BACKGROUND: Galectin-3 (Gal-3) is a promising target in cancer therapy with a high therapeutic potential due to its abundant localization within the tumor tissue and its involvement in tumor development and proliferation. Potential clinical application of Gal-3-targeted inhibitors is often complicated by their insufficient selectivity or low biocompatibility. Nanomaterials based on N-(2-hydroxypropyl)methacrylamide (HPMA) nanocarrier are attractive for in vivo application due to their good water solubility and lack of toxicity and immunogenicity. Their conjugation with tailored carbohydrate ligands can yield specific glyconanomaterials applicable for targeting biomedicinally relevant lectins like Gal-3. RESULTS: In the present study we describe the synthesis and the structure-affinity relationship study of novel Gal-3-targeted glyconanomaterials, based on hydrophilic HPMA nanocarriers. HPMA nanocarriers decorated with varying amounts of Gal-3 specific epitope GalNAcβ1,4GlcNAc (LacdiNAc) were analyzed in a competitive ELISA-type assay and their binding kinetics was described by surface plasmon resonance. We showed the impact of various linker types and epitope distribution on the binding affinity to Gal-3. The synthesis of specific functionalized LacdiNAc epitopes was accomplished under the catalysis by mutant β-N-acetylhexosaminidases. The glycans were conjugated to statistic HPMA copolymer precursors through diverse linkers in a defined pattern and density using Cu(I)-catalyzed azide-alkyne cycloaddition. The resulting water-soluble and structurally flexible synthetic glyconanomaterials exhibited affinity to Gal-3 in low μM range. CONCLUSIONS: The results of this study reveal the relation between the linker structure, glycan distribution and the affinity of the glycopolymer nanomaterial to Gal-3. They pave the way to specific biomedicinal glyconanomaterials that target Gal-3 as a therapeutic goal in cancerogenesis and other disorders.
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
- 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
- antitumorózní látky aplikace a dávkování farmakokinetika MeSH
- doxorubicin analogy a deriváty aplikace a dávkování MeSH
- finanční podpora výzkumu jako téma MeSH
- lymfom T-buněčný farmakoterapie metabolismus MeSH
- myši MeSH
- nádory farmakoterapie MeSH
- polymery aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- MeSH
- antitumorózní látky aplikace a dávkování farmakologie MeSH
- doxorubicin aplikace a dávkování farmakologie MeSH
- finanční podpora výzkumu jako téma MeSH
- léky s prodlouženým účinkem aplikace a dávkování farmakologie MeSH
- myši MeSH
- polymery aplikace a dávkování farmakologie chemie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
