Cyanocobalamin-Modified Colistin–Hyaluronan Conjugates: Synthesis and Bioactivity
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Published:2023-07-17
Issue:14
Volume:24
Page:11550
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Dubashynskaya Natallia V.1ORCID, Bokatyi Anton N.1ORCID, Sall Tatiana S.2, Egorova Tatiana S.3, Nashchekina Yuliya A.4, Dubrovskii Yaroslav A.5ORCID, Murashko Ekaterina A.5ORCID, Vlasova Elena N.1, Demyanova Elena V.3, Skorik Yury A.1ORCID
Affiliation:
1. Institute of Macromolecular Compounds of the Russian Academy of Sciences, Bolshoi VO 31, St. Petersburg 199004, Russia 2. Institute of Experimental Medicine, Acad. Pavlov St. 12, St. Petersburg 197376, Russia 3. State Research Institute of Highly Pure Biopreparations, Pudozhsakya 7, St. Petersburg 197110, Russia 4. Institute of Cytology of the Russian Academy of Sciences, Tikhoretsky 4, St. Petersburg 194064, Russia 5. Almazov National Medical Research Centre, Akkuratova 2, St. Petersburg 197341, Russia
Abstract
Polymeric drug delivery systems enhance the biopharmaceutical properties of antibiotics by increasing their bioavailability, providing programmable and controlled-release properties, and reducing toxicity. In addition, drug delivery systems are a promising strategy to improve the intestinal permeability of various antimicrobial agents, including colistin (CT). This study describes the modification of conjugates based on CT and hyaluronic acid (HA) with cyanocobalamin (vitamin B12). Vitamin B12 was chosen as a targeting ligand because it has its own absorption pathway in the small intestine. The resulting polysaccharide conjugates contained 95 μg/mg vitamin B12 and the CT content was 335 μg/mg; they consisted of particles of two sizes, 98 and 702 nm, with a ζ-potential of approximately −25 mV. An in vitro release test at pH 7.4 and pH 5.2 showed an ultra-slow release of colistin of approximately 1% after 10 h. The modified B12 conjugates retained their antimicrobial activity at the level of pure CT (minimum inhibitory concentration was 2 μg/mL). The resulting delivery systems also reduced the nephrotoxicity of CT by 30–40% (HEK 293 cell line). In addition, the modification of B12 improved the intestinal permeability of CT, and the apparent permeability coefficient of HA–CT–B12 conjugates was 3.5 × 10−6 cm/s, corresponding to an in vivo intestinal absorption of 50–100%. Thus, vitamin-B12-modified conjugates based on CT and HA may be promising oral delivery systems with improved biopharmaceutical properties.
Funder
Russian Science Foundation
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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