An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Publikační typ
- časopisecké články MeSH
- tisková chyba MeSH
Effective drug delivery is restricted by pathophysiological barriers in solid tumors. In human pancreatic adenocarcinoma, poorly-permeable blood vessels limit the intratumoral permeation and penetration of chemo or nanotherapeutic drugs. New and clinically viable strategies are urgently sought to breach the neoplastic barriers that prevent effective drug delivery. Here, we present an original idea to boost drug delivery by selectively knocking down the tumor vascular barrier in a human pancreatic cancer model. Clinical radiation activates the tumor endothelial-targeted gold nanoparticles to induce a physical vascular damage due to the high photoelectric interactions. Active modulation of these tumor neovessels lead to distinct changes in tumor vascular permeability. Noninvasive MRI and fluorescence studies, using a short-circulating nanocarrier with MR-sensitive gadolinium and a long-circulating nanocarrier with fluorescence-sensitive nearinfrared dye, demonstrate more than two-fold increase in nanodrug delivery, post tumor vascular modulation. Functional changes in altered tumor blood vessels and its downstream parameters, particularly, changes in Ktrans (permeability), Kep (flux rate), and Ve (extracellular interstitial volume), reflect changes that relate to augmented drug delivery. The proposed dual-targeted therapy effectively invades the tumor vascular barrier and improve nanodrug delivery in a human pancreatic tumor model and it may also be applied to other nonresectable, intransigent tumors that barely respond to standard drug therapies.
- MeSH
- endoteliální buňky pupečníkové žíly (lidské) metabolismus MeSH
- experimentální nádory * krevní zásobení diagnostické zobrazování farmakoterapie metabolismus MeSH
- kovové nanočástice * chemie terapeutické užití MeSH
- lidé MeSH
- magnetická rezonanční angiografie * MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- optické zobrazování * MeSH
- patologická angiogeneze * diagnostické zobrazování farmakoterapie metabolismus MeSH
- systémy cílené aplikace léků * MeSH
- zlato * chemie farmakokinetika farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- publikace stažené z tisku MeSH
- Názvy látek
- zlato * 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
