Widening the Therapeutic Perspectives of Clofazimine by Its Loading in Sulfobutylether β-Cyclodextrin Nanocarriers: Nanomolar IC₅₀ Values against MDR S. epidermidis

Abstract

Clofazimine (CLZ) is an antibiotic with a promising behavior against Gram-positive bacteria; however, the drug is completely insoluble in water and accumulates in fat tissues. We explored nanocarriers, labeled and not labeled with rhodamine, consisting of negatively charged sulfobutylether-β-cyclodextrins for CLZ loading. A new oligomeric carrier was obtained cross-linking βCyD with epichlorohydrin followed by sulfonation in a strongly alkaline aqueous medium. The oligomeric carrier has a MW of 53 kDa and forms small nanoparticles of a few tens of nm. With aqueous solutions containing a 25 mg/mL oligomeric carrier, we loaded up to 0.5 mg/mL of drug. The oligomers exhibited a 10-fold better loading capacity compared to monomers and formed nanoparticles with a size in the 20-60 nm range after drug loading. Circular dichroism confirmed encapsulation of the CLZ in the nanocarriers. All carriers with or without CLZ are not cytotoxic up to 1 μM, while CLZ alone is highly cytotoxic at the same concentration. The drug has IC values below 100 nM against S. epidermidis. The same holds true also for clinical isolates of S. epidermidis, some displaying MDR. So, the selectivity index significantly increased for CLZ/carrier systems compared to the drug alone. Taken all together, our results open new avenues for the clinical application of this antibiotic.

Single Crystal FLIM Characterization of Clofazimine Loaded in Silica-Based Mesoporous Materials and Zeolites

“…Similar behavior has been observed for CLZ loaded in MSPs [23]. Additionally, a bi-exponential fluorescence decay for CLZ in DMSO solution has been reported with lifetimes of 0.11 ns and 2.35 ns [29].…”

“…We assign the band centred at 449 nm of CLZ in DCM to the neutral form of CLZ, as reported also for CLZ in water at pH 7 and in DMSO [24,29,30]. The red shift of the main absorption maximum along with the presence of the second band/shoulder at 385 nm indicates that upon interaction with the silica materials CLZ is mainly present in its protonated form.…”

“…Several studies have reported on the emission spectrum of CLZ in DMSO, which presents a broad band with two maxima at 540 and 580 nm [29,46]. The lack of CLZ emission in other solvents can be related to fluorescence quenching due to formation of dimers and aggregates.…”

Recent Advances in Host–Guest Self‐Assembled Cyclodextrin Carriers: Implications for Responsive Drug Delivery and Biomedical Engineering

“…[8,17] Certainly, this polymer shows the synergic action and behaves better in dissolving the hydrophobic drug than the native CyD form. [18] Cyclodextrins has molecular cavity sizes ranging from 4.7 to 8.5 nm with cavity volume of 0.10-0.20 mL g −1 . It was assumed that mostly small molecules of aliphatic and aromatic structures interact very well with CyD inner cavity and outer rim of hydroxyl groups.…”

“…The guest containing electrophilic group donates its electron to the nucleophilic hydroxyl that group results in formation of a hydrogen bond association between host CyD and guest molecules 17. Certainly, this polymer shows the synergic action and behaves better in dissolving the hydrophobic drug than the native CyD form 18. Cyclodextrins has molecular cavity sizes ranging from 4.7 to 8.5 nm with cavity volume of 0.10–0.20 mL g −1 .…”