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

Cationic colloidal gold nanorods (GNRs) have a great potential as a theranostic tool for diverse medical applications. GNRs' properties such as cellular internalization and stability are determined by physicochemical characteristics of their surface coating. GNRs modified by (16-mercaptohexadecyl)trimethylammonium bromide (MTAB), MTABGNRs, show excellent cellular uptake. Despite their promise for biomedicine, however, relatively little is known about the cellular pathways that facilitate the uptake of GNRs, their subcellular fate and intracellular persistence. Here we studied the mechanism of cellular internalization and long-term fate of GNRs coated with MTAB, for which the synthesis was optimized to give higher yield, in various human cell types including normal diploid versus cancerous, and dividing versus nondividing (senescent) cells. The process of MTABGNRs internalization into their final destination in lysosomes proceeds in two steps: (1) fast passive adhesion to cell membrane mediated by sulfated proteoglycans occurring within minutes and (2) slower active transmembrane and intracellular transport of individual nanorods via clathrin-mediated endocytosis and of aggregated nanorods via macropinocytosis. The expression of sulfated proteoglycans was the major factor determining the extent of uptake by the respective cell types. Upon uptake into proliferating cells, MTABGNRs were diluted equally and relatively rapidly into daughter cells; however, in nondividing/senescent cells the loss of MTABGNRs was gradual and very modest, attributable mainly to exocytosis. Exocytosed MTABGNRs can again be internalized. These findings broaden our knowledge about cellular uptake of gold nanorods, a crucial prerequisite for future successful engineering of nanoparticles for biomedical applications such as photothermal cancer therapy or elimination of senescent cells as part of the emerging rejuvenation approach.

• MeSH
• buněčná membrána účinky léků   metabolismus   MeSH
• endocytóza účinky léků   fyziologie   MeSH
• exocytóza * účinky léků   fyziologie   MeSH
• konfokální mikroskopie MeSH
• kultivační média MeSH
• kvartérní amoniové sloučeniny chemická syntéza   chemie   MeSH
• lidé MeSH
• lyzozomy účinky léků   MeSH
• mikroskopie elektronová rastrovací MeSH
• nádorové buněčné linie MeSH
• nanotrubičky analýza   chemie   MeSH
• polylysin chemie   farmakokinetika   MeSH
• proliferace buněk účinky léků   MeSH
• proteoglykany chemie   metabolismus   MeSH
• průtoková cytometrie MeSH
• stabilita léku MeSH
• sulfhydrylové sloučeniny chemie   MeSH
• techniky syntetické chemie MeSH
• zlato chemie   farmakokinetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH