2018-188 - Food-Derived Chemicals for Modulating Permeability of Biological Barriers
Abstract
Pelargonidin: a strawberry-derived intestinal permeation enhancer for oral delivery of macromolecule drugs. Oral delivery of biologic drugs would revolutionize modern medicine, due to its ease of use, high patient compliance, and physiological advantages when compared with injections. However, successful oral formulations must overcome poor transport of large therapeutic molecules from the intestines to the bloodstream. Chemical permeation enhancers of the intestinal epithelial barrier have been identified, and some have entered clinical trials, but their translation has traditionally been hampered by cytotoxicity. This ongoing need inspired us to investigate food components as known non-toxic chemicals in the intestines, and their potential application as intestinal permeation enhancers. As a result, we have demonstrated that the strawberry pigment pelargonidin and some of its molecular relatives are effective, nontoxic enablers of oral biologic absorption (Figure 1). Pelargonidin and its molecular family, the anthocyanidins, are aglycone (sugar-free) versions of the anthocyanin pigments commonly found in wines, fruits, vegetables, and many flowers. The general structure (Figure 2a) comprises the three-ring flavylium cation with substitutions of –OH or –OCH3 groups at different combinations of the denoted "R" sites. In an intestinal cell culture screen of six anthocyanidins, three members of this family increased drug permeability across tissue, with pelargonidin (Plrgn) performing particularly well (Figure 2b). These findings underscore the importance of this particular molecular structure, and the potential for application of additional, effective compounds within the anthocyanidin family. We have further demonstrated that pelargonidin can be used to enable oral delivery of insulin, a 5.8 kDa protein, in mice (Figure 3a). Impressively, the oral combination of pelargonidin and a one unit per kilogram insulin dose provided a sustained decrease in blood sugar, amounting to 140% of the total drug activity when compared to the current gold standard of subcutaneous injection. Additionally, we showed that pelargonidin improves uptake of the linear polymers 40 kDa and 70 kDa dextran (Figure 3b). This implies that this system can be applied to bioactive polymers (including heparin) and nucleic acids (including siRNA). To this end, because the permeation enhancer strategy of oral macromolecule delivery is not dependent on the drug chemistry, anthocyanidins have the potential to orally deliver a broad range of current biologic drug candidates without further chemical development.
Market Application
Oral delivery of large molecules.
Publications
From Farm to Pharmacy: Strawberry-Enabled Oral Delivery of Protein DrugsNicholas G.Lamson,Katherine C.Fein,John P.Gleeson,SijieXian,AlexandraNewby,NamitChaudhary,Jilian R.Melamed,KyleCochran,Rebecca L.Ball,KanikaSuri,VishalAhuja,AnnaZhang,AdrianBerger,DmytroKolodieznyi,Brigitte F.Schmidt,Gloria L.Silva,View ORCID ProfileKathryn A.Whiteheaddoi:https://doi.org/10.1101/2020.03.11.987461This article is a preprint and has not been certified by peer reviewhttps://www.biorxiv.org/content/10.1101/2020.03.11.987461v1
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