Versatile Nasal Application of Cyclodextrins: Excipients and/or Actives?
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ABSTRACT:
SUBMITTER: Rassu G
PROVIDER: S-EPMC8401481 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cyclodextrins, representing a versatile family of cyclic oligosaccharides, have extensive pharmaceutical applications due to their unique truncated cone-shaped structure with a hydrophilic outer surface and a hydrophobic cavity, which enables them to form non-covalent host-guest inclusion complexes in pharmaceutical formulations to enhance the solubility, stability and bioavailability of numerous drug molecules. As a result, cyclodextrins are mostly considered as inert carriers during their medical application, while their ability to interact not only with small molecules but also with lipids and proteins is largely neglected. By forming inclusion complexes with cholesterol, cyclodextrins deplete cholesterol from cellular membranes and thereby influence protein function indirectly through alterations in biophysical properties and lateral heterogeneity of bilayers. In this review, we summarize the general chemical principles of direct cyclodextrin-protein interactions and highlight, through relevant examples, how these interactions can modify protein functions in vivo, which, despite their huge potential, have been completely unexploited in therapy so far. Finally, we give a brief overview of disorders such as Niemann-Pick type C disease, atherosclerosis, Alzheimer's and Parkinson's disease, in which cyclodextrins already have or could have the potential to be active therapeutic agents due to their cholesterol-complexing or direct protein-targeting properties.
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Project description:Gastrointestinal cancers are characterized by a frequent incidence, a high number of associated deaths, and a tremendous burden on the medical system and patients worldwide. As conventional chemotherapeutic drugs face numerous limitations, researchers started to investigate better alternatives for extending drug efficacy and limiting adverse effects. A remarkably increasing interest has been addressed to chitosan and cyclodextrins, two highly versatile natural carbohydrate materials endowed with unique physicochemical properties. In this respect, numerous studies reported on fabricating various chitosan and cyclodextrin-based formulations that enabled prolonged circulation times, improved cellular internalization of carried drugs, preferential uptake by the targeted cells, reduced side effects, enhanced apoptosis rates, and increased tumor suppression rates. Therefore, this paper aims to briefly present the advantageous properties of these oligo- and polysaccharides for designing drug delivery systems, further focusing the discussion on nanocarrier systems based on chitosan/cyclodextrins for treating different gastrointestinal cancers. Specifically, there are reviewed studies describing promising solutions for colorectal, liver, gastric, pancreatic, and other types of cancers of the digestive system towards creating an updated framework of what concerns anticancer chitosan/cyclodextrin-based drug delivery systems.
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Project description:Cyclodextrin polymers have high applicability in pharmaceutical formulations due to better biocompatibility, solubility enhancement, loading capacity and controlled drug release than their parent, cyclodextrins. The cytotoxicity and cell uptake of new cationic beta-cyclodextrin monomers and polymers were evaluated as suitable materials for nasal formulations and their protective effects on cells exposed to hydrogen peroxide were studied. PC12 and CACO-2 cells were selected as the neuronal- and epithelial-type cells, respectively, to mimic the structure of respiratory and olfactory epithelia of the nasal cavity. All cationic beta-cyclodextrin polymers tested showed dose- and time-dependent toxicity; nevertheless, at 5 µM concentration and 60 min of exposure, the quaternary-ammonium-beta-cyclodextrin soluble polymer could be recognized as nontoxic. Based on these results, a fluorescently labelled quaternary-ammonium-beta-cyclodextrin monomer and polymer were selected for uptake studies in CACO-2 cells. The monomeric and polymeric beta-cyclodextrins were internalized in the cytoplasm of CACO-2 cells; the cationic monomer showed higher permeability than the hydroxypropyl-beta-cyclodextrin, employed as comparison. Therefore, these cationic beta-cyclodextrins showed potential as excipients able to improve the nasal absorption of drugs. Furthermore, amino-beta-cyclodextrin and beta-cyclodextrin soluble polymers were able to reduce oxidative damage in PC12 and CACO-2 cells and thus could be studied as bioactive carriers or potential drugs for cell protection against oxidative stress.
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Project description:Fragment-based drug discovery (FBDD) is a powerful method to develop potent small-molecule compounds starting from fragments binding weakly to targets. As FBDD exhibits several advantages over high-throughput screening campaigns, it becomes an attractive strategy in target-based drug discovery. Many potent compounds/inhibitors of diverse targets have been developed using this approach. Methods used in fragment screening and understanding fragment-binding modes are critical in FBDD. This review elucidates fragment libraries, methods utilized in fragment identification/confirmation, strategies applied in growing the identified fragments into drug-like lead compounds, and applications of FBDD to different targets. As FBDD can be readily carried out through different biophysical and computer-based methods, it will play more important roles in drug discovery.
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