| Autor: |
Zlotnikov ID; Faculty of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1/3, 119991 Moscow, Russia., Vigovskiy MA; Medical Research and Education Center, Institute for Regenerative Medicine, Lomonosov Moscow State University, 27/10, Lomonosovsky Ave., 119192 Moscow, Russia.; Faculty of Medicine, Lomonosov Moscow State University, 27/1, Lomonosovsky Prosp., 119192 Moscow, Russia., Davydova MP; Faculty of Medicine, Lomonosov Moscow State University, 27/1, Lomonosovsky Prosp., 119192 Moscow, Russia., Danilov MR; Faculty of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1/3, 119991 Moscow, Russia., Dyachkova UD; Medical Research and Education Center, Institute for Regenerative Medicine, Lomonosov Moscow State University, 27/10, Lomonosovsky Ave., 119192 Moscow, Russia.; Faculty of Medicine, Lomonosov Moscow State University, 27/1, Lomonosovsky Prosp., 119192 Moscow, Russia., Grigorieva OA; Medical Research and Education Center, Institute for Regenerative Medicine, Lomonosov Moscow State University, 27/10, Lomonosovsky Ave., 119192 Moscow, Russia.; Faculty of Medicine, Lomonosov Moscow State University, 27/1, Lomonosovsky Prosp., 119192 Moscow, Russia., Kudryashova EV; Faculty of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1/3, 119991 Moscow, Russia. |
| Abstrakt: |
Macrophages are a promising target for drug delivery to influence macrophage-associated processes in the body, namely due to the presence of resistant microorganisms in macrophages. In this work, a series of mannosylated carriers based on mannan, polyethylenimine (PEI) and cyclodextrin (CD) was synthesized. The molecular architecture was studied using FTIR and 1 H NMR spectroscopy. The particle size, from small 10-50 nm to large 500 nm, depending on the type of carrier, is potentially applicable for the creation of various medicinal forms: intravenous, oral and inhalation. Non-specific capture by cells with a simultaneous increase in selectivity to CD206+ macrophages was achieved. ConA was used as a model mannose receptor, binding galactosylated (CD206 non-specific) carriers with constants of the order of 10 4 M -1 and mannosylated conjugates of 10 6 -10 7 M -1 . The results of such primary "ConA-screening" of ligands are in a good agreement in terms of the comparative effectiveness of the interaction of ligands with the CD206+ macrophages: non-specific (up to 10%) absorption of highly charged and small particles; weakly specific uptake of galactosylated polymers (up to 50%); and high affine capture (more than 70-80%) of the ligands with grafted trimannoside was demonstrated using the cytometry method. Double and multi-complexes of antibacterials (moxifloxacin with its adjuvants from the class of terpenoids) were proposed as enhanced forms against resistant pathogens. In vivo pharmacokinetic experiments have shown that polymeric carriers significantly improve the efficiency of the antibiotic: the half-life of moxifloxacin is increased by 2-3 times in conjugate-loaded forms, bio-distribution to the lungs in the first hours after administration of the drug is noticeably greater, and, after 4 h of observation, free moxifloxacin was practically removed from the lungs of rats. Although, in polymer systems, its content is significant-1.2 µg/g. Moreover, the importance of the covalent crosslinking carrier with mannose label was demonstrated. Thus, this paper describes experimental, scientifically based methods of targeted drug delivery to macrophages to create enhanced medicinal forms. |
