Sonopermeation Dotaz Zobrazit nápovědu
Rationale: The blood-brain barrier (BBB) is a major obstacle for drug delivery to the brain. Sonopermeation, which relies on the combination of ultrasound and microbubbles, has emerged as a powerful tool to permeate the BBB, enabling the extravasation of drugs and drug delivery systems (DDS) to and into the central nervous system (CNS). When aiming to improve the treatment of high medical need brain disorders, it is important to systematically study nanomedicine translocation across the sonopermeated BBB. To this end, we here employed multimodal and multiscale optical imaging to investigate the impact of DDS size on brain accumulation, extravasation and penetration upon sonopermeation. Methods: Two prototypic DDS, i.e. 10 nm-sized pHPMA polymers and 100 nm-sized PEGylated liposomes, were labeled with fluorophores and intravenously injected in healthy CD-1 nude mice. Upon sonopermeation, computed tomography-fluorescence molecular tomography, fluorescence reflectance imaging, fluorescence microscopy, confocal microscopy and stimulated emission depletion nanoscopy were used to study the effect of DDS size on their translocation across the BBB. Results: Sonopermeation treatment enabled safe and efficient opening of the BBB, which was confirmed by staining extravasated endogenous IgG. No micro-hemorrhages, edema and necrosis were detected in H&E stainings. Multimodal and multiscale optical imaging showed that sonopermeation promoted the accumulation of nanocarriers in mouse brains, and that 10 nm-sized polymeric DDS accumulated more strongly and penetrated deeper into the brain than 100 nm-sized liposomes. Conclusions: BBB opening via sonopermeation enables safe and efficient delivery of nanomedicine formulations to and into the brain. When looking at accumulation and penetration (and when neglecting issues such as drug loading capacity and therapeutic efficacy) smaller-sized DDS are found to be more suitable for drug delivery across the BBB than larger-sized DDS. These findings are valuable for better understanding and further developing nanomedicine-based strategies for the treatment of CNS disorders.
- Klíčová slova
- Blood-brain barrier, Drug delivery, Microbubbles, Nanomedicine, Ultrasound,
- MeSH
- fluorescenční barviva aplikace a dávkování MeSH
- hematoencefalická bariéra diagnostické zobrazování metabolismus MeSH
- liposomy aplikace a dávkování MeSH
- mikrobubliny MeSH
- mozek diagnostické zobrazování MeSH
- myši nahé MeSH
- myši MeSH
- nanomedicína metody MeSH
- nemoci mozku farmakoterapie MeSH
- optické zobrazování metody MeSH
- systémy cílené aplikace léků metody MeSH
- ultrasonografie metody MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- fluorescenční barviva MeSH
- liposomy MeSH
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.
- Klíčová slova
- Blood-brain barrier, Drug delivery, Microbubbles, Sonopermeation, Ultrasound,
- MeSH
- antivirové látky aplikace a dávkování chemie farmakologie farmakokinetika MeSH
- endoteliální buňky * účinky léků metabolismus MeSH
- hematoencefalická bariéra * metabolismus MeSH
- kokultivační techniky * MeSH
- lidé MeSH
- mikrobubliny * MeSH
- oligopeptidy * chemie aplikace a dávkování farmakokinetika MeSH
- pericyty * metabolismus účinky léků MeSH
- polymery chemie aplikace a dávkování MeSH
- ribavirin aplikace a dávkování chemie farmakokinetika MeSH
- systémy cílené aplikace léků metody MeSH
- ultrazvukové vlny MeSH
- zánět farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antivirové látky MeSH
- arginyl-glycyl-aspartic acid MeSH Prohlížeč
- oligopeptidy * MeSH
- polymery MeSH
- ribavirin MeSH