Cyclodextrins (CDs) are promising drug carriers that are used in medicine. We chose CDs with different substituents (polar/apolar, charged/neutral) to obtain polymers (CDpols) with different properties. CDpols are urethanes with average Mw of ~120 kDa; they form nanoparticles 100–150 nm in diameter with variable ζ-potential. We studied the interaction of CD and CDpols with model (liposomal) and bacterial membranes. Both types of CD carriers cause an increase in the liposomal membrane permeability, and for polymers, this effect was almost two times stronger. The formation of CD/CDpols complexes with levofloxacin (LV) enhances LV’s antibacterial action 2-fold in vitro on five bacterial strains. The most pronounced effect was determined for LV-CD complexes. LV-CDs and LV-CDpols adsorb on bacteria, and cell morphology influences this process dramatically. According to TEM studies, the rough surface and proteinaceous fimbria of Gram-negative E. coli facilitate the adsorption of CD particles, whereas the smooth surface of Gram-positive bacteria impedes it. In comparison with LV-CDs, LV-CDpols are adsorbed 15% more effectively by E. coli, 2.3-fold better by lactobacilli and 5-fold better in the case of B. subtilis. CDs and CDpols are not toxic for bacterial cells, but may cause mild defects that, in addition to LV-CD carrier adsorption, improve LV’s antibacterial properties.

The new method of antibacterial-drug-activity investigation in vitro is proposed as a powerful strategy for understanding how carriers affect drug action during long periods (7 days). In this paper, we observed fluoroquinolone moxifloxacin (MF) antibacterial-efficiency in non-covalent complexes, with the sulfobutyl ether derivative of β-cyclodextrin (SCD) and its polymer (SCDpol). We conducted in vitro studies on two Escherichia coli strains that differed in surface morphology. It was found that MF loses its antibacterial action after 3–4 days in liquid media, whereas the inclusion of the drug in SCD led to the increase of MF antibacterial activity by up to 1.4 times within 1–5 days of the experiment. In the case of MF-SCDpol, we observed a 12-fold increase in the MF action, and a tendency to prolonged antibacterial activity. We visualized this phenomenon (the state of bacteria, cell membrane, and surface morphology) during MF and MF-carrier exposure by TEM. SCD and SCDpol did not change the drug’s mechanism of action. Particle adsorption on cells was the crucial factor for determining the observed effects. The proteinaceous fimbriae on the bacteria surface gave a 2-fold increase of the drug carrier adsorption, hence the strains with fimbriae are more preferable for the proposed treatment. Furthermore, the approach to visualize the CD polymer adsorption on bacteria via TEM is suggested. We hope that the proposed comprehensive method will be useful for the studies of drug-delivery systems to uncover long-term antibacterial action.

Respiratory infectious diseases have challenged medical communities and researchers. Ceftriaxone, meropenem and levofloxacin are widely used for bacterial infection treatment, although they possess severe side effects. To overcome this, we propose cyclodextrin (CD) and CD-based polymers as a drug delivery system for the drugs under consideration. CD polymers demonstrate higher binding affinity for levofloxacin (Ka ≈ 10⁵ M) compared to drug–CD complexes. CDs slightly alter the drugs’ affinity for human serum albumin (HSA), whereas CD polymers increase the drugs’ binding affinity up to 100 times. The most significant effect was observed for more the hydrophilic drugs ceftriaxone and meropenem. The drug’s encapsulation in CD carriers leads to a decrease in the degree of change in the protein’s secondary structure. The drug–CD carrier–HSA complexes demonstrate satisfying antibacterial activity in vitro, and even a high binding affinity does not decrease the drug’s microbiological properties after 24 h. The proposed carriers are promising for a drug form with a prolonged drug release.

The aim of this work was to investigate the physico-chemical and biological properties of cyclodextrin-based polymers by the example of interaction with human serum albumin, erythrocytes, and bacteria to understand the prospects of their application as drug delivery systems. We synthesized polymers based on one of cyclodextrin derivatives with nonpolar (-CH₃) or polar (-CH₂CH(OH)CH₃) substituents by crosslinking with 1,6-hexamethylene diisocyanate or succinic anhydride. The polymers form particles with an average size of ~200 nm in the aqueous solutions; their structures were confirmed by FTIR and ¹H NMR. Cyclodextrin derivatives and their polymers did not affect the secondary structure content of human serum albumin, which might mean a mild effect on the structural and functional properties of the main blood plasma protein. Polymers extract drug molecules from albumin + drug complex by 8–10%, which was demonstrated using ibuprofen and bromophenol blue as model bioactive molecules for site I and site II in protein; thus, the nanoparticles might slightly change the drug’s pharmacokinetics. Using the hemolysis test, we found that polymers interact with red blood cells and can be assigned to non-hemolytic and slightly hemolytic groups as biocompatible materials, which are safe for in vivo use. The cyclodextrins and their polymers did not extract proteins from bacterial cell walls and did not demonstrate any antibacterial activity against Gram-positive and Gram-negative strains. Thus, the cyclodextrin-based polymers possess variable properties depending on the substituent in the monomer and linker type; demonstrated biocompatibility, biodegradability, and negligible toxicity that opens up prospects for their application in biomedicine and ecology.

Here, we propose a drug delivery system for ciprofloxacin (CF) based on cyclodextrin (CD) polymer. We obtained a 3D matrix system with encapsulated drug molecules by crosslinking CF+CD non-covalent complexes with 1.6-hexamethylene isocyanate. The obtained polycarbamide (MAX-system) represents particles (~225 nm in diameter) that demonstrate CF’s sustained release. We investigated how the carrier affects the drug’s interaction with the biological macromolecule human serum albumin (HSA) and CF’s antibacterial properties. Compared to a binary CF–HSA system, CD decreases CF’s binding efficiency to HSA by two times, whereas CF encapsulation in a polymer matrix doubles the Ka value and prevents protein aggregation. The changes in HSA’s secondary structure indicate no alterations in the main mechanism of complex formation between CF and HSA in the presence of both CD-based carriers. CD as well as MAX systems practically do not change CF’s activity against E. coli and B. subtilis, but for MAX systems, prolonged action is realized due to CF’s sustained release. We believe that our findings are important for the further development of new, efficient drug forms.

Human serum albumin (HSA) is a multifunctional protein, known to be a natural carrier for a number of endogenous and exogenous compounds, including drugs. HSA-based drugs formulation is a clinically validated approach to improve pharmacological properties and biodistribution (such as in Abraxane). Based on this, one might like to modify HSA in a way that its distribution is more favorable for certain therapeutic purposes. Levofloxacin (LV), a broad-spectrum antibiotic drug, could benefit from extended systemic exposure, and stronger interactions with plasma proteins could be useful for this purpose. We engrafted monomeric or polymeric cyclodextrins (CDs) on the surface of HSA molecules to strengthen the LV adsorption (the CD−LV dissociation constant is three orders of magnitude lower than that of HSA−LV). We found that (HSA−HPolS)_conj+LV exhibited the highest activity against E. coli, whereas (HSA−HPCD)_conj+LV was the most effective against B. subtilis, and both HSA conjugates were more potent than LV alone or LV with HSA. Further fine-tuning of HSA could yield an improvement in biodistribution and thus a more favorable risk/benefit ratio.