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.
Abstract—
The influence of the structure of fluoroquinolones (on the example of ciprofloxacin and levofloxacin) and their complexation with methyl-β-cyclodextrin on the interaction of the drug with human serum albumin was studied. It was found that the binding of the drug molecule with albumin is significantly affected by the structure of fluoroquinolone, as well as the presence of methyl-β-cyclodextrin. It was discovered that of the two fluoroquinolones, the more hydrophobic ciprofloxacin molecule interacts more strongly with the protein, using circular dichroism and fluorescence spectroscopy methods. It has also been shown that binding of albumin to the drug causes quenching of protein fluorescence, and this effect is more pronounced for ciprofloxacin. The complexation of fluoroquinolones with methyl-β-cyclodextrin leads to a change in the interaction of fluoroquinolones with the protein: in the case of complexes, more pronounced interactions are observed for levofloxacin. The results obtained will help to bring the use of fluoroquinolones to a new level in clinical practice, by creating new highly effective drugs with improved properties.
Here we report the development of new drug carriers for meropenem based on the hydroxypropyl-β-cyclodextrin (HPCD) polymers with variable linkers, namely, 1,6-hexamethylenediisocyanate (HMD), citric acid (CA), succinic anhydride (SA). The structures of obtained polyesters and polyurethanes nanoparticles (120–200 nm) were investigated by NMR and FTIR-spectroscopy. The PXRD pattern demonstrated that HPCD polymers form complexes with meropenem (MP), and the majority of MP molecules are encapsulated into a complex. MP’s imprinting in the HPCD-HMD polymer matrix lead to an encapsulation efficiency of up to 82%. HPCD-HMD and HPCD-SA polymers increase MP’s stability during the storage of its aqueous solution (in 1.4 and 1.2 times, respectively). In contrast, HPCD-CA polymer negatively affects MP’s stability. In prospect, the HPCD-HMD polymer may be promising for the development of a highly efficient drug delivery system for MP.
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The study has been devoted to the complexation of hydroxypropyl-β-cyclodextrin (HPCD) with antibacterial drugs, namely, ceftriaxone (CT) and levofloxacin (LV), which are used to treat respiratory diseases, including bacterial infections of the respiratory tract. FTIR and NMR spectroscopic investigations have shown that the LV–HPCD complex is formed mainly due to the inclusion of the aromatic fragment of LV into the HPCD cavity; while the CT–HPCD complex is realized on the HPCD surface. Being a more hydrophobic molecule, LV forms ten times stronger complexes with HPCD than does CT:
K
disLV-HPCD
~ 10
–3
M, while
K
disCT-HPCD
~10
–2
M at pH 7.4. It has been shown that, for singly charged forms of the drugs, the complexes are two times more stable. Fluorescence spectroscopy has been employed to study the thermodynamic parameters for the interaction of dosage forms with human serum albumin. Negative values of Δ
H
and Δ
S
of the reaction have indicated both hydrogen bonding and van der Waals interactions during the complexation of both drugs with human serum albumin. It has been found that the protein is ~4 times more strongly bound to LV at 37°C as compared with CT. The data obtained will make it possible to improve the characteristics of the studied drugs and bring the methods of treating severe forms of respiratory diseases to a new level.
The effect of two β-cyclodextrin derivatives on the interaction of levofloxacin fluoroquinolone with the liposomal bilayer (liposomes) and cell membranes of L. fermentum and E. coli bacteria was studied. It was found that the complex formation of levofloxacin-cyclodextrin enhances the adsorption of the drug on gram-negative cells.
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