Clay-based hybrids for controlled release of 7-azaindole derivatives as neuroprotective drugs in the treatment of Alzheimer's disease

Hybrid systems based on clay minerals and 7-azaindole derivatives, which show an interesting neuroprotective profile in several in vitro models of neurodegeneration, were developed in order to facilitate the oral administration of these drugs in the treatment of Alzheimer's disease and provide a controlled release. Two 7-azaindole derivatives with different substitution at position 5 (-OCH3, -H) were synthesized and adsorbed on nanocarriers of different morphology, the lamellar clay montmorillonite (MMT) and the halloysite nanotubes (HNT). The drugs intercalation in MMT was confirmed by X-ray diffraction, obtaining basal spacing values around 1.9-2.0 nm in the hybrids, with a drug loading around 31-36 g per 100 g of MMT, while the HNT-based hybrids show an uptake of 15-21 g per 100 g of HNT. Studies carried out in cultures of human neuroblastoma cells confirmed the lack of toxicity of the hybrids and their neuroprotective effect against okadaic acid (OA), the inhibitor of the protein phosphatase 2A (PP2A), similarly to the non-encapsulated drugs. The release assays carried out in systems that simulate the gastrointestinal tract show a rapid release of the drugs from the hybrid materials, making necessary their encapsulation in a protective biopolymer matrix to slow down the release kinetics. A blend of alginate and zein was chosen for this purpose, exploiting the gelation of alginate with calcium ions to process the material as microbeads and the hydrophobic character of zein to reduce the water uptake of the material. Therefore, these bionanocomposite systems integrating the drug/clay hybrids seem promising for the oral administration of drugs with multitarget activity for the treatment of Alzheimer's disease.