNA-DOTAP/DOPE lipoplexes or their co-formulation on the transfection of cancer cells in vitro and in vivo is analyzed. Sonotransfection improved mRNA delivery into 4T1 breast cancer cells in vitro with co-administration being more efficient than co-formulation. In vivo, the co-administration sonotransfection approach also resulted in higher transfection efficiency and reached deeper into the tumor tissue. On the contrary, co-formulation mainly promoted transfection of endothelial and perivascular cells. Furthermore, the co-formulation approach is much more dependent on the US trigger, resulting in significantly lower off-site transfection. Thus, the findings indicate that the choice of co-administration or co-formulation in sonotransfection should depend on the targeted cell population, tolerable off-site transfection, and the therapeutic purpose.

Evaluation of the radiofrequency performance of a wide-bore 1.5 T positron emission tomography/magnetic resonance imaging body coil for radiotherapy planning.

BACKGROUND AND PURPOSE: The restricted bore diameter of current simultaneous positron emission tomography/magnetic resonance imaging (PET/MRI) systems can be an impediment to achieving similar patient positioning during PET/MRI planning and radiotherapy. Our goal was to evaluate the B1 transmit (B1 +) uniformity, B1 + efficiency, and specific absorption rate (SAR) of a novel radiofrequency (RF) body coil design, in which RF shielded PET detectors were integrated with the specific aim of enabling a wide-bore PET/MRI system. MATERIALS AND METHODS: We designed and constructed a wide-bore PET/MRI RF body coil to be integrated with a clinical MRI system. To increase its inner bore diameter, the PET detectors were positioned between the conductors and the RF shield of the RF body coil. Simulations and experiments with phantoms and human volunteers were performed to compare the B1 + uniformity, B1 + efficiency, and SAR between our design and the clinical body coil. RESULTS: In the simulations, our design achieved nearly the same B1 + field uniformity as the clinical body coil and an almost identical SAR distribution. The uniformity findings were confirmed by the physical experiments. The B1 + efficiency was 38% lower compared to the clinical body coil. CONCLUSIONS: To achieve wide-bore PET/MRI, it is possible to integrate shielding for PET detectors between the body coil conductors and the RF shield without compromising MRI performance. Reduced B1 + efficiency may be compensated by adding a second RF amplifier. This finding may facilitate the application of simultaneous whole-body PET/MRI in radiotherapy planning.