"NV15-25781A"
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Závěrečná zpráva o řešení grantu Agentury pro zdravotnický výzkum MZ ČR
Nestr.
Hlavním cílem projektu je zlepšení péče o onkologické pacienty vyvinutím nových diagnostik pro neinvazivní zobrazování založených na polysacharidických materiálech. Tyto systémy mohou sloužit jako adaptovatelné molekulární stavebnice pro cílené doručení aktivních komponent (gadoliniové komplexy pro zobrazování magnetickou rezonancí, fluorescenční barviva nebo radionuklidy) do tkáně pevných nádorů se samocílícím efektem díky velikosti (EPR efekt) nebo díky selektivní vazbě na nádorové buňky (ligandové cílení). Polysacharidy představují biodegradovatelné polymerní nosiče přírodního původu z obnovitelných zdrojů s výhodnými vlastnostmi pro taková použití v medicíně. Aktivní cílení bude dáno afinitou D-galaktosylovaných struktur k asialoglykoproteinovým receptorům, které jsou vysoce exprimované v hepatocelulárních karcinomech, a na pevné vazbě ligandů pro muskarinové a benzodiazepinové receptory na melanomové buňky.; The ultimate goal of this project is to improve care about the patients with cancer by developing new noninvasive diagnostic and possibly also theranostic imaging tools based on polysaccharide materials. They may serve as customizable toolbox-like carriers selectively delivering active imaging components (such as gadolinium complexes suitable for magnetic resonance imaging, fluorescent dyes or radionuclides) to the solid tumor tissue with self-targeting effect due to size (EPR effect) or due to selective binding to cancer cell-specific structures (ligand targeting). Polysaccharides represent nontoxic natural-sourced biodegradable biocompatible polymer carriers from renewable resources with promising properties for such use in medicine. The active ligand-based targeting will be due to affinity of D-galactosylated structures (such as guar gum itself) to asialoglycoprotein receptors highly overexpressed in hepatocellular carcinomas or based on muscarinic and benzodiazepine receptor ligands that tightly bind to melanoma cells.
- MeSH
- glykogen MeSH
- karcinom diagnostické zobrazování MeSH
- magnetická rezonanční tomografie metody MeSH
- melanom diagnostické zobrazování MeSH
- nádory diagnostické zobrazování MeSH
- polysacharidy MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- onkologie
- radiologie, nukleární medicína a zobrazovací metody
- NLK Publikační typ
- závěrečné zprávy o řešení grantu AZV MZ ČR
Novel multiresponsive hybrid biocompatible systems of κ-carrageenan-graft-poly(2-isopropyl-2-oxazoline-co-2-butyl-2-oxazoline)s with unique combination of responsiveness to external stimuli were synthesized and studied. The polymer thermoresponsive behavior proved the existence of both lower and upper critical solution temperatures in aqueous milieu, forming gel at lower temperature, a solution at room temperature and cloudy nanophase-separated dispersion at elevated temperature. The limit temperatures can easily be adjusted by the polyoxazoline graft length and grafting density. Moreover, the polymer behavior is additionally dependent on the concentration of potassium ions. The polymers behave similarly as the original κ-carrageenan, and thus, the poly(2-alkyl-2-oxazoline) grafts do not decrease the ability of the κ-carrageenan to form the self-assembled structures. Molecular principles beyond this multistimuli-responsive behavior were elucidated with the use of dynamic light scattering, magnetic resonance and fluorescence measurements as well as atomic force microscopy. These polymers could be used in a wide range of biological applications demanding thermo- and potassium-responsiveness.
- Publikační typ
- časopisecké články MeSH
Multimodal probes, which can be simultaneously visualized by multiple imaging modalities, enable the cellular uptake, intracellular fate, biodistribution and elimination to be tracked in organisms. In this study, we report the synthesis of crystalline WO3 and CaWO4 doped with Eu3+ or Tb3+ nanoparticles (size range of 10-160 nm) coated with polysaccharides, and these nanoparticles constitute a versatile easy-to-construct modular toolbox for multimodal imaging. The particles adsorb significant amounts of polysaccharides from the solution, providing biocompatibility and may serve as a platform for labeling. For WO3, the sorption is reversible. However, on CaWO4, stable coating is formed. CaWO4/Tb3+ coated with chemisorbed dextrin, mannan, guar gum and sodium alginate successfully underwent endocytosis with HepG2 cells and was visualized using confocal microscopy.
- MeSH
- biokompatibilní materiály chemie MeSH
- buňky Hep G2 MeSH
- endocytóza fyziologie MeSH
- konfokální mikroskopie MeSH
- lidé MeSH
- luminiscence * MeSH
- nanočástice aplikace a dávkování chemie účinky záření MeSH
- polysacharidy chemie MeSH
- terbium chemie MeSH
- wolfram chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Novel multiresponsive hybrid biocompatible systems of κ-carrageenan-graft-poly(2-isopropyl-2-oxazoline-co-2-butyl-2-oxazoline)s with unique combination of responsiveness to external stimuli were synthesized and studied. The polymer thermoresponsive behavior proved the existence of both lower and upper critical solution temperatures in aqueous milieu, forming gel at lower temperature, a solution at room temperature and cloudy nanophase-separated dispersion at elevated temperature. The limit temperatures can easily be adjusted by the polyoxazoline graft length and grafting density. Moreover, the polymer behavior is additionally dependent on the concentration of potassium ions. The polymers behave similarly as the original κ-carrageenan, and thus, the poly(2-alkyl-2-oxazoline) grafts do not decrease the ability of the κ-carrageenan to form the self-assembled structures. Molecular principles beyond this multistimuli-responsive behavior were elucidated with the use of dynamic light scattering, magnetic resonance and fluorescence measurements as well as atomic force microscopy. These polymers could be used in a wide range of biological applications demanding thermo- and potassium-responsiveness.
- MeSH
- imunokonjugáty chemie MeSH
- intravitální mikroskopie MeSH
- lymfatické uzliny diagnostické zobrazování MeSH
- mannany * chemická syntéza MeSH
- multimodální zobrazování * metody MeSH
- myši MeSH
- optické zobrazování metody MeSH
- techniky in vitro MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Wilson's disease is a genetic disorder that causes excessive accumulation of copper in the body, leading to toxic damage, especially in the liver and nervous system. The current treatment cause burdensome side effects. We describe the use of chemically modified biopolymer carriers based on microcrystalline cellulose and chitosan containing the highly specific copper chelator 8-hydroxyquinoline as a new type of therapy for Wilson's disease. The chelators can scavenges copper ions released from food during digestion and copper ions present in secretions in the gastrointestinal tract. Because the chelator is covalently bound to indigestible biopolymer carriers (crosslinked chitosan or modified cellulose), it is not taken up by the gastrointestinal tract and it can be eliminated through the feces, avoiding unwanted side effects. This concept was tested on Wistar rats, which received a radioactive 64CuCl2 solution together with the polymers with covalently bound 8-hydroxyquinoline through a gastric probe. 64Copper complex uptake from the gastrointestinal tract was significantly inhibited by both chelating polymers. With the modified polymers, the presence of 64Cu was detected mostly in the gastrointestinal tract, not in the internal organs. These findings indicate modified cellulose and crosslinked chitosan, with covalently bound 8-hydroxyquinoline exhibited the potential to be excellent therapeutics for treating Wilson's disease.
- MeSH
- celulosa aplikace a dávkování farmakokinetika MeSH
- chitosan aplikace a dávkování farmakokinetika MeSH
- gastrointestinální trakt metabolismus MeSH
- hepatolentikulární degenerace farmakoterapie metabolismus MeSH
- měď MeSH
- oxychinolin aplikace a dávkování farmakokinetika MeSH
- potkani Wistar MeSH
- radioizotopy mědi aplikace a dávkování farmakokinetika MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The effective drug delivery systems for cancer treatment are currently on high demand. In this paper, biological behavior of the novel hybrid copolymers based on polysaccharide glycogen were characterized. The copolymers were modified by fluorescent dyes for flow cytometry, confocal microscopy, and in vivo fluorescence imaging. Moreover, the effect of oxazoline grafts on degradation rate was examined. Intracellular localization, cytotoxicity, and internalization route of the modified copolymers were examined on HepG2 cell line. Biodistribution of copolymers was addressed by in vivo fluorescence imaging in C57BL/6 mice. Our results indicate biocompatibility, biodegradability, and non-toxicity of the glycogen-based hybrid copolymers. Copolymers were endocyted into the cytoplasm, most probably via caveolae-mediated endocytosis. Higher content of oxazoline in polymers slowed down cellular uptake. No strong colocalization of the glycogen-based probe with lysosomes was observed; thus, it seems that the modified externally administered glycogen is degraded in the same way as an endogenous glycogen. In vivo experiment showed relatively fast biodistribution and biodegradation. In conclusion, this novel nanoprobe offers unique chemical and biological attributes for its use as a novel drug delivery system that might serve as an efficient carrier for cancer therapeutics with multimodal imaging properties.
- MeSH
- buňky Hep G2 MeSH
- endocytóza MeSH
- fluorescein-5-isothiokyanát aplikace a dávkování farmakokinetika MeSH
- fluorescenční barviva aplikace a dávkování farmakokinetika MeSH
- glykogen aplikace a dávkování farmakokinetika MeSH
- heterocyklické sloučeniny aplikace a dávkování farmakokinetika MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- nosiče léků aplikace a dávkování farmakokinetika MeSH
- organokovové sloučeniny aplikace a dávkování farmakokinetika MeSH
- polyaminy aplikace a dávkování farmakokinetika MeSH
- tkáňová distribuce MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Herein, we provide a direct proof for differences in the micellar structure of amphiphilic diblock and gradient copolymers, thereby unambiguously demonstrating the influence of monomer distribution along the polymer chains on the micellization behavior. The internal structure of amphiphilic block and gradient co poly(2-oxazolines) based on the hydrophilic poly(2-methyl-2-oxazoline) (PMeOx) and the hydrophobic poly(2-phenyl-2-oxazoline) (PPhOx) was studied in water and water-ethanol mixtures by small-angle X-ray scattering (SAXS), small-angle neutron scattering (SANS), static and dynamic light scattering (SLS/DLS), and 1H NMR spectroscopy. Contrast matching SANS experiments revealed that block copolymers form micelles with a uniform density profile of the core. In contrast to popular assumption, the outer part of the core of the gradient copolymer micelles has a distinctly higher density than the middle of the core. We attribute the latter finding to back-folding of chains resulting from hydrophilic-hydrophobic interactions, leading to a new type of micelles that we refer to as micelles with a "bitterball-core" structure.
Owing to their tunable blood circulation time and suitable plasma stability, polymer-based nanomaterials hold a great potential for designing and utilising multifunctional nanocarriers for efficient imaging and effective treatment of cancer. When tagged with appropriate radionuclides, they may allow for specific detection (diagnosis) as well as the destruction of tumours (therapy) or even customization of materials, aiming to both diagnosis and therapy (theranostic approach). This review provides an overview of recent developments of radiolabelled polymeric nanomaterials (natural and synthetic polymers) for molecular imaging of cancer, specifically, applying nuclear techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). Different approaches to radiolabel polymers are evaluated from the methodical radiochemical point of view. This includes new bifunctional chelating agents (BFCAs) for radiometals as well as novel labelling methods. Special emphasis is given to eligible strategies employed to evade the mononuclear phagocytic system (MPS) in view of efficient targeting. The discussion encompasses promising strategies currently employed as well as emerging possibilities in radionuclide-based cancer therapy. Key issues involved in the clinical translation of radiolabelled polymers and future scopes of this intriguing research field are also discussed.
- MeSH
- izotopové značení metody MeSH
- lidé MeSH
- nádory * diagnostické zobrazování radioterapie MeSH
- pozitronová emisní tomografie * MeSH
- radiofarmaka terapeutické užití MeSH
- SPECT/CT * MeSH
- teranostická nanomedicína metody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
V článku se popisuje historie buněčného zobrazování pomocí magnetické rezonance v České republice, naše zkušenosti v této oblasti získané na pracovišti MR v Institutu klinické a experimentální medicíny a nejnovější trendy v této oblasti, včetně použití multimodálních kontrastních látek. V článku jsou uvedené i aplikace z experimentální medicíny na různých zvířecích modelech a příklad klinické studie, kde se využívaly kontrastní látky ke značení transplantovaných pankreatických ostrůvků.
We describe the history of molecular/cellular imaging using magnetic resonance imaging in the Czech Republic, our experience gained at the Department of Magnetic Resonance at the Institute for Clinical and Experimental Medicine and the latest trends in this field, including the use of multimodal contrast agents. The article also contains applications from experimental medicine on various animal models and an example of a clinical study using contrast agents to label transplanted pancreatic islets.
We report on the physicochemical properties and self-assembly behavior of novel efficient pH-sensitive nanocontainers based on the Food and Drug Administration-approved anionic polymer Eudragit L100-55 (poly(methacrylic acid-co-ethyl acrylate) 1:1) and nonionic surfactant Brij98. The features of the interaction between Eudragit L100-55 and Brij98 at different pH values and their optimal ratio for nanoparticle formation were studied using isothermal titration calorimetry. The influence of the polymer-to-surfactant ratio on the size and structure of particles was studied at different pH values using dynamic light scattering and small-angle X-ray scattering methods. It was shown that stable nanoparticles are formed at acidic pH at polymer-to-surfactant molar ratios from 1:43 to 1:139. Trypsin was successfully encapsulated into Eudragit-Brij98 nanoparticles as a model bioactive component. The loading efficiency was determined by labeling trypsin with radioactive iodine-125. Eudragit-Brij98 nanoparticles effectively protected trypsin against pepsin digestion. The results showed that trypsin encapsulated into novel pH-sensitive nanocontainers retained more than 50% of its activity after treatment with pepsin compared with nonencapsulated trypsin. The described concept will contribute both to understanding the principles of and designing next-generation nanocontainers.
- MeSH
- akrylové pryskyřice chemie MeSH
- difrakce rentgenového záření MeSH
- dynamický rozptyl světla MeSH
- koncentrace vodíkových iontů MeSH
- maloúhlový rozptyl MeSH
- nanočástice chemie MeSH
- nosiče léků chemie MeSH
- oleje rostlin chemie MeSH
- polyelektrolyty chemie MeSH
- polyethylenglykoly chemie MeSH
- povrchově aktivní látky chemie MeSH
- radioizotopy jodu MeSH
- skot MeSH
- trypsin chemie MeSH
- velikost částic MeSH
- zvířata MeSH
- Check Tag
- skot MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
