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
• lékové transportní systémy * MeSH
• lidé MeSH
• magnetická rezonanční angiografie * MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• optické zobrazování * MeSH
• patologická angiogeneze * diagnostické zobrazování   farmakoterapie   metabolismus   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

Here, we describe a novel polymer platform suitable for efficient diagnostics and potential theranostics based on 89Zr-labeled N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymer conjugates. A set of polymers differing in molecular weight with either low dispersity or high dispersity were designed and synthesized and their biodistribution in vivo was successfully and precisely observed over 72 h. Moreover, the feasibility of two imaging techniques, fluorescence imaging (FI) and positron emission tomography (PET), was compared using labeled polymer conjugates. Both methods gave comparable results thus showing the enhanced diagnostic potential of the prepared polymer-dye or polymer-chelator-89Zr constructs. The in vivo and ex vivo PET/FI studies indicated that the dispersity and molecular weight of the linear HPMA polymers have a significant influence on the pharmacokinetics of the polymer conjugates. The higher molecular weight and narrower distribution of molecular weights of the polymer carriers improve their pharmacokinetic profile for highly prolonged blood circulation and enhanced tumor uptake. Moreover, the same polymer carrier with the anticancer drug doxorubicin bound by a pH-sensitive hydrazone bond showed higher cytotoxicity and cellular uptake in vitro. Therefore, HPMA copolymers with low dispersity and a molecular weight near the limit of renal filtration can be used as highly efficient polymer carriers of tumor-targeted therapeutics or for theranostics with minimal side effects.

• MeSH
• doxorubicin aplikace a dávkování   farmakokinetika   MeSH
• experimentální nádory * diagnostické zobrazování   farmakoterapie   MeSH
• Jurkat buňky MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nosiče léků * chemie   MeSH
• optické zobrazování * MeSH
• polymery * chemie   MeSH
• pozitronová emisní tomografie * MeSH
• radionuklidy MeSH
• teranostická nanomedicína * MeSH
• tkáňová distribuce MeSH
• zirkonium MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH

A series of phosphoramidate-based prostate specific membrane antigen (PSMA) inhibitors of increasing lipophilicity were synthesized (4, 5, and 6), and their fluorine-18 analogs were evaluated for use as positron emission tomography (PET) imaging agents for prostate cancer. To gain insight into their modes of binding, they were also cocrystallized with the extracellular domain of PSMA. All analogs exhibited irreversible binding to PSMA with IC50 values ranging from 0.4 to 1.3 nM. In vitro assays showed binding and rapid internalization (80-95%, 2 h) of the radiolabeled ligands in PSMA(+) cells. In vivo distribution demonstrated significant uptake in CWR22Rv1 (PSMA(+)) tumor, with tumor to blood ratios of 25.6:1, 63.6:1, and 69.6:1 for [(18)F]4, [(18)F]5, and [(18)F]6, respectively, at 2 h postinjection. Installation of aminohexanoic acid (AH) linkers in the phosphoramidate scaffold improved their PSMA binding and inhibition and was critical for achieving suitable in vivo imaging properties, positioning [(18)F]5 and [(18)F]6 as favorable candidates for future prostate cancer imaging clinical trials.

• MeSH
• amidy chemická syntéza   chemie   farmakologie   MeSH
• antigeny povrchové MeSH
• experimentální nádory diagnostické zobrazování   MeSH
• glutamátkarboxypeptidasa II antagonisté a inhibitory   MeSH
• kyseliny fosforečné chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• nádory prostaty diagnostické zobrazování   MeSH
• peptidomimetika chemická syntéza   chemie   farmakologie   MeSH
• pozitronová emisní tomografie * MeSH
• radioizotopy fluoru MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH