Tuberculosis remains a major global health problem. The use of ethionamide (ETH), a second line drug, is associated to severe side-effects due to its low therapeutic index. We addressed this problem by loading ETH in ?-cyclodextrin (?CyD)-based carriers. The drug was incorporated in a molecular state avoiding crystallization even for long-term storage and obtaining a tenfold increased solubility up to 25 mM. The binding of ETH to polymeric ?CyD nanoparticles (p?CyD NPs) labelled and not with fluorescein (FITC) was investigated in neutral aqueous medium by means of solubility phase diagrams, circular dichroism (CD) and UV-Vis absorption and compared with the corresponding ?CyD monomer. The binding constants and the absolute CD spectra of the drug complexes were determined by global analysis of multiwavelength data from spectroscopic titrations. The spectroscopic and photophysical properties of the complexes evidenced an alcohol-like environment for ETH included in the cavity. Additionally, ETH was found to be located not only in ?CyD cavities, but also in confined microdomains inside the crosslinked NPs. This double modality of complexation together with a slightly higher binding constant makes the utilization of p?CyD NPs preferable over the monomeric ?CyDs. The ?CyD-based polymeric carrier appeared as versatile "green" system for efficient incorporation and future delivery of ETH. Finally, the drug-loaded NPs were passed through a Microsprayer® to evaluate the feasibility to administer p?CyD NPs by pulmonary route.
Encapsulation of Ethionamide in ?-cyclodextrin-based polymers organizing in nanoparticles for pulmonary antitubercular drug delivery
Ilse Manet
2017
Abstract
Tuberculosis remains a major global health problem. The use of ethionamide (ETH), a second line drug, is associated to severe side-effects due to its low therapeutic index. We addressed this problem by loading ETH in ?-cyclodextrin (?CyD)-based carriers. The drug was incorporated in a molecular state avoiding crystallization even for long-term storage and obtaining a tenfold increased solubility up to 25 mM. The binding of ETH to polymeric ?CyD nanoparticles (p?CyD NPs) labelled and not with fluorescein (FITC) was investigated in neutral aqueous medium by means of solubility phase diagrams, circular dichroism (CD) and UV-Vis absorption and compared with the corresponding ?CyD monomer. The binding constants and the absolute CD spectra of the drug complexes were determined by global analysis of multiwavelength data from spectroscopic titrations. The spectroscopic and photophysical properties of the complexes evidenced an alcohol-like environment for ETH included in the cavity. Additionally, ETH was found to be located not only in ?CyD cavities, but also in confined microdomains inside the crosslinked NPs. This double modality of complexation together with a slightly higher binding constant makes the utilization of p?CyD NPs preferable over the monomeric ?CyDs. The ?CyD-based polymeric carrier appeared as versatile "green" system for efficient incorporation and future delivery of ETH. Finally, the drug-loaded NPs were passed through a Microsprayer® to evaluate the feasibility to administer p?CyD NPs by pulmonary route.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
