Ferritin, a naturally occurring iron storage protein, has gained significant attention as a drug delivery platform due to its inherent biocompatibility and capacity to encapsulate therapeutic agents. In this study, we successfully genetically engineered human H ferritin by incorporating 4 or 6 tryptophan residues per subunit, strategically oriented towards the inner cavity of the nanoparticle. This modification aimed to enhance the encapsulation of hydrophobic drugs into the ferritin cage. Comprehensive characterization of the mutants revealed that only the variant carrying four tryptophan substitutions per subunit retained the ability to disassemble and reassemble properly. As a proof of concept, we evaluated the loading capacity of this mutant with ellipticine, a natural hydrophobic indole alkaloid with multimodal anticancer activity. Our data demonstrated that this specific mutant exhibited significantly higher efficiency in loading ellipticine compared to human H ferritin. Furthermore, to evaluate the versatility of this hydrophobicity-enhanced ferritin nanoparticle as a drug carrier, we conducted a comparative study by also encapsulating doxorubicin, a commonly used anticancer drug. Subsequently, we tested both ellipticine and doxorubicin-loaded nanoparticles on a promyelocytic leukemia cell line, demonstrating efficient uptake by these cells and resulting in the expected cytotoxic effect.

• MeSH
• antitumorózní látky * farmakologie   chemie   MeSH
• apoferritiny genetika   MeSH
• doxorubicin farmakologie   chemie   MeSH
• elipticiny * MeSH
• ferritin genetika   chemie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nanočástice * chemie   MeSH
• nosiče léků chemie   MeSH
• systémy cílené aplikace léků MeSH
• tryptofan MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

There is increasing pharmaceutical interest in deep eutectic solvents not only as a green alternative to organic solvents in drug manufacturing, but also as liquid formulation for drug delivery. The present work introduces a hydrophobic deep eutectic solvent (HDES) to the field of lipid-based formulations (LBF). Phase behavior of a mixture with 2:1 M ratio of decanoic- to dodecanoic acid was studied experimentally and described by thermodynamic modelling. Venetoclax was selected as a hydrophobic model drug and studied by atomistic molecular dynamics simulations of the mixtures. As a result, valuable molecular insights were gained into the interaction networks between the different components. Moreover, experimentally the HDES showed greatly enhanced drug solubilization compared to conventional glyceride-based vehicles, but aqueous dispersion behavior was limited. Hence surfactants were studied for their ability to improve aqueous dispersion and addition of Tween 80 resulted in lowest droplet sizes and high in vitro drug release. In conclusion, the combination of HDES with surfactant(s) provides a novel LBF with high pharmaceutical potential. However, the components must be finely balanced to keep the integrity of the solubilizing HDES, while enabling sufficient dispersion and drug release.

• MeSH
• chemie farmaceutická metody   MeSH
• hydrofobní a hydrofilní interakce * MeSH
• kyseliny laurové chemie   MeSH
• lipidy * chemie   MeSH
• oleje chemie   MeSH
• polysorbáty chemie   MeSH
• povrchově aktivní látky * chemie   MeSH
• příprava léků * metody   MeSH
• rozpouštědla * chemie   MeSH
• rozpustnost * MeSH
• simulace molekulární dynamiky * MeSH
• sulfonamidy chemie   aplikace a dávkování   MeSH
• uvolňování léčiv * MeSH
• Publikační typ
• časopisecké články MeSH

A freeze-drying method enabling solubilization of hydrophobic species in aqueous solutions of native hyaluronan is described. The method is based on opening the access to supposed hydrophobic patches on hyaluronan by disturbing its massive hydration shell. Hydrophobic and/or polarity-sensitive fluorescence probes were used as hydrophobic models or indicators of interactions with hydrophobic patches. Fluorescence parameters specific to individual probes confirmed the efficiency of the freeze-drying method. This work is the first step in developing biocompatible and biodegradable carriers for hydrophobic drugs with targeted distribution of the active compound from native, chemically non-modified hyaluronan.

• MeSH
• biopolymery chemie   MeSH
• fluorescenční spektrometrie metody   MeSH
• hydrofobní a hydrofilní interakce * MeSH
• kyselina hyaluronová chemie   MeSH
• lyofilizace * MeSH
• molekulární struktura MeSH
• Publikační typ
• časopisecké články MeSH

By means of fluorescence microscopy the intracellular distribution of fluorescent drugs with different hydrophobicity (quinizarin, emodin and hypericin) was studied. Selective photoactivation of these drugs in precisely defined position (nuclear envelope) allowed moderately hydrophobic emodin enter the nucleus. Highly hydrophobic hypericin was predominantly kept in the membranes with no fluorescence observed in the nucleus. The redistribution of quinizarin, emodin and hypericin between lipids, proteins and DNA was studied in solutions and cells. Based on these results was proposed theoretical model of hydrophobic drugs' nuclear internalization after photo-activation. Molecular docking models showed that hypericin has the strongest affinity to P-glycoprotein involved in the cell detoxification. Presence of 10 μM quinizarin, emodin or hypericin increased P-glycoprotein function in U87 MG cells. Moreover, emodin pretreatment allowed quinizarin nuclear internalization without photo-activation, which was not the case for hypericin. The synergy of such pretreatment and photo-activation should lessen the drug doses with simultaneous increase of drug efficacy triggering cell apoptosis/necrosis.

• MeSH
• anthrachinony chemie   farmakologie   účinky záření   MeSH
• buněčné jádro metabolismus   účinky záření   MeSH
• DNA chemie   MeSH
• emodin chemie   farmakologie   účinky záření   MeSH
• gliom metabolismus   MeSH
• hydrofobní a hydrofilní interakce MeSH
• LDL-cholesterol chemie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• P-glykoprotein metabolismus   MeSH
• perylen analogy a deriváty   chemie   farmakologie   účinky záření   MeSH
• sérový albumin chemie   MeSH
• simulace molekulového dockingu MeSH
• světlo MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In a previous study we showed that the cause of failure of a new, proposed, targeting ligand, the AETP moiety, when attached to a PEGylated liposome, was occlusion by the poly(ethylene glycol) (PEG) layer due to its hydrophobic nature, given that PEG is not entirely hydrophilic. At the time we proposed that possible replacement with a more hydrophilic protective polymer could alleviate this problem. In this study we have used computational molecular dynamics modelling, using a model with all atom resolution, to suggest that a specific alternative protective polymer, poly(2-methyloxazoline) (PMOZ), would perform exactly this function. Our results show that when PEG is replaced by PMOZ the relative exposure to the solvent of AETP is increased to a level even greater than that we found in previous simulations for the RGD peptide, a targeting moiety that has previously been used successfully in PEGylated liposome based therapies. While the AETP moiety itself is no longer under consideration, the results of this computational study have broader significance: the use of PMOZ as an alternative polymer coating to PEG could be efficacious in the context of more hydrophobic targeting ligands. In addition to PMOZ we studied another polyoxazoline, poly(2-ethyloxazoline) (PEOZ), that has also been mooted as a possible alternate protective polymer. It was also found that the RDG peptide occlusion was significantly greater for the case of both oxazolines as opposed to PEG and that, unlike PEG, neither oxazoline entered the membrane. As far as we are aware this is the first time that polyoxazolines have been studied using molecular dynamics simulation with all atom resolution.

• MeSH
• cholesterol chemie   MeSH
• fosfatidylcholiny chemie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• lidé MeSH
• ligandy MeSH
• liposomy chemie   MeSH
• oligopeptidy chemie   MeSH
• polyaminy chemie   MeSH
• polyethylenglykoly chemie   MeSH
• povrchové vlastnosti MeSH
• simulace molekulární dynamiky MeSH
• systémy cílené aplikace léků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Various conjugates of anticancer drug doxorubicin (Dox) covalently bound by the hydrolytically degradable hydrazone bond to the drug carrier based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers were synthesised. Structure of the conjugates differed in the type and the content of hydrophobic substituent (dodecyl, oleic acid and cholesterol moieties) introduced into the polymer structure. In aqueous solutions the conjugates self-assembled into high-molecular-weight supramolecular structures, such as polymeric micelles or stable hydrophilic nanoparticles 13-37 nm in diameter, depending on the type and the content of hydrophobic substituents. Treatment of mice bearing EL-4 T cell lymphoma with the conjugates in the therapeutic regime of drug administration (i.v.) resulted in significant tumour regression with up to 100% of long-term survivors, depending on the dose and the detailed structure of the carrier. The nanoparticles formed by the conjugate bearing cholesterol moiety exhibited prolonged blood circulation and enhanced tumour accumulation indicating an important role of the EPR effect in excellent anticancer activity of the conjugate.

• MeSH
• antibiotika antitumorózní farmakokinetika   farmakologie   chemie   MeSH
• doxorubicin analogy a deriváty   farmakokinetika   farmakologie   chemie   MeSH
• financování organizované MeSH
• hydrofobní a hydrofilní interakce MeSH
• kyseliny polymethakrylové farmakokinetika   farmakologie   chemie   MeSH
• lidé MeSH
• methakryláty farmakokinetika   farmakologie   chemie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   metabolismus   MeSH
• nosiče léků farmakokinetika   farmakologie   chemie   MeSH
• proliferace buněk účinky léků   MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH

The rate of drug release from polymer matrix-based sustained release formulations is often controlled by the thickness of a gel layer that forms upon contact with dissolution medium. The effect of formulation parameters on the kinetics of elementary rate processes that contribute to gel layer formation, such as water ingress, polymer swelling and erosion, is therefore of interest. In the present work, gel layer formation has been investigated by magnetic resonance imaging (MRI), which is a non-destructive method allowing direct visualization of effective water concentration inside the tablet and its surrounding. Using formulations with Levetiracetam as the active ingredient, HPMC as a hydrophilic matrix former and carnauba wax (CW) as a hydrophobic component in the matrix system, the effect of different ratios of these two ingredients on the kinetics of gel formation (MRI) and drug release (USP 4 like dissolution test) has been investigated and interpreted using a mathematical model.

• MeSH
• deriváty hypromelózy chemie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• kinetika MeSH
• léky s prodlouženým účinkem chemie   MeSH
• magnetická rezonanční tomografie MeSH
• piracetam analogy a deriváty   chemie   MeSH
• rozpustnost MeSH
• tablety MeSH
• teoretické modely MeSH
• uvolňování léčiv MeSH
• vosky chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Twelve novel analogs of STAT3 inhibitor BP-1-102 were designed and synthesised with the aim to modify hydrophobic fragments of the molecules that are important for interaction with the STAT3 SH2 domain. The cytotoxic activity of the reference and novel compounds was evaluated using several human and two mouse cancer cell lines. BP-1-102 and its two analogs emerged as effective cytotoxic agents and were further tested in additional six human and two murine cancer cell lines, in all of which they manifested the cytotoxic effect in a micromolar range. Reference compound S3I-201.1066 was found ineffective in all tested cell lines, in contrast to formerly published data. The ability of selected BP-1-102 analogs to induce apoptosis and inhibition of STAT3 receptor-mediated phosphorylation was confirmed. The structure-activity relationship confirmed a demand for two hydrophobic substituents, i.e. the pentafluorophenyl moiety and another spatially bulky moiety, for effective cytotoxic activity and STAT3 inhibition.

• MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• fosforylace účinky léků   MeSH
• hydrofobní a hydrofilní interakce MeSH
• kultivované buňky MeSH
• kyseliny aminosalicylové chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• proliferace buněk účinky léků   MeSH
• racionální návrh léčiv * MeSH
• sulfonamidy chemická syntéza   chemie   farmakologie   MeSH
• transkripční faktor STAT3 antagonisté a inhibitory   metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The interaction of a double stranded small interference RNA (siRNA Nef) with cationic carbosilane dendrimers of generations 1-3 with two different ammonium functions at the periphery ([-NMe2R]+, R=Me, (CH2)2OH) has been studied by experimental techniques (zeta potential, electrophoresis, single molecule pulling experiments) and molecular dynamic calculations. These studies state the presence of different forces on dendriplex formation, depending on generation and type of ammonium group. Whilst for higher dendrimers electrostatic forces mainly drive the stability of dendriplexes, first generation compounds can penetrate into siRNA strands due to the establishment of hydrophobic interactions. Finally, in the particular case of first generation dendrimer [G1O3(NMe2(CH2)2OH))6]6+; the presence of hydroxyl groups reinforces dendriplex stability by hydrogen bonds formation. However, since these small dendrimers do not cover the RNA, only higher generation derivatives protect RNA from degradation.

• MeSH
• dendrimery chemie   metabolismus   MeSH
• genové produkty nef - virus lidské imunodeficience antagonisté a inhibitory   chemie   genetika   metabolismus   MeSH
• hydrofobní a hydrofilní interakce MeSH
• kinetika MeSH
• leukocyty mononukleární cytologie   MeSH
• lidé MeSH
• malá interferující RNA chemie   genetika   metabolismus   MeSH
• molekulární konformace MeSH
• primární buněčná kultura MeSH
• silany chemie   metabolismus   MeSH
• simulace molekulární dynamiky MeSH
• stabilita léku MeSH
• statická elektřina MeSH
• technika přenosu genů * MeSH
• termodynamika MeSH
• velikost částic MeSH
• vodíková vazba MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

A new hydrophobic platinum(IV) complex, LA-12, a very efficient anticancer drug lacking cross-resistance with cisplatin (CDDP), is now being tested in clinical trials. Here we investigated the apoptogenic activity of LA-12 and its effect on gap-junctional intercellular communication (GJIC) in the rat liver epithelial cell line WB-F344. LA-12 induced apoptosis much more efficiently than did CDDP due to a combination of rapid penetration into the cell and attack on DNA, leading to fast activation of p53 and caspase-3. Exposure of WB-F344 cells to LA-12 led to rapid induction of the time- and dose-dependent decrease in GJIC. On the molecular level, loss of GJIC induced by LA-12 was mediated by activation of extracellular signal-regulated kinase (ERK)-1 and ERK-2, as demonstrated by the use of inhibitors of ERK activation. Inhibition of GJIC was linked to rapid hyperphosphorylation of connexin-43 and disappearance of connexon clusters from membranes, which was not observed in the case of CDDP.

• MeSH
• amantadin analogy a deriváty   farmakologie   MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza MeSH
• buněčné linie MeSH
• cisplatina farmakologie   MeSH
• epitelové buňky metabolismus   MeSH
• financování organizované MeSH
• fosforylace MeSH
• hydrofobní a hydrofilní interakce MeSH
• konexin 43 metabolismus   MeSH
• krysa rodu rattus MeSH
• mezerový spoj účinky léků   MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• sloučeniny platiny chemie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH