Ultrasound-enhanced brain delivery of edaravone provides additive amelioration on disease progression in an ALS mouse model.

BACKGROUND: Although amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and unfortunately incurable yet, incremental attention has been drawn to targeting the health of corticospinal motor neurons. Focused ultrasound combined with systemically circulating microbubbles (FUS/MB) is an emerging modality capable of site-specific molecular delivery temporarily and noninvasively within a range of appropriate parameters. OBJECTIVE: To investigate the effect of FUS/MB-enhanced delivery of therapeutics to the motor cortex on the disease progression by using a transgenic mouse model of ALS. METHODS: Multiple FUS/MB-enhanced deliveries of Edaravone (Eda) to the motor cortex were performed on the SOD1G93A mouse model of ALS. The motor function of the animals was evaluated by gait analysis, grip strength and wire hanging tests. Corticospinal and spinal motor neuronal health, misfolded SOD1 protein and neuroinflammation after treatments were evaluated by histological examination. RESULTS: Ultrasound-enhanced delivery of Eda in the targeted motor cortex was achieved by a two-fold increase without gross tissue damage. Compared with the ALS mice administered Eda treatments only, the animals given additionally FUS/MB-enhanced brain delivery of Eda (FUS/MB + Eda) exhibited further improvements in neuromuscular functions characterized by gait patterns, muscular strength, and motor coordination along with rescued muscle atrophy. FUS/MB + Eda treatments conferred remarkable neuroprotection to both upper and lower motor neurons revealed by normalized neuronal morphology with increasing cell body size and profoundly alleviated neuroinflammation and misfolded SOD1 protein in the brains and lumbar spinal cords. CONCLUSION: We report a pilot study that non-invasive ultrasound-enhanced brain delivery of Eda provides additive amelioration on disease progression of ALS and suggest that broadening the target from spinal to cortical network functions using the FUS/MB-enhanced delivery can be a rational therapeutic strategy of this debilitating disorder.

Delivery of DNA octahedra enhanced by focused ultrasound with microbubbles for glioma therapy.

DNA nanostructures, with good biosafety, highly programmable assembly, flexible modification, and precise control, are tailored as drug carriers to deliver therapeutic agents for cancer therapy. However, they face considerable challenges regarding their delivery into the brain, mainly due to the blood-brain barrier (BBB). By controlling the acoustic parameters, focused ultrasound combined with microbubbles (FUS/MB) can temporarily, noninvasively, and reproducibly open the BBB in a localized region. We investigated the delivery outcome of pH-responsive DNA octahedra loading Epirubicin (Epr@DNA-Octa) via FUS/MB and its therapeutic efficiency in a mouse model bearing intracranial glioma xenograft. Using FUS/MB to locally disrupt the BBB or the blood-tumor barrier (BTB) and systemic administration of Epr@DNA-Octa (Epr@DNA-Octa + FUS/MB) (2 mg/kg of loaded Epr), we achieved an Epr concentration of 292.3 ± 10.1 ng/g tissue in glioma, a 4.4-fold increase compared to unsonicated animals (p < 0.001). The in vitro findings indicated that Epr released from DNA strands accumulated in lysosomes and induced enhanced cytotoxicity compared to free Epr. Further two-photon intravital imaging of spatiotemporal patterns of the DNA-Octa leakage revealed that the FUS/MB treatment enhanced DNA-Octa delivery across several physiological barriers at microscopic level, including the first extravasation across the BBB/BTB and then deep penetration into the glioma center and engulfment of DNA-Octa into the tumor cell body. Longitudinal in vivo bioluminescence imaging and histological analysis indicated that the intracranial glioma progression in nude mice treated with Epr@DNA-Octa + FUS/MB was effectively retarded compared to other groups. The beneficial effect on survival was most significant in the Epr@DNA-Octa + FUS/MB group, with a 50% increase in median survival and a 73% increase in the maximum survival compared to control animals. Our work demonstrates the potential viability of FUS/MB as an alternative strategy for glioma delivery of anticancer drugs using DNA nanostructures as the drug delivery platform for brain cancer therapy.