Assessment of nanoparticle delivery in the brain and brain tumor following microbubble-enhanced focused ultrasound mediated blood-brain-barrier opening
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Padmanabhan, Samhita
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Abstract
RNA therapeutics have dramatically altered the ability to target and modify gene expression associated with human diseases. Despite progress, the effective systemic delivery of RNA molecules presents an enormous challenge. The RNA molecule must resist enzymatic degradation or renal clearance, traverse to the brain, penetrate the extracellular matrix, and finally find its target inside the cell. Consequently, encapsulating them in large carriers like nanoparticles with specific properties becomes essential. While RNA encapsulation addresses some of challenges like degradation and clearance from blood circulation it also exaggerates others. Predominantly, in the brain crossing the blood-brain-barrier and penetrating the extracellular matrix remains a major challenge post encapsulation. The goal of this study is to 1) assess the impact of nanoparticle size and charge on cellular uptake in GL261 murine cancer cell line, and blood circulation half-life, 2) test the abilities of microbubble-enhanced focused ultrasound (MB-FUS) to transiently disrupt the blood-brain barrier and facilitate the penetration of nanoparticles into the targeted/FUS treated regions in the brain and brain tumor. In-vivo animal work involving lipid-polymer and gold nanoparticles (AuNPs) in healthy and glioblastoma cancer models showed positive results with respect to nanoparticle accumulation in the FUS targeted areas for the 45 nm particle size. Moreover, the delivery of nanoparticles correlated with the k-trans values obtained from dynamic contrast-enhanced MRI. This imaging technique can serve as a surrogate method to indirectly measure and predict the targeted delivery of nanoparticles. Together these findings indicate that the effectiveness of RNA delivery and, by extension, of gene therapy in brain tumors could be improved with 45 nm nanoparticles.
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2024-07-23
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