Stepwise Glucoheptoamidation of Poly(Amidoamine) Dendrimer G3 to Tune Physicochemical Properties of the Potential Drug Carrier: In Vitro Tests for Cytisine Conjugates
| Autor: | Małgorzata Walczak, Łukasz Uram, Stanisław Wołowiec, Anna Czerniecka-Kubicka, Ewelina Chmiel, Piotr Tutka, Marek Pyda, Maria Misiorek |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Amidoamine
Pharmaceutical Science lcsh:RS1-441 02 engineering and technology Article BJ normal human fibroblasts lcsh:Pharmacy and materia medica 03 medical and health sciences Cytisine chemistry.chemical_compound Dendrimer cytisine conjugate 030304 developmental biology 0303 health sciences glucoheptoamidation PAMAM G3 dendrimer dynamic light scattering Poly(amidoamine) 021001 nanoscience & nanotechnology Combinatorial chemistry internalization chemistry Drug delivery cytotoxicity Amine gas treating differential scanning calorimetry 0210 nano-technology Drug carrier Conjugate |
| Zdroj: | Pharmaceutics, Vol 12, Iss 473, p 473 (2020) Pharmaceutics Volume 12 Issue 5 |
| ISSN: | 1999-4923 |
| Popis: | Third-generation poly(amidoamine) dendrimer (PAMAM) was modified by stepwise primary amine group amidation with d-glucoheptono-1,4-lactone. The physicochemical properties of the conjugates&mdash size, &zeta potential in lysosomal pH 5 and in neutral aqueous solutions, as well as intramolecular dynamics by differential scanning calorimetry&mdash were determined. Internalization and toxicity of the conjugates against normal human fibroblasts BJ were monitored in vitro in order to select an appropriate carrier for a drug delivery system. It was found that initial glucoheptoamidation (up to 1/3 of amine groups of neat dendrimers available) resulted in increase of conjugate size and &zeta potential. Native or low substituted dendrimer conjugates accumulated efficiently in fibroblast cells at nontoxic 1 µ M concentration. Further substitution of dendrimer caused consistent decrease of size and &zeta potential, cell accumulation, and toxicity. All dendrimers are amorphous at 36.6 ° C as determined by differential scanning calorimetry (DSC). The optimized dendrimer, half-filled with glucoheptoamide substituents, was applied as carrier bearing two covalently attached cytisine molecules: a rigid and hydrophobic alkaloid. The conjugate with 2 cytisine and 16 glucoheptoamide substituents showed fast accumulation and no toxicity up to 200 µ M concentration. The half-glucoheptoamidated PAMAM dendrimer was selected as a promising anticancer drug carrier for further applications. |
| Databáze: | OpenAIRE |
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