Polymer carriers based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers with incorporated organic nitrates as nitric oxide (NO) donors were designed with the aim to localise NO generation in solid tumours, thus highly increasing the enhanced permeability and retention (EPR) effect. The NO donors were coupled to the polymer carrier either through a stable bond or through a hydrolytically degradable, pH sensitive, bond. In vivo, the co-administration of the polymer NO donor and HPMA copolymer-bound cytotoxic drug (doxorubicin; Dox) resulted in an improvement in the treatment of murine EL4 T-cell lymphoma. The polymer NO donors neither potentiated the in vitro toxicity of the cytotoxic drug nor exerted any effect on in vivo model without the EPR effect, such as BCL1 leukaemia. Thus, an increase in passive accumulation of the nanomedicine carrying cytotoxic drug via NO-enhanced EPR effect was the operative mechanism of action. The most significant improvement in the therapy was observed in a combination treatment with such a polymer conjugate of Dox, which is characterised by increased circulation in the blood and efficient accumulation in solid tumours. Notably, the combination treatment enabled the development of an anti-tumour immune response, which was previously demonstrated as an important feature of HPMA-based polymer cytotoxic drugs.

• Klíčová slova
• Drug delivery, EL4 lymphoma, HPMA copolymers, anti-tumour immune response, enhanced EPR effect, polymer NO donor, polymer cytotoxic drugs, solid tumour treatment,
• MeSH
• antitumorózní látky aplikace a dávkování   metabolismus   MeSH
• donory oxidu dusnatého aplikace a dávkování   metabolismus   MeSH
• experimentální nádory farmakoterapie   metabolismus   patologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nanočástice aplikace a dávkování   metabolismus   MeSH
• nosiče léků aplikace a dávkování   metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• polymery aplikace a dávkování   metabolismus   MeSH
• tumor burden účinky léků   fyziologie   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky MeSH
• donory oxidu dusnatého MeSH
• nosiče léků MeSH
• oxid dusnatý MeSH
• polymery MeSH

INTRODUCTION: Fine needle aspiration biopsy (FNAB) is an easy method with an option of repetitive withdrawal of cell material. METHODS: First, mice were inoculated with mouse T-lymphoma, after 10 d the samples from tumor, lymph nodes and spleen gained by FNAB and excision were analyzed by flow cytometry. Tumor progression was compared to the control group simultaneously. Then, 10 d after tumor cell inoculation free doxorubicin (DOX) or different PHPMA DOX conjugates were injected. Cell material was analyzed to detect subpopulations of lymphocyte infiltrate, and levels of cytokines in correlation with progression or regression of the disease. RESULTS: FNAB has no influence on the tumor's growth or survival of experimental animals. After treatment with PHPMA conjugates there was a significant increase of T-lymphocyte subpopulations in tumor microenvironment compared to controls or free DOX, but only in mice with confirmed macroscopic regression of tumor within two weeks. Mice treated with conjugates showed significantly lower cancer infiltration of lymph nodes and spleen. CONCLUSION: FNAB provides a great benefit to in vivo monitoring of cell changes directly in the tumor after treatment. The number of infiltrating T-lymphocytes increases in correlation with consecutive tumor eradication after treatment with PHPMA. This proves that not only direct cytotoxic but also imunostimulating effect are necessary for successful treatment.

• MeSH
• antitumorózní látky aplikace a dávkování   chemie   terapeutické užití   MeSH
• doxorubicin aplikace a dávkování   chemie   terapeutické užití   MeSH
• experimentální nádory farmakoterapie   patologie   MeSH
• jehlová biopsie * MeSH
• kyseliny polymethakrylové chemie   MeSH
• metastázy nádorů * MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• proliferace buněk * MeSH
• T-lymfocyty patologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• doxorubicin MeSH
• Duxon MeSH Prohlížeč
• kyseliny polymethakrylové MeSH

Pharmacotherapy during pregnancy is often inevitable for medical treatment of the mother, the fetus or both. The knowledge of drug transport across placenta is, therefore, an important topic to bear in mind when deciding treatment in pregnant women. Several drug transporters of the ABC and SLC families have been discovered in the placenta, such as P-glycoprotein, breast cancer resistance protein, or organic anion/cation transporters. It is thus evident that the passage of drugs across the placenta can no longer be predicted simply on the basis of their physical-chemical properties. Functional expression of placental drug transporters in the trophoblast and the possibility of drug-drug interactions must be considered to optimize pharmacotherapy during pregnancy. In this review we summarize current knowledge on the expression and function of ABC and SLC transporters in the trophoblast. Furthermore, we put this data into context with medical conditions that require maternal and/or fetal treatment during pregnancy, such as gestational diabetes, HIV infection, fetal arrhythmias and epilepsy. Proper understanding of the role of placental transporters should be of great interest not only to clinicians but also to pharmaceutical industry for future drug design and development to control the degree of fetal exposure.

• MeSH
• ABC transportéry metabolismus   MeSH
• biologický transport MeSH
• komplikace těhotenství farmakoterapie   patofyziologie   MeSH
• léčivé přípravky aplikace a dávkování   metabolismus   MeSH
• lékové interakce MeSH
• lidé MeSH
• maternofetální výměna látek fyziologie   MeSH
• membránové transportní proteiny metabolismus   MeSH
• placenta metabolismus   MeSH
• racionální návrh léčiv MeSH
• těhotenství MeSH
• trofoblasty metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• ABC transportéry MeSH
• léčivé přípravky MeSH
• membránové transportní proteiny MeSH

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
• antibiotika antitumorózní aplikace a dávkování   chemie   farmakokinetika   MeSH
• dendrimery chemie   MeSH
• doxorubicin aplikace a dávkování   chemie   farmakokinetika   MeSH
• koncentrace vodíkových iontů MeSH
• léky s prodlouženým účinkem MeSH
• lymfom T-buněčný farmakoterapie   patologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nosiče léků chemie   MeSH
• rozpustnost MeSH
• systémy cílené aplikace léků * 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
• Názvy látek
• akrylamidy MeSH
• antibiotika antitumorózní MeSH
• dendrimery MeSH
• doxorubicin MeSH
• léky s prodlouženým účinkem MeSH
• N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
• nosiče léků MeSH
• PAMAM Starburst MeSH Prohlížeč
• voda MeSH

We have investigated the effects of low-frequency pulsed electromagnetic field (LF-EMF) produced by BEMER device on experimental mouse T-cell lymphoma EL4 growing on conventional and/or athymic (nude) mice. Exposure to EMF-BEMER slowed down the growth of tumor mass and prolonged the survival of experimental animals. The effect was more pronounced in immuno-compromised nude mice compared to conventional ones. Acceleration of tumor growth was never observed. No measurable levels of Hsp 70 or increased levels of specific anti-EL4 antibodies were detected in the serum taken from experimental mice before and at different intervals during the experiment, i.e. before solid tumor appeared, at the time of its aggressive growth, and at the terminal stage of the disease. A significant synergizing antitumor effect was seen when EL4 tumor-bearing mice were simultaneously exposed to EMF-BEMER and treated with suboptimal dose of synthetic HPMA copolymer-based doxorubicin, DOX(HYD)-HPMA. Such a combination may be especially useful for heavily treated patients suffering from advanced tumor and requiring additional aggressive chemotherapy which, however, at that time could represent almost life-threatening way of medication.

• MeSH
• antibiotika antitumorózní aplikace a dávkování   farmakologie   MeSH
• doxorubicin aplikace a dávkování   analogy a deriváty   farmakologie   MeSH
• elektromagnetická pole * MeSH
• hostitel s imunodeficiencí MeSH
• kombinovaná terapie MeSH
• kyseliny polymethakrylové aplikace a dávkování   farmakologie   MeSH
• lymfom T-buněčný patologie   terapie   MeSH
• míra přežití MeSH
• myši inbrední C57BL MeSH
• myši nahé MeSH
• myši MeSH
• proteiny tepelného šoku HSP70 metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antibiotika antitumorózní MeSH
• doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate MeSH Prohlížeč
• doxorubicin MeSH
• kyseliny polymethakrylové MeSH
• proteiny tepelného šoku HSP70 MeSH

Synthesis and characterization of N-(2-hydroxypropyl)methacrylamide (HPMA)-copolymer-based drug carriers targeted on specific receptors in the membrane of endothelial cells by oligopeptides (GRGDG, cyclo(RGDfK), and PHSCN) are described in this study. The copolymers containing targeting oligopeptides bound to the polymer via dodeca(ethylene glycol) spacer showed a receptor-specific time-dependent uptake with selected endothelial cell lines. The polymers were labeled with a fluorescent dye to enable monitoring of the interaction of the polymer conjugate with cells using fluorescence microscopy. Cellular uptake and apoptosis induction have been studied in vitro using various cell lines (EA.hy926, 3T3, SW620, and EL4). In vivo accumulation of the conjugate specifically targeted with cyclo(RGDfK) within the tumor vasculature was detected using fluorescence intravital microscopy in mice. The conjugate targeted by cyclo(RGDfK) was accumulated preferentially in the periphery of the growing tumor suggesting that the cyclo(RGDfK) peptide targets the polymer conjugate to the site of neoangiogenesis, rather than to the tumor mass.

• MeSH
• akrylamidy chemie   MeSH
• apoptóza účinky léků   MeSH
• buněčné linie MeSH
• časové faktory MeSH
• cévní endotel metabolismus   patologie   MeSH
• fluorescenční mikroskopie MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   patologie   MeSH
• oligopeptidy aplikace a dávkování   chemická syntéza   farmakokinetika   MeSH
• patologická angiogeneze MeSH
• systémy cílené aplikace léků * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akrylamidy MeSH
• N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
• oligopeptidy MeSH

Polymeric conjugates based on N-(2-hydroxypropyl)methacrylamide (HPMA) have been tested as potential carrier for anticancer drug - doxorubicin (Dox). Two types of conjugates were synthesized: (a) conjugates containing Dox bound through an amidic bond to an oligopeptidic side-chain (usually GFLG) and (b) hydrolytically cleavable conjugates wherein Dox is bound to the polymeric carrier through a pH sensitive bond. The mechanism of action of both conjugates is different and reflects the diverse way and intensity of their intracellular accumulation. All conjugates containing doxorubicin bound via an amidic bond directly penetrate the plasma membrane and are detectable in all associated cellular membranes, i.e. membranes of the endocytic compartment, a nuclear membrane as well as membranes of Golgi and endoplasmic reticulum. We have never been able to detect released doxorubicin inside the nuclei of the treated cells. The cytotoxicity of these conjugates seems to be primarily caused by the damage of cellular membranes. Necrosis is the main mechanism of the cell death. Conjugates containing hydrolytically bound doxorubicin are internalized by endocytosis and fluid phase pinocytosis and doxorubicin is cleaved from the polymeric carrier at low pH in late endosomes and lysosomes. An apoptosis is the main mechanism of the cell death. The spacer influences the rate of the intracellular release of the drug rather than the rate of internalization.

• MeSH
• akrylamidy chemie   MeSH
• antibiotika antitumorózní chemie   farmakokinetika   farmakologie   MeSH
• buněčná membrána chemie   účinky léků   metabolismus   MeSH
• buněčné jádro účinky léků   metabolismus   MeSH
• buňky 3T3 MeSH
• dextrany chemie   metabolismus   MeSH
• doxorubicin chemie   farmakokinetika   farmakologie   MeSH
• endocytóza fyziologie   MeSH
• endoplazmatické retikulum účinky léků   metabolismus   MeSH
• fluorescenční mikroskopie MeSH
• Golgiho aparát účinky léků   metabolismus   MeSH
• heterocyklické sloučeniny tetra- a více cyklické chemie   metabolismus   MeSH
• intracelulární tekutina metabolismus   MeSH
• lidé MeSH
• lyzozomy účinky léků   metabolismus   MeSH
• methanol farmakologie   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• pinocytóza fyziologie   MeSH
• proliferace buněk účinky léků   MeSH
• průtoková cytometrie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akrylamidy MeSH
• antibiotika antitumorózní MeSH
• dextrany MeSH
• doxorubicin MeSH
• heterocyklické sloučeniny tetra- a více cyklické MeSH
• methanol MeSH
• N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
• vacuolin-1 MeSH Prohlížeč

The paper is dealing with the synthesis and properties of new non-targeted or antibody-targeted polymer drug conjugates, bearing doxorubicin (DOX) attached via a spacer susceptible to pH-controlled hydrolysis (hydrazone conjugates), designed as anticancer drugs facilitating site-specific therapy. These conjugates are stable in a pH 7.4 buffer, modeling conditions during transport in the body, but release DOX and activate it inside target cells as a result of pH changes when going from outside to inside the cells. Conjugates containing an antibody directed against T lymphocytes bind effectively and specifically T cell lymphoma EL 4 cells. Cytotoxicity of the hydrazone conjugates is higher than that of classic conjugates, depending on the detailed structure of the polymer, the spacer between the drug and polymer carrier and method of antibody conjugation. Cytotoxicity of some of the conjugates is comparable even with that of the free drug. In both protective and therapeutic regimes of drug administration, the in vivo anti-tumor activity of the conjugates containing DOX was enhanced with long-term survivors (T-cell lymphoma EL 4, C57BL/6 mice) in comparison with much less effective free DOX or a classic P(N-(2-hydroxypropyl)methacrylamide)HPMA-DOX conjugate (already clinically tested).

• MeSH
• antilymfocytární sérum aplikace a dávkování   MeSH
• antitumorózní látky aplikace a dávkování   chemie   MeSH
• chemie farmaceutická MeSH
• doxorubicin aplikace a dávkování   chemie   MeSH
• koncentrace vodíkových iontů MeSH
• léky antitumorózní - screeningové testy metody   MeSH
• lymfom T-buněčný farmakoterapie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• polymery aplikace a dávkování   chemie   MeSH
• systémy cílené aplikace léků metody   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• antilymfocytární sérum MeSH
• antitumorózní látky MeSH
• doxorubicin MeSH
• polymery MeSH

Recently hydrophilic poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) was used for BS-RNase modification to prevent its degradation in bloodstream or fast elimination. Polymer-conjugated BS-RNase preparations proved to be cytotoxic after intravenous or intraperitoneal application, whereas native BS-RNase was ineffective. Here RNase A unimer was conjugated with two HPMA polymers (classic and star) and their antitumor effects both in vitro and in vivo were compared with those of BS-RNase polymers. Surprisingly, the antitumor effect of RNase A conjugates was also pronounced. The RNase A conjugates (classic and star) injected intravenously to mice bearing melanoma tumor caused a significant reduction in tumor volume following ten doses of 5 and 1 mg/kg, respectively. Despite the antitumor activity observed in vivo, the in vitro tested cytotoxic activity of RNase A did not differ from that caused by native RNase A while native BS-RNase (50 microg/ml) totally inhibited DNA synthesis in treated cells. The experiments with 125I-labeled preparations demonstrated concentration-dependent internalization of native BS-RNase by tumor cells within an hour, whereas the polymer conjugate (S-BS) was not internalized. On the contrary, the in vivo experiments showed that whereas 40% of S-BS conjugate persisted in bloodstream for 24h after administration, 98% of the native BS-RNase was already eliminated. Improved antitumor activities of PHPMA-modified RNases in vivo might be ascribed to their prolonged retention in bloodstream, better proteolytic stability and resistance to the action of the ribonuclease inhibitor.

• MeSH
• antitumorózní látky aplikace a dávkování   chemie   terapeutické užití   MeSH
• endoribonukleasy aplikace a dávkování   chemie   terapeutické užití   MeSH
• injekce intraperitoneální MeSH
• injekce intravenózní MeSH
• konformace proteinů MeSH
• kyseliny polymethakrylové aplikace a dávkování   chemie   MeSH
• lidé MeSH
• lymfocyty metabolismus   MeSH
• melanom experimentální farmakoterapie   patologie   MeSH
• molekulární struktura MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buňky kultivované metabolismus   MeSH
• nosiče léků MeSH
• pankreatická ribonukleasa aplikace a dávkování   chemie   terapeutické užití   MeSH
• radioizotopy jodu MeSH
• skot MeSH
• vazebná místa fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• způsoby aplikace léků MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• skot MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• Duxon MeSH Prohlížeč
• endoribonukleasy MeSH
• kyseliny polymethakrylové MeSH
• nosiče léků MeSH
• pankreatická ribonukleasa MeSH
• radioizotopy jodu MeSH
• ribonuclease SPL MeSH Prohlížeč

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers containing the anticancer agent doxorubicin and targeted to the transferrin receptor either with anti-mouse CD71 monoclonal antibody (mAb) or with transferrin were synthesized to evaluate their binding and anti-proliferative activity in vitro and anti-tumor potential against 38C13 B-cell lymphoma in vivo. Both the doxorubicin and the targeting moieties were bound to HPMA copolymer chain by aminolysis via a Gly-Phe(D,L)-Leu-Gly spacer to ensure controlled intracellular release of the conjugated drug. We demonstrated that HPMA copolymer-bound doxorubicin targeted to the transferrin receptor with anti-mouse CD71 mAb strongly retards tumor growth, prolongs the survival and completely cures three out of nine experimental mice with established 38C13 tumors. The conjugate targeted with transferrin was less effective in vitro as well as in vivo. It completely cured only one out of seven experimental mice. Free or non-targeted HPMA copolymer-bound doxorubicin showed only a mild anti-tumor effect within the therapeutic schedule used. In vitro, HPMA copolymer-bound doxorubicin targeted with anti-mouse CD71 mAb shows approximately 4-fold higher cytotoxic effect than HPMA copolymer-bound doxorubicin targeted with transferin and 9-fold higher cytotoxic effect than non-targeted HPMA copolymer-bound doxorubicin.

• MeSH
• antibiotika antitumorózní aplikace a dávkování   chemie   farmakologie   MeSH
• B-buněčný lymfom metabolismus   MeSH
• biotin chemie   MeSH
• buněčné dělení MeSH
• doxorubicin aplikace a dávkování   chemie   farmakologie   MeSH
• indikátory a reagencie MeSH
• ligandy MeSH
• methakryláty chemie   MeSH
• monoklonální protilátky aplikace a dávkování   chemie   MeSH
• myši inbrední C3H MeSH
• myši MeSH
• průtoková cytometrie MeSH
• receptory transferinu účinky léků   metabolismus   MeSH
• transferin aplikace a dávkování   chemie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibiotika antitumorózní MeSH
• biotin MeSH
• doxorubicin MeSH
• hydroxypropyl methacrylate MeSH Prohlížeč
• indikátory a reagencie MeSH
• ligandy MeSH
• methakryláty MeSH
• monoklonální protilátky MeSH
• receptory transferinu MeSH
• transferin MeSH