Hyaluronan/Diethylaminoethyl Chitosan Polyelectrolyte Complexes as Carriers for Improved Colistin Delivery

Dubashynskaya, Natallia V.; Raik, Sergei V.; Dubrovskii, Yaroslav A.; Demyanova, Elena; Shcherbakova, Elena S.; Poshina, Daria N.; Shasherina, Anna Yu.; Anufrikov, Yuri A.; Skorik, Yury А.

doi:10.3390/ijms22168381

Cited by 18 publications

(12 citation statements)

References 49 publications

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“…The development of AMP delivery systems can be a successful solution in overcoming existing obstacles in their application. In recent years, a number of delivery systems of different nature were reported [9][10][11][12][13][14][15][16]. Among them, there are systems physically retaining AMPs [9][10][11][12][13] and covalent conjugates [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

“…In recent years, a number of delivery systems of different nature were reported [9][10][11][12][13][14][15][16]. Among them, there are systems physically retaining AMPs [9][10][11][12][13] and covalent conjugates [16][17][18]. For example, the preparation of nanoparticles (NPs) by complexation of colistin (PMX E) with poly(glutamic acid) stabilized by PEG-derivative [9], hyaluronan/colistin [10] or oligochitosan/starch/colistin/tobramycin polyelectrolyte complexes [14] were recently reported as improved PMX delivery systems.…”

Section: Introductionmentioning

confidence: 99%

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Polymyxin B Conjugates with Bio-Inspired Synthetic Polymers of Different Nature

Dvoretckaia

Egorova

Dzhuzha

et al. 2023

IJMS

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The emergence and growth of bacterial resistance to antibiotics poses an enormous threat to humanity in the future. In this regard, the discovery of new antibiotics and the improvement of existing ones is a priority task. In this study, we proposed the synthesis of new polymeric conjugates of polymyxin B, which is a clinically approved but limited-use peptide antibiotic. In particular, three carboxylate-bearing polymers and one synthetic glycopolymer were selected for conjugation with polymyxin B (PMX B), namely, poly(,L-glutamic acid) (PGlu), copolymer of L-glutamic acid and L-phenylalanine (P(Glu-co-Phe)), copolymer of N-vinyl succinamic acid and N-vinylsuccinimide (P(VSAA-co-VSI)), and poly(2-deoxy-2-methacrylamido-D-glucose) (PMAG). Unlike PGlu and PMAG, P(Glu-co-Phe) and P(VSAA-co-VSI) are amphiphilic and form nanoparticles in aqueous media. A number of conjugates with different polymyxin B loading were synthesized and characterized. In addition, the complex conjugates of PGLu or PMAG with polymyxin B and deferoxamine (siderophore) were obtained. A release of PMX B from Schiff base and amide-linked polymer conjugates was studied in model buffer media with pH 7.4 and 5.8. In both cases, a more pronounced release was observed under slightly acidic conditions. The cytotoxicity of free polymers and PMX B as well as their conjugates was examined in human embryonic kidney cells (HEK 293T cell line). All conjugates demonstrated reduced cytotoxicity compared to the free antibiotic. Finally, the antimicrobial efficacy of the conjugates against Pseudomonas aeruginosa was determined and compared. The lowest values of minimum inhibitory concentrations (MIC) were observed for polymyxin B and polymyxin B/deferoxamine conjugated with PMAG. Among the polymers tested, PMAG appears to be the most promising carrier for delivery of PMX B in conjugated form due to the good preservation of the antimicrobial properties of PMX B and the ability of controlled drug release.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Polymyxin B Conjugates with Bio-Inspired Synthetic Polymers of Different Nature

Dvoretckaia

Egorova

Dzhuzha

et al. 2023

IJMS

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“…Since Cs and its derivatives have their primary amino groups protonated at a low pH (below their p K a value), making Cs a water-soluble cationic polyelectrolyte, a spontaneous association occurs between it and negatively charged polyions to generate polyelectrolyte complexes, which exhibit remarkable physicochemical properties while preserving the biocompatible characteristics. − To favor the formation of these complexes, Cs derivatives incorporating functional groups such as diethylaminoethyl (DEAE) have been produced in order to improve the aqueous solubility and to generate secondary and tertiary amino groups in the polysaccharide structure, resulting in materials with greater colloidal stability . These characteristics have been reported in various research studies, in which polyelectrolyte complexes based on chitosan–DEAE (Cs–DEAE) have been obtained with RNA, DNA, or hyaluronic acid (HA). − In previous work, our group conjugated DEAE moieties to Cs polymeric chains.…”

Section: Introductionmentioning

confidence: 99%

DEAE/Catechol–Chitosan Conjugates as Bioactive Polymers: Synthesis, Characterization, and Potential Applications

et al. 2023

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This work provides the first description of the synthesis and characterization of water-soluble chitosan (Cs) derivatives based on the conjugation of both diethylaminoethyl (DEAE) and catechol groups onto the Cs backbone (Cs−DC) in order to obtain a Cs derivative with antioxidant and antimicrobial properties. The degree of substitution [DS (%)] was 35.46% for DEAE and 2.53% for catechol, determined by spectroscopy. Changes in the molecular packing due to the incorporation of both pendant groups were described by X-ray diffraction and thermogravimetric analysis. For Cs, the crystallinity index was 59.46% and the maximum decomposition rate appeared at 309.3 °C, while for Cs−DC, the values corresponded to 16.98% and 236.4 °C, respectively. The incorporation of DEAE and catechol groups also increases the solubility of the polymer at pH > 7 without harming the antimicrobial activity displayed by the unmodified polymer. The catecholic derivatives increase the radical scavenging activity in terms of the half-maximum effective concentration (EC 50 ). An EC 50 of 1.20 μg/mL was found for neat hydrocaffeic acid (HCA) solution, while for chitosan−catechol (Cs−Ca) and Cs−DC solutions, concentrations equivalent to free HCA of 0.33 and 0.41 μg/mL were required, respectively. Cell culture results show that all Cs derivatives have low cytotoxicity, and Cs−DC showed the ability to reduce the activity of reactive oxygen species by 40% at concentrations as low as 4 μg/mL. Polymeric nanoparticles of Cs derivatives with a hydrodynamic diameter (D h ) of around 200 nm, unimodal size distributions, and a negative ζ-potential were obtained by ionotropic gelation and coated with hyaluronic acid in aqueous suspension, providing the multifunctional nanoparticles with higher stability and a narrower size distribution.

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“…Similar systems based on PECs formed by a polycation (oligochitosan) and a polyanion (anionic starch) for co-delivery of colistin and tobramycin were recently studied by Yasar et al [ 15 ]. Hyaluronan/diethylaminoethyl chitosan PECs for improved colistin delivery have been reported by Dubashynskaya et al [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Hybrid Nanoparticles and Composite Hydrogel Systems for Delivery of Peptide Antibiotics

Iudin

Vasilieva

Knyazeva

et al. 2022

IJMS

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The growing number of drug-resistant pathogenic bacteria poses a global threat to human health. For this reason, the search for ways to enhance the antibacterial activity of existing antibiotics is now an urgent medical task. The aim of this study was to develop novel delivery systems for polymyxins to improve their antimicrobial properties against various infections. For this, hybrid core–shell nanoparticles, consisting of silver core and a poly(glutamic acid) shell capable of polymyxin binding, were developed and carefully investigated. Characterization of the hybrid nanoparticles revealed a hydrodynamic diameter of approximately 100 nm and a negative electrokinetic potential. The nanoparticles demonstrated a lack of cytotoxicity, a low uptake by macrophages, and their own antimicrobial activity. Drug loading and loading efficacy were determined for both polymyxin B and E, and the maximal loaded value with an appropriate size of the delivery systems was 450 µg/mg of nanoparticles. Composite materials based on agarose hydrogel were prepared, containing both the loaded hybrid systems and free antibiotics. The features of polymyxin release from the hybrid nanoparticles and the composite materials were studied, and the mechanisms of release were analyzed using different theoretical models. The antibacterial activity against Pseudomonas aeruginosa was evaluated for both the polymyxin hybrid and the composite delivery systems. All tested samples inhibited bacterial growth. The minimal inhibitory concentrations of the polymyxin B hybrid delivery system demonstrated a synergistic effect when compared with either the antibiotic or the silver nanoparticles alone.

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Hyaluronan/Diethylaminoethyl Chitosan Polyelectrolyte Complexes as Carriers for Improved Colistin Delivery

Cited by 18 publications

References 49 publications

Polymyxin B Conjugates with Bio-Inspired Synthetic Polymers of Different Nature

Polymyxin B Conjugates with Bio-Inspired Synthetic Polymers of Different Nature

DEAE/Catechol–Chitosan Conjugates as Bioactive Polymers: Synthesis, Characterization, and Potential Applications

Hybrid Nanoparticles and Composite Hydrogel Systems for Delivery of Peptide Antibiotics

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