Reversible inhibition of efflux transporters by hydrogel microdevices.

Oral drug delivery is a preferred administration route due to its low cost, high patient compliance and fewer adverse events compared to intravenous administration. However, many pharmaceuticals suffer from poor solubility and low oral bioavailability. One major factor that contributes to low bioavailability are efflux transporters which prevent drug absorption through intestinal epithelial cells. P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are two important efflux transporters in the intestine functioning to prevent toxic materials from entering systemic circulation. However, due to its broad substrate specificity, P-gp limits the absorption of many therapeutics, including chemotherapeutics and antibacterial agents. Methods to inhibit P-gp with competitive inhibitors have not been clinically successful. Here, we show that micron scale devices (microdevices) made from a commonly used biomaterial, polyethylene glycol (PEG), inhibit P-gp through a biosimilar mucus in Caco-2 cells and that transporter function is restored when the microdevices are removed. Microdevices were shown to inhibit P-gp mediated transport of calcein AM, doxorubicin, and rhodamine 123 (R123) and BCRP mediated transport of BODIPY-FL-prazosin. When in contact with Caco-2 cells, microdevices decrease the cell surface amount of P-gp without affecting the passive transport. Moreover, there was an increase in mucosal to serosal transport of R123 with microdevices in an ex-vivo mouse model and increased absorption in vivo. This biomaterial-based approach to inhibit efflux transporters can be applied to a range of drug delivery systems and allows for a nonpharmacologic method to increase intestinal drug absorption while limiting toxic effects

Long‐term daily oral administration of intestinal permeation enhancers is safe and effective in mice

Abstract Although protein drugs are powerful biologic therapeutics, they cannot be delivered orally because their large size and hydrophilicity limit their absorption across the intestinal epithelium. One potential solution is the incorporation of permeation enhancers into oral protein formulations; however, few have advanced clinically due to toxicity concerns surrounding chronic use. To better understand these concerns, we conducted a 30‐day longitudinal study of daily oral permeation enhancer use in mice and resultant effects on intestinal health. Specifically, we investigated three permeation enhancers: sodium caprate (C10), an industry standard, as well as 1‐phenylpiperazine (PPZ) and sodium deoxycholate (SDC). Over 30 days of treatment, all mice gained weight, and none required removal from the study due to poor health. Furthermore, intestinal permeability did not increase following chronic use. We also quantified the gene expression of four tight junction proteins (claudin 2, claudin 3, ZO‐1, and JAM‐A). Significant differences in gene expression between untreated and permeation enhancer‐treated mice were found, but these varied between treatment groups, with most differences resolving after a 1‐week washout period. Immunofluorescence microscopy revealed no observable differences in protein localization or villus architecture between treated and untreated mice. Overall, PPZ and SDC performed comparably to C10, one of the most clinically advanced enhancers, and results suggest that the chronic use of some permeation enhancers may be therapeutically viable from a safety standpoint

The pH of Piperazine Derivative Solutions Predicts Their Utility as Transepithelial Permeation Enhancers

The oral delivery of macromolecular drugs, including proteins and nucleic acids, is one of the greatest unmet needs in modern biomedicine. Although engineering solutions have been used to overcome enzymatic degradation and the low pH in the stomach, poor absorption across the intestinal epithelium into the bloodstream continues to pose the most significant challenge to clinical translation. One common approach to increase the flux of macromolecules across the intestinal epithelium is the use of chemical permeation enhancers. Unfortunately, the vast majority of effective enhancers have been thwarted by toxicity, and the structural and molecular parameters that contribute to this behavior are poorly understood. Previous work has shown that select piperazine-derived molecules favorably affect transepithelial and intracellular delivery outcomes, suggesting that piperazine-derived molecules interface uniquely with cellular barriers. To gain a better understanding of piperazine-mediated permeation enhancement, this work examined piperazine and 13 of its simple, hydrocarbon-substituted derivatives using Caco-2 monolayers as a model of the intestinal epithelium. After evaluating each piperazine for permeation enhancement efficacy and cytotoxicity at three concentrations, it became clear that piperazine derivatives consistently enhance permeability with each derivative resulting in noncytotoxic permeation enhancement at one or more concentrations. In attempting to identify structure–function relationships for the piperazine derivatives, it was found that treatment concentration, structural characteristics, and molecular p<i>K</i>_a were not reliable indicators of permeation potential. Interestingly, the pH of the enhancer solution was identified as a controlling parameter even when accounting for the effects from pH change alone. Specifically, piperazine treatments with a pH between 9.2 and 9.6 guaranteed noncytotoxic efficacy. Furthermore, all effective treatments resulted in pH values between 8.7 and 9.6, behavior that was not shared by the other small, noncyclic amines studied. These data have important implications in the design of oral biologic delivery systems that employ permeation enhancers and underscore the need to carefully control the final treatment pH of the local intestinal epithelial environment

Indicative Distribution Maps for Ecological Functional Groups - Level 3 of IUCN Global Ecosystem Typology

This dataset includes the original version of the indicative distribution maps and profiles for Ecological Functional Groups - Level 3 of IUCN Global Ecosystem Typology (v2.0). Please refer to Keith et al. (2020). The descriptive profiles provide brief summaries of key ecological traits and processes for each functional group of ecosystems to enable any ecosystem type to be assigned to a group. Maps are indicative of global distribution patterns are not intended to represent fine-scale patterns. The maps show areas of the world containing major (value of 1, coloured red) or minor occurrences (value of 2, coloured yellow) of each ecosystem functional group. Minor occurrences are areas where an ecosystem functional group is scattered in patches within matrices of other ecosystem functional groups or where they occur in substantial areas, but only within a segment of a larger region. Most maps were prepared using a coarse-scale template (e.g. ecoregions), but some were compiled from higher resolution spatial data where available (see details in profiles). Higher resolution mapping is planned in future publications. We emphasise that spatial representation of Ecosystem Functional Groups does not follow higher-order groupings described in respective ecoregion classifications. Consequently, when Ecosystem Functional Groups are aggregated into functional biomes (Level 2 of the Global Ecosystem Typology), spatial patterns may differ from those of biogeographic biomes. Differences reflect the distinctions between functional and biogeographic interpretations of the term, biome