Insights into the multi-equilibrium, superstructure system based on β-cyclodextrin and a highly water soluble guest

Area of Science:

• Pharmacology
• Materials Science
• Medicinal Chemistry

Background:

• Pentamidine isethionate (PNT) is an antiprotozoal drug effective against leishmaniasis.
• Current limitations of PNT include high toxicity and the need for parenteral administration.
• Developing improved drug delivery systems for PNT is crucial for enhancing its therapeutic profile.

Purpose of the Study:

• To encapsulate pentamidine isethionate (PNT) into beta-cyclodextrin (βCD) to improve its physicochemical properties and oral bioavailability.
• To characterize the PNT-βCD inclusion complex using various analytical techniques.
• To evaluate the in vivo antiprotozoal activity of the PNT-βCD complex against leishmaniasis.

Main Methods:

• Complexation of PNT with βCD at 1:1 and 2:1 molar ratios.
• Characterization using isothermal titration calorimetry (ITC), electrospray ionization mass spectrometry (ESI-MS), and nuclear magnetic resonance (NMR - 1H NMR, ROESY).
• Solid-state characterization via FTIR, TG/DTA, and SEM. In vivo antiprotozoal activity assessment in mice.

Main Results:

• Thermodynamic and structural studies (ITC, ESI-MS, NMR) confirmed the formation of PNT-βCD inclusion complexes in solution, indicating deep inclusion of PNT within the βCD cavity.
• Solid-state characterization techniques (FTIR, TG/DTA, SEM) provided evidence for the formation of the inclusion complex.
• Oral administration of the PNT-βCD inclusion complex in mice resulted in a significant reduction in parasite load compared to free PNT.

Conclusions:

• Beta-cyclodextrin encapsulation is an effective strategy to improve the properties of pentamidine isethionate.
• The PNT-βCD inclusion complex demonstrates enhanced oral efficacy against leishmaniasis in vivo.
• This approach offers a promising alternative for PNT delivery, potentially overcoming limitations of toxicity and administration route.