Liposaccharide-based nanoparticulate drug delivery systemAdel S. Abdelrahima, Pavla Simerskaa,*, Istvan Totha,baThe University of Queensland, School of Chemistry and Molecular Biosciences (SCMB), St Lucia, Brisbane, Queensland 4072, AustraliabThe University of Queensland, School of Pharmacy, Woolloongabba, Queensland 4102, Australiaa r t i c l e i n f oArticle history:Received 3 February 2012Received in revised form 30 March 2012Accepted 16 April 2012Available online 23 April 2012Keywords:Charged liposaccharideMicrocalorimetryTobramycinAbsorption enhancerNanoparticleDrug deliverya b s t r a c tA series of anionic liposaccharide derivatives were synthesized in order to develop a system, whichwould have the capacity to act as an absorption enhancer and to improve oral bioavailability of drugs.The addition of a liposaccharide to a drug enhances drug stability against enzymatic degradation, whilethe lipophilicity can be controlled by variation of the lipid side chain. All liposaccharide derivatives werepurified and fully characterized by nuclear magnetic resonance and high-resolution mass spectrometry.The thermodynamic profiles, critical aggregation concentrations and size of the synthesized lip-osaccharides were determined by isothermal titration microcalorimetry, transmission electron micros-copy and dynamic light scattering. These liposaccharides formed nanoparticles with sizes below 100 nm.? 2012 Elsevier Ltd. All rights reserved.1. IntroductionA large number of newly developed drug candidates cannot beadministered orally for various reasons such as poor penetrationthrough the intestinal mucosa, and/or binding in the gastrointes-tinal tract due to the highly hydrophilic properties.1Therefore, theadministration of these drugs is limited to intravenous or in-tramuscular routes. To overcome these challenges, medicinal andpharmaceutical research has focused on development of alterna-tives with enhanced oral bioavailability.2One of the main strategiesbeing investigated is increasing the lipophilicity of the constructs,thereby facilitating their penetration across the intestine. Recently,many studies have been carried out to study the influence of ab-sorption enhancers (e.g., bile salts, fatty acids, surfactants) on thedrug’s intestinal absorption and membrane permeability, especiallyby passive diffusion.3The addition of a safe and effective absorptionenhancer into the conventional oral dosageform is considered tobeeasier and cheaper than development of a novel drug or pro-drug.4Also aggregation, surfactant and ion-pairing characteristics of theformed compounds can increase intestinal uptake.5We have demonstrated earlier that the co-administration ofliposaccharide-based absorption enhancers with various drugs(e.g., piperacillin6and gentamicin7) improved absorption of theparent drug invivo. However, the permeability of those compoundswas still low.8To further improve the permeability, we describe thesynthesis and characterization of a novel series of anionic lip-osaccharide derivatives with good absorption enhancing activity.These derivatives are unique amphiphilic synthetic compoundswith a lipophilic tail (lipoamino acid) and a hydrophilic head con-taining a carbohydrate (glucose) and a glutamic acid sodium salt.Sodium salt formation of an acidic drug increases the solubility andstability during oral administration.9This structural arrangementmodulates aqueous solubility as well as the lipophilicity of thedrugeliposaccharide complex. The incorporation of a lipoaminoacid (LAA),10an amino acid with a lipophilic alkyl side chain, intothe molecules was previously reported to increase oral absorptionof drugs with poor bioavailability.11It has been shown, when LAAsform amphiphilic ion pairs with macrolide class antibiotics (e.g.,erythromycin) there was no decrease in its antibacterial activity.12The incorporation of a carbohydrate into the system not only im-proves water solubility, but also can utilize active or facilitatedglucose transport systems during absorption.The amphoteric structural design of the molecules was de-veloped in order to promote surfactant like properties and furtheraggregation and/or micellization of the liposaccharides. Isothermaltitration calorimetry (ITC) was performed to determine the criticalaggregation concentration (CAC) of the synthesized compounds.Enthalpy of aggregation (DHagg), the Gibbs’ free energy of aggre-gation (DGagg) and the entropy of aggregation (DSagg) were alsocalculated. The size and shape of the liposaccharides were mea-sured by transmission electron microscopy (TEM) and dynamiclight scattering (DLS).* Corresponding author. Tel.: þ61 7 33469892; fax: þ61 7 33654273; e-mailaddress: p.simerska@uq.edu.au (P. Simerska).Contents lists available at SciVerse ScienceDirectTetrahedronjournal homepage: www.elsevier.com/locate/tet0040-4020/$ e see front matter ? 2012 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2012.04.064Tetrahedron 68 (2012) 4967e4975
