Burst drug release is often considered a negative phenomenon resulting in unexpected toxicity or tissue irritation. Optimal release of a highly soluble active pharmaceutical ingredient (API) from hypromellose (HPMC) matrices is technologically impossible; therefore, a combination of polymers is required for burst effect reduction. Promising variant could be seen in combination of HPMC and insoluble Eudragits® as water dispersions. These can be applied only on API/insoluble filler mixture as over-wetting prevention. The main hurdle is a limited water absorption capacity (WAC) of filler. Therefore, the object of this study was to investigate the dissolution behavior of levetiracetam from HPMC/Eudragit®NE matrices using magnesium aluminometasilicate (Neusilin® US2) as filler with excellent WAC. Part of this study was also to assess influence of thermal treatment on quality parameters of matrices. The use of Neusilin® allowed the application of Eudragit® dispersion to API/Neusilin® mixture in one step during high-shear wet granulation. HPMC was added extragranularly. Obtained matrices were investigated for qualitative characteristics, NMR solid-state spectroscopy (ssNMR), gel layer dynamic parameters, SEM, and principal component analysis (PCA). Decrease in burst effect (max. of 33.6%) and dissolution rate, increase in fitting to zero-order kinetics, and paradoxical reduction in gel layer thickness were observed with rising Eudragit® NE concentration. The explanation was done by ssNMR, which clearly showed a significant reduction of the API particle size (150-500 nm) in granules as effect of surfactant present in dispersion in dependence on Eudragit®NE amount. This change in API particle size resulted in a significantly larger interface between these two entities. Based on ANOVA and PCA, thermal treatment was not revealed as a useful procedure for this system.
- MeSH
- aplikace orální MeSH
- gely MeSH
- kyseliny polymethakrylové aplikace a dávkování chemie metabolismus MeSH
- léky s prodlouženým účinkem aplikace a dávkování chemie metabolismus MeSH
- magnetická rezonanční spektroskopie metody MeSH
- pomocné látky chemie MeSH
- rozpustnost MeSH
- silikáty aplikace a dávkování chemie metabolismus MeSH
- sloučeniny hliníku aplikace a dávkování chemie metabolismus MeSH
- sloučeniny hořčíku aplikace a dávkování chemie metabolismus MeSH
- uvolňování léčiv MeSH
- velikost částic MeSH
- Publikační typ
- časopisecké články MeSH
Nanomedicines have provided fresh impetus in the fight against cancer due to their selectivity and power. However, these agents are limited when delivered intravenously due to their rapid clearance from the bloodstream and poor passage from the bloodstream into target tumours. Here we describe a novel stealthing strategy which addresses both these limitations and thereby demonstrate that both the passive and mechanically-mediated tumour accumulation of the model nanomedicine adenovirus (Ad) can be substantially enhanced. In our strategy gold nanoparticles were thoroughly modified with 2kDa polyethyleneglycol (PEG) and then linked to Ad via a single reduction-cleavable 5kDa PEG. The resulting Ad-gold-PEG construct was compared to non-modified Ad or conventionally stealthed Ad-poly[N-(2-hydroxypropyl)methacrylamide] (Ad-PHPMA). Notably, although Ad-gold-PEG was of similar size and surface charge to Ad-PHPMA the increase in density, resulting from the inclusion of the gold nanoparticles, provided a substantial enhancement of ultrasound-mediated transport. In an in vitro tumour mimicking phantom, the level and distance of Ad-gold-PEG transport was shown to be substantially greater than achieved with Ad-PHPMA. In in vivo studies 0.1% of an unmodified Ad dose was shown to accumulate in tumours, whereas over 12% of the injected dose was recovered from the tumours of mice treated with Ad-gold-PEG and ultrasound. Ultimately, a significant increase in anti-tumour efficacy resulted from this strategy. This stealthing and density-increasing technology could ultimately enhance clinical utility of intravenously delivered nanoscale medicines including viruses, liposomes and antibodies.
- MeSH
- Adenoviridae genetika MeSH
- játra metabolismus MeSH
- kovové nanočástice * aplikace a dávkování chemie MeSH
- kyseliny polymethakrylové aplikace a dávkování chemie MeSH
- lidé MeSH
- myši inbrední BALB C MeSH
- myši nahé MeSH
- nádorové buněčné linie MeSH
- nádory metabolismus terapie MeSH
- nanomedicína MeSH
- onkolytická viroterapie MeSH
- polyethylenglykoly * aplikace a dávkování chemie MeSH
- ultrazvuk MeSH
- zelené fluorescenční proteiny genetika MeSH
- zlato * aplikace a dávkování chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Treatment of murine EL4 T cell lymphoma with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates of doxorubicin (Dox) leads to complete tumor regression and to the development of therapy-dependent longlasting cancer resistance. This phenomenon occurs with two types of Dox conjugates tested, despite differences in the covalent linkage of Dox to the polymer carrier. Such a cancer resistance cannot fully express in conventional treatment with free Dox, due to substantial immunotoxicity of the treatment, which was not observed in the polymer conjugates. In this study, calreticulin (CRT) translocation and high mobility group box-1 protein (HMGB1) release was observed in EL4 cells treated with a conjugate releasing Dox by a pH-dependent manner. As a result, the treated tumor cells were engulfed by dendritic cells (DC) in vitro, and induced their expression of CD80, CD86, and MHC II maturation markers. Conjugates with Dox bound via an amide bond only increased translocation of HSPs to the membrane, which led to an elevated phagocytosis but was not sufficient to induce increase of the maturation markers on DCs in vitro. Both types of conjugates induced engulfment of the target tumor cells in vivo, that was more intense than that seen with free Dox. It means that the induction of anti-tumor immunity documented upon treatment of EL4 lymphoma with HPMA-bound Dox conjugates does not rely solely on CRT-mediated cell death, but involves multiple mechanisms.
- MeSH
- antigeny CD80 metabolismus MeSH
- antigeny CD86 metabolismus MeSH
- antitumorózní látky aplikace a dávkování chemie toxicita MeSH
- apoptóza účinky léků MeSH
- chemorezistence účinky léků MeSH
- dendritické buňky cytologie imunologie MeSH
- doxorubicin aplikace a dávkování analogy a deriváty chemie toxicita MeSH
- fagocytóza MeSH
- kalretikulin metabolismus MeSH
- koncentrace vodíkových iontů MeSH
- kyseliny polymethakrylové aplikace a dávkování chemie toxicita MeSH
- lymfom T-buněčný farmakoterapie imunologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nosiče léků chemie MeSH
- protein HMGB1 metabolismus MeSH
- proteiny tepelného šoku metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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
Coated hard capsules are becoming increasingly important for a number of reasons such as administration of new active ingredients, oral vaccination, colon drug delivery or their use in preclinical and clinical trials. The independency of coating composition on capsules filling is the major advantage of this dosage form. In our study, two types of hard capsules (gelatin and hypromellose) were coated by non-aqueous solutions of Eudragit L and S 12.5, respectively, to achieve intestinal and distal ileic drug delivery. Gelatin hard capsules were coated with Eudragit film either directly or using hydroxypropyl cellulose sub-coating prior to the final coating. Hypromellose capsules were coated directly. Coated capsules were evaluated for coating thickness by optical microscope and for dissolution in different pH media. Gelatin capsules do not seem to be suitable for direct coating with Eudragit due to insufficient film adhesion to the smooth capsule surface and a brittleness of formed films. These problems can be solved by hydroxypropyl celullose interlayer application. Hypromellose hard capsules could be directly easily coated with both Eudragit solutions. Dissolution of caffeine from coated capsules showed the potency for enteric delivery in gelatin capsules with interlayer and Eudragit L film in 7.5 and 10.0% concentrations and in hypromellose capsules coated with EudragitL in 5-17.5% coating levels. Gelatine capsules with interlayer and 10% Eudragit S film and hypromellose capsules only with high coating level (20%) provided potential distal ileum targeting of incorporated drug. Eudragit S film sprayed onto hypromellose capsules surface was brittle especially in the junction zone between capsule cap and body. Better plasticity of Eudragit S coating could be probably achieved using a different plasticizer.
This paper reviews an early clinical experience with anthracycline (epirubicin; Epi or doxorubicin; Dox) containing an N-(2-hydroyxypropyl)methacrylamide copolymer carrier targeted with autologous or commercial human immunoglobulin in six patients aged 28-55 suffering from therapy-resistant metastatic cancer. More than 100 biochemical, hematological and immunological parameters, including nine tumor markers, were tested in blood samples taken 24 h after the first and up to 10 months after the last application. The intravenous application proceeded without serious adverse or side effects and did not require hospitalization. Cardiotoxicity was not observed. Four of six monitored patients attained stabilization of disease (liver ultrasound scan and bone computer tomography) with a very good quality of life lasting from seven up to 18 months. Positive response to the treatment was, among others, evaluated as decreased CA 15-3 and CEA tumor markers. In three of five tested patients the serum level of C-reactive protein was temporarily increased 72 h after the treatment. A stable or elevated number of peripheral blood reticulocytes together with activation of natural killer (NK) cells and lymphokine-activated killer (LAK) cells supports the data previously obtained in experimental animals pointing to a dual role, i.e. the cytotoxic and immunomobilizing character of doxorubicin-HPMA conjugates.
- MeSH
- akrylamidy MeSH
- antibiotika antitumorózní aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- chemorezistence MeSH
- dospělí MeSH
- doxorubicin analogy a deriváty aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- epirubicin aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- hemangiosarkom farmakoterapie MeSH
- imunoglobulin G aplikace a dávkování imunologie MeSH
- imunologické faktory aplikace a dávkování imunologie MeSH
- intravenózní imunoglobuliny aplikace a dávkování imunologie MeSH
- kvalita života MeSH
- kyseliny polymethakrylové aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů MeSH
- nádorové biomarkery krev MeSH
- nádory prsu farmakoterapie MeSH
- nosiče léků chemie MeSH
- systémy cílené aplikace léků MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Synthesis and preliminary anticancer activity of new star-shaped immunoglobulin-containing polymer-doxorubicin (DOX) conjugates were investigated. The polymer precursors used for the synthesis of immunoglobulin-polymer-drug conjugates are based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers, the anticancer drug DOX is attached to the immunoglobulin-modified polymer via a pH-sensitive hydrazone linkage. Such polymer-DOX conjugates are stable in aqueous solution at pH 7.4 (pH of blood plasma) and the drug is released in mildly acid environment at pH 5-5.5 (pH in endosomes or lysosomes of target cells). Semitelechelic copolymer chains are linked to the immunoglobulin via one-point attachment to avoid branching of the conjugate observed in our earlier studied systems. The cytostatic activity of the conjugates tested on several cancer cell lines was similar to that of free DOX.HCl and correlated with the sensitivity of a particular cell line to DOX. The star-shaped conjugates containing immunoglobulin showed a significantly higher antitumor activity in vivo than immunoglobulin-free non-targeted polymer conjugates when tested in mice bearing EL4 T-cell lymphoma.
- MeSH
- antibiotika antitumorózní aplikace a dávkování farmakologie chemie MeSH
- doxorubicin analogy a deriváty aplikace a dávkování farmakologie chemie MeSH
- financování organizované MeSH
- imunoglobuliny aplikace a dávkování chemie MeSH
- imunokonjugáty aplikace a dávkování chemie MeSH
- kyseliny polymethakrylové aplikace a dávkování farmakologie chemie MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- lymfom T-buněčný farmakoterapie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nosiče léků aplikace a dávkování chemická syntéza chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- 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
