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Pharmaceutics 2018, 10(3), 81; https://doi.org/10.3390/pharmaceutics10030081

Synthesis, Structure–Activity Relationships and In Vitro Toxicity Profile of Lactose-Based Fatty Acid Monoesters as Possible Drug Permeability Enhancers

1
Department of Biomolecular Sciences, School of Pharmacy, University of Urbino, 61029 Urbino (PU), Italy
2
Drug Delivery and Tissue Engineering Division, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK
3
Department of Pharmacology & Pharmacy, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, China
4
School of Pharmacy, University of Camerino, 62032 Camerino (MC), Italy
5
Science and Technology Facilities Council (STFC), ISIS Neutron and Muon Source, Rutherford Appleton Laboratory, Didcot OX11 0QX, UK
*
Author to whom correspondence should be addressed.
Received: 30 May 2018 / Revised: 26 June 2018 / Accepted: 2 July 2018 / Published: 3 July 2018
(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)
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Abstract

Permeability enhancers are receiving increased attention arising from their ability to increase transepithelial permeability and thus, bioavailability of orally or pulmonary administered biopharmaceutics. Here we present the synthesis and the in vitro assaying of a series of lactose-based non-ionic surfactants, highlighting the relationship between their structure and biological effect. Using tensiometric measurements the critical micelle concentrations (CMCs) of the surfactants were determined and demonstrate that increasing hydrophobic chain length reduces surfactant CMC. In vitro testing on Caco-2 intestinal and Calu-3 airway epithelia revealed that cytotoxicity, assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays, is presented for most of the surfactants at concentrations greater than their CMCs. Further biological study demonstrates that application of cytotoxic concentrations of the surfactants is associated with depolarizing mitochondrial membrane potential, increasing nuclear membrane permeability and activation of effector caspases. It is, therefore, proposed that when applied at cytotoxic levels, the surfactants are inducing apoptosis in both cell lines tested. Importantly, through the culture of epithelial monolayers on Transwell® supports, the surfactants demonstrate the ability to reversibly modulate transepithelial electrical resistance (TEER), and thus open tight junctions, at non-toxic concentrations, emphasizing their potential application as safe permeability enhancers in vivo. View Full-Text
Keywords: absorption enhancers; sugar-based surfactants; biocompatibility studies; transmucosal drug delivery absorption enhancers; sugar-based surfactants; biocompatibility studies; transmucosal drug delivery
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Lucarini, S.; Fagioli, L.; Cavanagh, R.; Liang, W.; Perinelli, D.R.; Campana, M.; Stolnik, S.; Lam, J.K.W.; Casettari, L.; Duranti, A. Synthesis, Structure–Activity Relationships and In Vitro Toxicity Profile of Lactose-Based Fatty Acid Monoesters as Possible Drug Permeability Enhancers. Pharmaceutics 2018, 10, 81.

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