The Letter describes the preparation and characterization of a conjugate of isoniazid (INH) with magnetic nanoparticles Fe3O4@SiO2 115±60 nm in size. The INH molecules were attached to the surface of nanoparticles by a covalent pH-sensitive amidine bond. The conjugate was characterized by X-ray diffraction, SEM, dynamic light scattering, IR spectroscopy and microanalysis. The conjugate released isoniazid under in vitro conditions (pH=4; 37 °C; t1/2≈115 s). In addition, the cytotoxicity of the Fe3O4@SiO2-INH conjugate was evaluated in SK-BR-3 cells using the xCELLigence system.
- MeSH
- antibakteriální látky chemická syntéza chemie toxicita MeSH
- difrakce rentgenového záření MeSH
- isoniazid chemická syntéza chemie toxicita MeSH
- koncentrace vodíkových iontů MeSH
- kultivované buňky MeSH
- magnetismus * MeSH
- mikroskopie elektronová rastrovací MeSH
- nanočástice chemie MeSH
- oxid křemičitý chemie MeSH
- proliferace buněk účinky léků MeSH
- železité sloučeniny chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
This mini-review summarizes the development of the derivatives and conjugates of Amphotericin B (AMB) which have not been clinically applied so far but are therapeutically promising. Effects of chemical modifications of AMB upon biological activities of the resulting derivatives are discussed. The examples presented include variation of functional groups in AMB, covalent conjugates with other molecules, poly(ethylene glycols) and polysaccharides. Possibilities of targeted delivery of AMB are discussed.
A new targeting potentially intravenous conjugate Amphotericin B (AMB)-star poly(ethylene glycol) (sPEG) (M=25,160) has been synthesized and characterized. It contains a beta-d-glucopyranoside molecular switch which is sensitive to beta-glucosidases (E.C.3.2.1.21). The beta-glucosidase-catalyzed release of AMB from the polymeric carrier was proved in vitro by means of spectrophotometry and HPLC.
- MeSH
- amfotericin B analogy a deriváty farmakologie chemická syntéza MeSH
- antifungální látky farmakologie chemická syntéza MeSH
- beta-glukosidasa metabolismus MeSH
- chemické modely MeSH
- financování organizované MeSH
- katalýza MeSH
- lidé MeSH
- polyethylenglykoly farmakologie chemická syntéza MeSH
- racionální návrh léčiv MeSH
- spektrofotometrie ultrafialová MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Check Tag
- lidé MeSH
New intravenous conjugates of amphotericin B (AMB) with poly(ethylene glycols) (PEG) (M=5000, 10,000, 20,000) have been synthesized and characterised. The intermediate PEGs possess a 1,4-disubstituted benzene ring with aldehyde group at the end of the chain. The benzene ring is connected with PEG at its 4-position (with respect to the aldehyde group) by various functional groups (ether, amide, ester). Reaction of terminal aldehyde group of the substituted PEGs with AMB gave conjugates containing a pH-sensitive imine linkage, which can be presumed to exhibit antimycotic effect at sites with lowered pH value. All types of the conjugates are relatively stable in phosphate buffer at physiological conditions of pH 7.4 (37 degrees C), less than 5 mol% AMB being split off from them within 24 h. For a model medium of afflicted tissue was used a phosphate buffer (pH 5.5, 37 degrees C), in which controlled release of AMB from the conjugates takes place. The imine linkage is split to give free AMB with half-lives of 2-45 min. The rate of acid catalysed hydrolysis depends upon substitution of the benzene ring; however, it does not depend on molecular weights of the PEGs used. The conjugates with ester linkage undergo enzymatic splitting in human blood plasma and/or blood serum at pH 7.4 (37 degrees C) with half-lives of 2-5 h depending on molecular weights of the PEGs used (M = 5000, 10,000, 20,000). At first, the splitting of ester linkage produces the relatively stable pro-drug, that is, 4-carboxybenzylideniminoamphotericin B, which is decomposed to AMB and 4-formylbenzoic acid in a goal-directed manner only at pH 7 (t1/2 = 2 min, pH 5.5, 37 degrees C). A goal-directed release of AMB is only achieved by acid catalysed hydrolysis of imine linkage, either from the polymeric conjugate or from the pro-drug released thereof. The LD50 values determined in vivo (mouse) are 20.7 mg/kg and 40.5 mg/kg for the conjugates with ester linkage (M = 10,000 and 5000, respectively), which means that they are ca. 6-11 times less toxic than free AMB.
- MeSH
- amfotericin B chemická syntéza chemie MeSH
- financování organizované MeSH
- hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
- hydrolýza MeSH
- koncentrace vodíkových iontů MeSH
- krev MeSH
- lidé MeSH
- myši MeSH
- polyethylenglykoly chemická syntéza chemie MeSH
- spektrofotometrie infračervená MeSH
- spektrofotometrie ultrafialová MeSH
- techniky in vitro MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
This paper reports on the synthesis, characterisation, and efficiency of a new intravenous conjugate of amphotericin B (AMB). Twelve molecules of AMB were attached to block copolymer poly(ethylene glycol)-b-poly(L-lysine) via pH-sensitive imine linkages. In vitro drug release studies demonstrated the conjugate (M(w)=26,700) to be relatively stable in human plasma and in phosphate buffer (pH 7.4, 37 degrees C). Controlled release of AMB was observed in acidic phosphate buffer (pH 5.5, 37 degrees C) with the half-life of 2 min. The LD(50) value determined in vivo (mouse) is 45 mg/kg.
- MeSH
- amfotericin B analogy a deriváty chemická syntéza MeSH
- antifungální látky farmakologie chemická syntéza MeSH
- chemické modely MeSH
- farmaceutická chemie metody MeSH
- financování organizované MeSH
- koncentrace vodíkových iontů MeSH
- molekulární konformace MeSH
- polyethylenglykoly chemie MeSH
- polylysin chemie MeSH
- polymery chemie MeSH
- racionální návrh léčiv MeSH
- spektrofotometrie ultrafialová metody MeSH
- teplota MeSH
