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.
- 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
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
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
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
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
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 farmakokinetika chemická syntéza MeSH
- patologická angiogeneze MeSH
- systémy cílené aplikace léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- antilymfocytární sérum aplikace a dávkování MeSH
- antitumorózní látky aplikace a dávkování MeSH
- doxorubicin aplikace a dávkování chemie MeSH
- finanční podpora výzkumu jako téma MeSH
- myši MeSH
- polymery aplikace a dávkování chemie MeSH
- systémy cílené aplikace léků metody MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- MeSH
- antibakteriální látky aplikace a dávkování farmakologie chemie MeSH
- antracykliny MeSH
- B-buněčný lymfom metabolismus MeSH
- doxorubicin aplikace a dávkování farmakologie chemie MeSH
- methakryláty chemie MeSH
- monoklonální protilátky aplikace a dávkování chemie MeSH
- myši MeSH
- receptory transferinu metabolismus účinky léků MeSH
- transferin aplikace a dávkování chemie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- MeSH
- antitumorózní látky terapeutické užití MeSH
- kyseliny polymethakrylové aplikace a dávkování MeSH
- lidé MeSH
- melanom experimentální farmakoterapie MeSH
- pankreatická ribonukleasa aplikace a dávkování chemie terapeutické užití MeSH
- ribonukleasa H terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
