Novel star polymer-doxorubicin conjugates designed for passive tumor targeting have been developed and their potential for treatment of cancer has been investigated. In the present study the synthesis, physico-chemical characterization, drug release, bio-distribution and preliminary data of in vivo efficacy of the conjugates are described. In the water-soluble conjugates the core of a molecule formed by poly(amido amine) (PAMAM) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers bearing doxorubicin (Dox) attached by hydrazone bonds enabling intracellular pH-controlled hydrolytic drug release, or by GFLG sequence susceptible to enzymatic degradation. The controlled synthesis utilizing semitelechelic copolymer precursors facilitated preparation of polymer conjugates in a broad range of molecular weights (1.1-3.0·10(5) g/mol). In contrast to free drug or linear conjugates the star polymer-Dox conjugates exhibited prolonged blood circulation and enhanced tumor accumulation in tumor-bearing mice indicating important role of the EPR effect. The star polymer-Dox conjugates showed significantly higher anti-tumor activity in vivo than Dox?HCl or its linear or graft polymer conjugates, if treated with a single dose 15 or 5 mg Dox eq./kg. Method of tumor initialization (acute or chronic experimental tumor models) significantly influenced effectiveness of the treatment with much lower success in treatment of mice bearing chronic tumors.

• MeSH
• akrylamidy chemie   MeSH
• dendrimery chemie   MeSH
• doxorubicin aplikace a dávkování   chemie   farmakokinetika   MeSH
• koncentrace vodíkových iontů MeSH
• lékové transportní systémy MeSH
• léky s prodlouženým účinkem MeSH
• lymfom T-buněčný farmakoterapie   patologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nosiče léků chemie   MeSH
• protinádorová antibiotika aplikace a dávkování   chemie   farmakokinetika   MeSH
• rozpustnost MeSH
• tkáňová distribuce MeSH
• voda chemie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie 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.

• MeSH
• akrylamidy aplikace a dávkování   MeSH
• enbukrylát MeSH
• kontrastní látky aplikace a dávkování   MeSH
• krevní objem MeSH
• lékové transportní systémy * MeSH
• mikrobubliny MeSH
• myši nahé MeSH
• nádorové buněčné linie MeSH
• nádory krevní zásobení   metabolismus   patofyziologie   ultrasonografie   MeSH
• permeabilita MeSH
• regionální krevní průtok MeSH
• tomografie metody   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Synthesis, physicochemical behavior, tumor accumulation and preliminary anticancer activity of a new biodegradable graft copolymer-doxorubicin (DOX) conjugates designed for passive tumor targeting were investigated. In the graft high-molecular-weight conjugates the multivalent N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer was grafted with a similar but semitelechelic HPMA copolymer; both types of polymer chains were bearing doxorubicin attached by hydrazone bonds enabling intracellular pH-controlled drug release. The polymer grafts were attached to the main chain through spacers, degradable enzymatically or reductively, facilitating, after the drug release, intracellular degradation of the graft polymer carrier to short fragments excretable from the organism by glomerular filtration. The graft polymer-DOX conjugate exhibited prolonged blood circulation and enhanced tumor accumulation in tumor-bearing mice indicating the important role of the EPR effect in the anticancer activity. The graft polymer-DOX conjugates showed a significantly higher antitumor activity in vivo than DOX.HCl or the linear polymer conjugate when tested in mice bearing 38C13 B-cell or EL4 T-cell lymphoma, with a significant number of long-term-surviving (LTS) mice with EL4 T-cell lymphoma treated with a single dose 15 mg DOX equiv./kg on day 10.

• MeSH
• akrylamidy aplikace a dávkování   farmakokinetika   farmakologie   chemická syntéza   MeSH
• biologický transport MeSH
• buněčné linie MeSH
• doxorubicin aplikace a dávkování   farmakokinetika   farmakologie   chemická syntéza   MeSH
• farmaceutická chemie MeSH
• hydrolýza MeSH
• injekce intravenózní MeSH
• koncentrace vodíkových iontů MeSH
• léky s prodlouženým účinkem MeSH
• lymfom farmakoterapie   metabolismus   patologie   MeSH
• molekulová hmotnost MeSH
• myši inbrední C3H MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nosiče léků MeSH
• protinádorová antibiotika aplikace a dávkování   farmakokinetika   farmakologie   chemická syntéza   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

New biodegradable star polymer-doxorubicin (Dox) conjugates designed for passive tumor targeting were investigated and the present study described their synthesis, physico-chemical characterization, drug release and biodegradation. In the conjugates the core formed by poly(amido amine) (PAMAM) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers bearing doxorubicin attached by hydrazone bonds, which enabled intracellular pH-controlled drug release, or by a GFLG sequence, which was susceptible to enzymatic degradation. The controlled synthesis utilizing semitelechelic copolymer precursors facilitated preparation of biodegradable polymer conjugates in a broad range of molecular weights (110-295 kDa) while still maintaining low polydispersity (∼1.7). The polymer grafts were attached to the dendrimers either through stable amide bonds or enzymatically or reductively degradable spacers, which enabled intracellular degradation of the high molecular weight polymer carrier to products that were able to be excreted from the body by glomerular filtration. Biodegradability tests showed that the rate of degradation was much faster for reductively degradable conjugates (completed within 4 h) than the degradation of conjugates linked via an enzymatically degradable oligopeptide GFLG sequence (within 72 h). This finding was likely due to the difference in steric hindrance for the small molecule glutathione and the enzyme cathepsin B. As for drug release, the conjugates were fairly stable in buffer at pH 7.4 (model of blood stream) but released doxorubicin either under mild acidic conditions or in the presence of lysosomal enzyme cathepsin B, both of which modeled the tumor cell microenvironment.

• MeSH
• biokompatibilní materiály chemická syntéza   chemie   MeSH
• dendrimery chemie   MeSH
• doxorubicin aplikace a dávkování   chemie   MeSH
• methakryláty chemie   MeSH
• molekulární struktura MeSH
• nosiče léků chemická syntéza   chemie   MeSH
• protinádorová antibiotika aplikace a dávkování   chemie   MeSH
• rozpustnost MeSH
• stabilita léku MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Expozice pasivnímu kouření je prokazatelným zdravotním rizikem, zejména pro děti, které jsou k účinkům škodlivin vnímavější než dospělí. Legislativní opatření chránící nekuřáky formou zákazů kouření na veřejných místech se míjejí účinkem u dětí, které jsou nejvíce exponovány ve svých domovech, případně v osobních autech. Proto je nutné zvýšit edukační činnost ve společnosti i u jednotlivců zaměřenou na ochranu dětí před expozicí kuřákům. V některých zemích se rozvíjí aktivní poradenství zdravotníků v rodinách nemocných dětí a programy "Smoke-free homes" s různou efektivitou. V České republice zahrnují školní programy výchovy k nekouření i působení na rodiče, aby chránili děti před expozicí pasivnímu kouření. Výsledky jsou zatím spíše rozpačité: chybí politická vůle podporovat intenzivně omezování tabakismu a společnost je ke konzumaci legálních drog tolerantní.

Exposure to passive smoking has been recognized as serious health hazard, especially for children who are more vulnerable than adults to the damage caused by chemicals. Legislation restricting smoking in public places cannot protect children as they are primarily exposed in their homes and/or cars. Therefore, it is necessary to improve both public and individual health education concerned with protection of children against exposure to tobacco smoke. In some countries, the active advice services by health professionals are targeted on families with ailing children and "Smoke-free homes" programmes are being developed. In the Czech Republic, school-based educational anti-smoking programmes address parental interest in protecting children against passive smoking. The results so for have been ambiguous: there is a lack of intensive political support of tobacco control and society tolerates the consumption of legal drugs.

• Klíčová slova
• možnosti ochrany dětí,
• MeSH
• dítě MeSH
• financování organizované MeSH
• inhalační expozice prevence a kontrola   škodlivé účinky   MeSH
• kouření psychologie   škodlivé účinky   MeSH
• lidé MeSH
• ochrana práv dítěte MeSH
• postoj ke zdraví MeSH
• zdraví rodiny MeSH
• znečištění tabákovým kouřem prevence a kontrola   škodlivé účinky   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH

Controlled radical reversible addition-fragmentation chain transfer (RAFT) polymerisation was used to prepare water-soluble polymer-drug carriers based on copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) with a hydrazide group-containing monomer, showing well-defined structure with narrow molecular weight distribution (approx. 1.1-1.2). The anticancer therapeutic doxorubicin was bound to the polymeric carrier by a hydrazone bond, enabling pH-controlled release under mildly acid conditions that mimics the environment in endosomes/lysosomes of tumour cells. RAFT polymerisation facilitated the synthesis of semitelechelic copolymers, which were used in the synthesis of monoclonal anti-CD20 antibody-polymer-drug conjugate designed for cell-specific tumour targeting. They were also used for producing a biodegradable high-molecular-weight graft polymer-drug conjugate that degrade in the presence of glutathione, which is designed for passive targeting to solid tumours. The conjugates exhibited well-defined structures with narrow molecular weight distributions of approx. 1.3 and pH-controlled drug release.

• MeSH
• akrylamidy chemie   MeSH
• doxorubicin chemie   farmakologie   MeSH
• kinetika MeSH
• koncentrace vodíkových iontů MeSH
• lékové transportní systémy metody   MeSH
• molekulární struktura MeSH
• monoklonální protilátky MeSH
• nosiče léků chemie   MeSH
• polymerizace MeSH
• protinádorová antibiotika chemie   farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In recent years, polymer drug carriers based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers with pH-triggered drug release have shown enhanced uptake in solid tumors and excellent antitumor activity. Here, the impact of the structure of the acid-labile spacer between the drug and the polymer carrier on the biodistribution of both the drug and the carrier was studied using in vivo noninvasive multispectral optical imaging of dual fluorescently labeled HPMA copolymers. Five different spacers containing a pH-sensitive hydrazone bond were synthesized and used to combine a fluorescent model drug with a polymer backbone, conjugated with another non-releasable fluorescent dye. Two copolymers differing in polymer chain structure (linear and star-like) and molecular weight (30 and 200kDa) were used to distinguish between carriers with molecular weights above and below the limit for renal filtration. The rate of model drug release from the conjugates was determined in vitro. The biodistributions of the six most promising conjugates were investigated in vivo in athymic nude mice inoculated with human colon carcinoma xenograft. The structure of the spacer in the vicinity of the hydrazone bond significantly influenced the release rate of the model drug. The slow release rate of a pyridyl group bearing spacer resulted in a greater amount of the model drug being transported to the tumor, which was independent of the carrier structure. The results of this study emphasize the importance of careful selection of the structure and appropriate spacer when designing polymer conjugates intended for passive tumor targeting.

• MeSH
• akrylamidy analýza   MeSH
• fluorescenční barviva aplikace a dávkování   farmakokinetika   MeSH
• indoly aplikace a dávkování   farmakokinetika   MeSH
• karbocyaniny aplikace a dávkování   farmakokinetika   MeSH
• koncentrace vodíkových iontů MeSH
• léky s prodlouženým účinkem analýza   MeSH
• lidé MeSH
• molekulární modely MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory tračníku farmakoterapie   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

With a growing health threat of bacterial resistance to antibiotics, the nanomaterials have been extensively studied as an alternative. It is assumed that antimicrobial nanomaterials can affect bacteria by several mechanisms simultaneously and thereby overcome antibiotic resistance. Another promising potential use is employing nanomaterials as nanocarriers for antibiotics in order to overcome bacterial defense mechanisms. The passive targeting of nanomaterials is the often used strategy for bacterial treatment, including intracellular infections of macrophages. Furthermore, the specific targeting enhances the efficacy of antimicrobials and reduces side effects. This review aims to discuss advantages, disadvantages, and challenges of nanomaterials in the context of the targeting strategies for antimicrobials as advanced tools for treatments of bacterial infections. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease.

• MeSH
• antiinfekční látky * MeSH
• bakteriální infekce farmakoterapie   MeSH
• bakteriální léková rezistence MeSH
• lidé MeSH
• nanomedicína MeSH
• nanostruktury * MeSH
• objevování léků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Non-target analysis (NTA) employing high-resolution mass spectrometry is a commonly applied approach for the detection of novel chemicals of emerging concern in complex environmental samples. NTA typically results in large and information-rich datasets that require computer aided (ideally automated) strategies for their processing and interpretation. Such strategies do however raise the challenge of reproducibility between and within different processing workflows. An effective strategy to mitigate such problems is the implementation of inter-laboratory studies (ILS) with the aim to evaluate different workflows and agree on harmonized/standardized quality control procedures. Here we present the data generated during such an ILS. This study was organized through the Norman Network and included 21 participants from 11 countries. A set of samples based on the passive sampling of drinking water pre and post treatment was shipped to all the participating laboratories for analysis, using one pre-defined method and one locally (i.e. in-house) developed method. The data generated represents a valuable resource (i.e. benchmark) for future developments of algorithms and workflows for NTA experiments.

• MeSH
• algoritmy MeSH
• benchmarking * MeSH
• hmotnostní spektrometrie * MeSH
• laboratoře MeSH
• pitná voda analýza   MeSH
• průběh práce MeSH
• Publikační typ
• časopisecké články MeSH
• dataset MeSH
• práce podpořená grantem MeSH

The concentrations of seven perfluoroalkyl substances (PFASs) were investigated in 36 European chub (Squalius cephalus) individuals from six localities in the Czech Republic. Chub muscle and liver tissue were analysed at all sampling sites. In addition, analyses of 16 target PFASs were performed in Polar Organic Chemical Integrative Samplers (POCISs) deployed in the water at the same sampling sites. We evaluated the possibility of using passive samplers as a standardized method for monitoring PFAS contamination in aquatic environments and the mutual relationships between determined concentrations. Only perfluorooctane sulphonate was above the LOQ in fish muscle samples and 52% of the analysed fish individuals exceeded the Environmental Quality Standard for water biota. Fish muscle concentration is also particularly important for risk assessment of fish consumers. The comparison of fish tissue results with published data showed the similarity of the Czech results with those found in Germany and France. However, fish liver analysis and the passive sampling approach resulted in different fish exposure scenarios. The total concentration of PFASs in fish liver tissue was strongly correlated with POCIS data, but pollutant patterns differed between these two matrices. The differences could be attributed to the metabolic activity of the living organism. In addition to providing a different view regarding the real PFAS cocktail to which the fish are exposed, POCISs fulfil the Three Rs strategy (replacement, reduction, and refinement) in animal testing.

• MeSH
• chemické látky znečišťující vodu analýza   MeSH
• Cyprinidae metabolismus   MeSH
• fluorokarbony analýza   MeSH
• játra chemie   MeSH
• kyseliny alkansulfonové analýza   MeSH
• monitorování životního prostředí metody   MeSH
• svaly chemie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH