Dataset Information

Conjugates of Chitosan with β-Cyclodextrins as Promising Carriers for the Delivery of Levofloxacin: Spectral and Microbiological Studies.

ABSTRACT: In this work, we synthesized chitosan 5 kDa conjugates with β-cyclodextrins with various substituents as promising mucoadhesive carriers for the delivery of fluoroquinolones using the example of levofloxacin. The obtained conjugates were comprehensively characterized by spectral methods (UV-Vis, ATR-FTIR, 1H NMR, SEM). The physico-chemical properties of the complex formations were studied by IR, UV, and fluorescence spectroscopy. The dissociation constants of complexes with levofloxacin were determined. Complexation with conjugates provided four times slower drug release in comparison with plain CD and more than 20 times in comparison with the free drug. The antibacterial activity of the complexes was tested on model microorganisms Gram-negative bacteria Escherichia coli ATCC 25922 and Gram-positive Bacillus subtilis ATCC 6633. The complex with the conjugate demonstrated the same initial levofloxacin antibacterial activity but provided significant benefits, e.g., prolonged release.

SUBMITTER: Le-Deygen IM

PROVIDER: S-EPMC9960298 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Conjugates of Chitosan with β-Cyclodextrins as Promising Carriers for the Delivery of Levofloxacin: Spectral and Microbiological Studies.

Le-Deygen Irina M IM Skuredina Anna A AA Mamaeva Polina V PV Kolmogorov Ilya M IM Kudryashova Elena V EV

Life (Basel, Switzerland) 20230118 2

In this work, we synthesized chitosan 5 kDa conjugates with β-cyclodextrins with various substituents as promising mucoadhesive carriers for the delivery of fluoroquinolones using the example of levofloxacin. The obtained conjugates were comprehensively characterized by spectral methods (UV-Vis, ATR-FTIR, 1H NMR, SEM). The physico-chemical properties of the complex formations were studied by IR, UV, and fluorescence spectroscopy. The dissociation constants of complexes with levofloxacin were det ...[more]

PMID: 36836630

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Project description:The development of a new class of antibiotics to fight bacterial resistance is a time-consuming effort associated with high-cost and commercial risks. Thus, modification, conjugation or combination of existing antibiotics to enhance their efficacy is a suitable strategy. We have previously reported that the amphiphilic cyclic peptide [R?W?] had antibacterial activity with a minimum inhibitory concentration (MIC) of 2.97 µg/mL against Methicillin-resistant Staphylococcus aureus (MRSA). Herein, we hypothesized that conjugation or combination of the amphiphilic cyclic peptide [R?W?] with levofloxacin or levofloxacin-Q could improve the antibacterial activity of levofloxacin and levofloxacin-Q. Fmoc/tBu solid-phase chemistry was employed to synthesize conjugates of [R?W?K]-levofloxacin-Q and [R?W?K]-levofloxacin. The carboxylic acid group of levofloxacin or levofloxacin-Q was conjugated with the amino group of ?-alanine attached to lysine in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa?uorophosphate (HBTU) and N,N-diisopropylethylamine (DIPEA) for 3 h to afford the products. Antibacterial assays were conducted to determine the potency of conjugates [R?W?K]-levofloxacin-Q and [R?W?K]-levofloxacin against MRSA and Klebsiella pneumoniae. Although levofloxacin-Q was inactive even at a concentration of 128 µg/mL, [R?W?K]-levofloxacin-Q conjugate and the corresponding physical mixture showed MIC values of 8 µg/mL and 32 µg/mL against MRSA and Klebsiella pneumonia, respectively, possibly due to the activity of the peptide. On the other hand, [R?W?K]-levofloxacin conjugate (MIC = 32 µg/mL and MIC = 128 µg/mL) and the physical mixture (MIC = 8 µg/mL and 32 µg/mL) was less active than levofloxacin (MIC = 2 µg/mL and 4 = µg/mL) against MRSA and Klebsiella pneumoniae, respectively. The data showed that the conjugation of levofloxacin with [R?W?K] significantly reduced the antibacterial activity compared to the parent analogs, while [R?W?K]-levofloxacin-Q conjugate was more significantly potent than levofloxacin-Q alone.

Project description:We have explored the merits of a novel delivery strategy for the antisense oligomers based on cell penetrating peptide (CPP) conjugated to a carrier PNA with sequence complementary to part of the antisense oligomer. The effect of these carrier CPP-PNAs was evaluated by using antisense PNA targeting splicing correction of the mutated luciferase gene in the HeLa pLuc705 cell line, reporting cellular (nuclear) uptake of the antisense PNA via luciferase activity measurement. Carrier CPP-PNA constructs were studied in terms of construct modification (with octaarginine and/or decanoic acid) and carrier PNA length (to adjust binding affinity). In general, the carrier CPP-PNA constructs including the ones with decanoyl modification provided significant increase of the activity of unmodified antisense PNA as well as of antisense octaarginine-PNA conjugates. Antisense activity, and by inference cellular delivery, of unmodified antisense PNA was enhanced at least 20-fold at 6 μM upon the complexation with an equimolar amount of nonamer carrier decanoyl-CPP-PNA (Deca-cPNA1(9)-(D-Arg)8). The antisense activity of a CPP-PNA ((D-Arg)8-asPNA) (at 2 μM) was improved 6-fold and 8-fold by a heptamer carrier CPP-PNA (cPNA1(7)-(D-Arg)8) and hexamer carrier decanoyl-CPP-PNA (Deca-cPNA1(6)-(D-Arg)8), respectively, without showing significant additional cellular toxicity. Most interestingly, the activity reached the same level obtained by enhancement with endosomolytic chloroquine (CQ) treatment, suggesting that the carrier might facilitate endosomal escape. Furthermore, 50% downregulation of luciferase expression at 60 nM siRNA was obtained using this carrier CPP-PNA delivery strategy (with CQ co-treatment) for a single stranded antisense RNA targeting normal luciferase mRNA. These results indicated that CPP-PNA carriers may be used as effective cellular delivery vectors for different types of antisense oligomers and also allows use of combinations of (at least two) different CPP ligands.

Dataset Information

Conjugates of Chitosan with β-Cyclodextrins as Promising Carriers for the Delivery of Levofloxacin: Spectral and Microbiological Studies.

Publications

Conjugates of Chitosan with β-Cyclodextrins as Promising Carriers for the Delivery of Levofloxacin: Spectral and Microbiological Studies.

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