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
Tumors are characterized by leaky blood vessels, and by an abnormal and heterogeneous vascular network. These pathophysiological characteristics contribute to the enhanced permeability and retention (EPR) effect, which is one of the key rationales for developing tumor-targeted drug delivery systems. Vessel abnormality and heterogeneity, however, which typically result from excessive pro-angiogenic signaling, can also hinder efficient drug delivery to and into tumors. Using histidine-rich glycoprotein (HRG) knockout and wild type mice, and HRG-overexpressing and normal t241 fibrosarcoma cells, we evaluated the effect of genetically induced and macrophage-mediated vascular normalization on the tumor accumulation and penetration of 10-20 nm-sized polymeric drug carriers based on poly(N-(2-hydroxypropyl)methacrylamide). Multimodal and multiscale optical imaging was employed to show that normalizing the tumor vasculature improves the accumulation of fluorophore-labeled polymers in tumors, and promotes their penetration out of tumor blood vessels deep into the interstitium.
- Klíčová slova
- Drug delivery, EPR, HRG, Nanomedicine, Tumor targeting, Vascular normalization, pHPMA,
- MeSH
- kyseliny polymethakrylové metabolismus farmakokinetika MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory krevní zásobení genetika metabolismus MeSH
- nosiče léků metabolismus farmakokinetika MeSH
- permeabilita MeSH
- proteiny genetika metabolismus MeSH
- systémy cílené aplikace léků metody MeSH
- tkáňová distribuce MeSH
- upregulace MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- Duxon MeSH Prohlížeč
- histidine-rich proteins MeSH Prohlížeč
- kyseliny polymethakrylové MeSH
- nosiče léků MeSH
- proteiny MeSH
The Enhanced Permeability and Retention (EPR) effect is extensively used in drug delivery research. Taking into account that EPR is a highly variable phenomenon, we have here set out to evaluate if contrast-enhanced functional ultrasound (ceUS) imaging can be employed to characterize EPR-mediated passive drug targeting to tumors. Using standard fluorescence molecular tomography (FMT) and two different protocols for hybrid computed tomography-fluorescence molecular tomography (CT-FMT), the tumor accumulation of a ~10 nm-sized near-infrared-fluorophore-labeled polymeric drug carrier (pHPMA-Dy750) was evaluated in CT26 tumor-bearing mice. In the same set of animals, two different ceUS techniques (2D MIOT and 3D B-mode imaging) were employed to assess tumor vascularization. Subsequently, the degree of tumor vascularization was correlated with the degree of EPR-mediated drug targeting. Depending on the optical imaging protocol used, the tumor accumulation of the polymeric drug carrier ranged from 5 to 12% of the injected dose. The degree of tumor vascularization, determined using ceUS, varied from 4 to 11%. For both hybrid CT-FMT protocols, a good correlation between the degree of tumor vascularization and the degree of tumor accumulation was observed, within the case of reconstructed CT-FMT, correlation coefficients of ~0.8 and p-values of <0.02. These findings indicate that ceUS can be used to characterize and predict EPR, and potentially also to pre-select patients likely to respond to passively tumor-targeted nanomedicine treatments.
- Klíčová slova
- Cancer, Drug targeting, EPR, HPMA, Nanomedicine, Theranostics,
- MeSH
- akrylamidy aplikace a dávkování MeSH
- enbukrylát MeSH
- kontrastní látky aplikace a dávkování MeSH
- krevní objem MeSH
- mikrobubliny MeSH
- myši nahé MeSH
- nádorové buněčné linie MeSH
- nádory krevní zásobení diagnostické zobrazování metabolismus patofyziologie MeSH
- permeabilita MeSH
- regionální krevní průtok MeSH
- systémy cílené aplikace léků * MeSH
- tomografie metody MeSH
- ultrasonografie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- akrylamidy MeSH
- enbukrylát MeSH
- kontrastní látky MeSH