PURPOSE: Focused ultrasound-induced blood-brain barrier (BBB) opening is a promising method for neurotherapeutic delivery. The standard for quantifying induced BBB permeability is the K trans $$ {K}^{\mathrm{trans}} $$ parameter, which reflects both permeability and plasma flow. The influence of plasma flow can be eliminated by estimating the PS parameter. However, this parameter has been largely unexplored in this application. This study aims to compare permeability estimates based on K trans $$ {K}^{\mathrm{trans}} $$ and PS in focused ultrasound-induced BBB opening experiments. METHODS: We used the extended Tofts model (ETM) and the two-compartment exchange model (2CXM) to estimate K trans $$ {K}^{\mathrm{trans}} $$ and PS parameters, respectively. Permeability estimates were compared using simulated concentration curves, simulated DCE-MRI data, and real datasets. We explored the influence of spatially-regularized model fitting on the results. RESULTS: For opened BBB, K trans $$ {K}^{\mathrm{trans}} $$ was minimally influenced by plasma flow under the tested conditions. However, fitting the ETM often introduced outliers in K trans $$ {K}^{\mathrm{trans}} $$ estimates in regions with closed BBB. The 2CXM outperformed the ETM at high signal-to-noise ratios, but its higher complexity led to lower precision at low signal-to-noise ratios. Both these issues were successfully compensated by spatially-regularized model fitting. CONCLUSION: Both K trans $$ {K}^{\mathrm{trans}} $$ and PS seem to be eligible options for the quantification of BBB opening, and the correct choice depends on the specifics of the acquired DCE-MRI data. Additionally, spatial regularization has demonstrated its importance in enhancing the accuracy and reproducibility of results for both models.

• Klíčová slova
• BBB opening, DCE‐MRI, focused ultrasound, perfusion analysis, simulation,
• MeSH
• hematoencefalická bariéra * diagnostické zobrazování   metabolismus   účinky záření   MeSH
• kontrastní látky MeSH
• lidé MeSH
• magnetická rezonanční tomografie * metody   MeSH
• mozek diagnostické zobrazování   MeSH
• permeabilita MeSH
• počítačová simulace MeSH
• počítačové zpracování obrazu metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• kontrastní látky MeSH

Disruption of the blood-brain barrier (BBB) is a key feature of various brain disorders. To assess its integrity a parametrization of dynamic magnetic resonance imaging (DCE MRI) with a contrast agent (CA) is broadly used. Parametrization can be done quantitatively or semi-quantitatively. Quantitative methods directly describe BBB permeability but exhibit several drawbacks such as high computation demands, reproducibility issues, or low robustness. Semi-quantitative methods are fast to compute, simply mathematically described, and robust, however, they do not describe the status of BBB directly but only as a variation of CA concentration in measured tissue. Our goal was to elucidate differences between five semi-quantitative parameters: maximal intensity (Imax), normalized permeability index (NPI), and difference in DCE values between three timepoints: baseline, 5 min, and 15 min (delta5-0, delta15-0, delta15-5) and two quantitative parameters: transfer constant (Ktrans) and an extravascular fraction (Ve). For the purpose of comparison, we analyzed DCE data of four patients 12-15 days after the stroke with visible CA enhancement. Calculated parameters showed abnormalities spatially corresponding with the ischemic lesion, however, findings in individual parameters morphometrically differed. Ktrans and Ve were highly correlated. Delta5-0 and delta15-0 were prominent in regions with rapid CA enhancement and highly correlated with Ktrans. Abnormalities in delta15-5 and NPI were more homogenous with less variable values, smoother borders, and less detail than Ktrans. Moreover, only delta15-5 and NPI were able to distinguish vessels from extravascular space. Our comparison provides important knowledge for understanding and interpreting parameters derived from DCE MRI by both quantitative and semi-quantitative methods.

• MeSH
• hematoencefalická bariéra * diagnostické zobrazování   MeSH
• kontrastní látky MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• nemoci mozku * MeSH
• reprodukovatelnost výsledků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kontrastní látky MeSH

Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi-target-directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD-relevant biological property. Herein, supported by a proposed combination therapy of 1 and the quinone drug idebenone, we rationally designed novel 1-based MTDLs targeting Aβ and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with a 1,4-naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the "physicochemical challenge" typical of large hybrid-based MTDLs. A preliminary investigation of their multi-target profile identified 9, which showed a potent and selective butyrylcholinesterase inhibitory activity, together with antioxidant and antiaggregating properties. In addition, it displayed a promising drug-like profile.

• Klíčová slova
• Alzheimer's disease, drug design, medicinal chemistry, multi-target drug discovery, polypharmacology,
• MeSH
• acetylcholinesterasa chemie   metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• amyloidní beta-protein antagonisté a inhibitory   metabolismus   MeSH
• antioxidancia chemie   metabolismus   farmakologie   MeSH
• cholinesterasové inhibitory chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• donepezil chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• hematoencefalická bariéra diagnostické zobrazování   metabolismus   MeSH
• indany chemie   MeSH
• lidé MeSH
• ligandy * MeSH
• nádorové buněčné linie MeSH
• neuroprotektivní látky chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• oxidační stres účinky léků   MeSH
• proteinové agregáty účinky léků   MeSH
• racionální návrh léčiv MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• amyloidní beta-protein MeSH
• antioxidancia MeSH
• cholinesterasové inhibitory MeSH
• donepezil MeSH
• indacrinone MeSH Prohlížeč
• indany MeSH
• ligandy * MeSH
• neuroprotektivní látky MeSH
• proteinové agregáty MeSH

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
• lékové transportní systémy metody   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
• 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