International Journal of Molecular Sciences Concept Paper Lipids and Lipid-Processing Pathways in Drug Delivery and Therapeutics Milica Markovic 1 , Shimon Ben-Shabat 1, Aaron Aponick 2 , Ellen M. Zimmermann 3 and Arik Dahan 1,* 1 Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel; [email protected] (M.M.); [email protected] (S.B.-S.) 2 Department of Chemistry, University of Florida, Gainesville, FL 32603, USA; [email protected]fl.edu 3 Department of Medicine, Division of Gastroenterology, University of Florida, Gainesville, FL 32610, USA; [email protected]fl.edu * Correspondence: [email protected] Received: 13 April 2020; Accepted: 2 May 2020; Published: 4 May 2020 Abstract: The aim of this work is to analyze relevant endogenous lipid processing pathways, in the context of the impact that lipids have on drug absorption, their therapeutic use, and utilization in drug delivery. Lipids may serve as biomarkers of some diseases, but they can also provide endogenous therapeutic effects for certain pathological conditions. Current uses and possible clinical benefits of various lipids (fatty acids, steroids, triglycerides, and phospholipids) in cancer, infectious, inflammatory, and neurodegenerative diseases are presented. Lipids can also be conjugated to a drug molecule, accomplishing numerous potential benefits, one being the improved treatment effect, due to joined influence of the lipid carrier and the drug moiety. In addition, such conjugates have increased lipophilicity relative to the parent drug. This leads to improved drug pharmacokinetics and bioavailability, the ability to join endogenous lipid pathways and achieve drug targeting to the lymphatics, inflamed tissues in certain autoimmune diseases, or enable overcoming different barriers in the body. Altogether, novel mechanisms of the lipid role in diseases are constantly discovered, and new ways to exploit these mechanisms for the optimal drug design that would advance different drug delivery/therapy aspects are continuously emerging. Keywords: lipid; fatty acid; glyceride; steroid; phospholipid; oral drug absorption; prodrug; phospholipase A2 (PLA2) 1. Introduction Lipids are hydrophobic biomolecules, which include fatty acids (FA), glycerides, phospholipids (PL), sterols, sphingolipids, and prenol lipids (Figure1)[ 1]. Lipids play an important role in energy metabolism and storage, as structural components, in signaling, and as hormones. The disruption of lipid metabolic enzymes and pathways occurs in many disease such as cancer, diabetes, infectious, neurodegenerative, and inflammatory diseases [2]. The aim of this work is to elucidate the effect of lipids, and lipid excipients on drug absorption, to describe the metabolic lipid pathways and to demonstrate the role that lipids have in many pathological conditions, as well as their endogenous pharmacological activity. An additional section is dedicated to lipidic prodrugs that can exploit lipid processing pathways in order to achieve their effect. The presence of dietary lipids or lipids from drug formulations/lipidic prodrugs can influence drug absorption by incorporating to the natural lipid metabolic pathways. Hereinafter, we provide a small overview of the lipid influence on drug absorption. Int. J. Mol. Sci. 2020, 21, 3248; doi:10.3390/ijms21093248 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 3248 2 of 15 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 15 Figure 1.1. Main lipid categories: examples of chemical structures. Molecular revolution, such as development of in-vitroin-vitro high-throughputhigh-throughput screening methods and combinatorial chemistry,chemistry, resulted resulted in ain high a high number number of poor of aqueouspoor aqueous solubility solubility molecules molecules to be selected to be asselected drug candidates.as drug candidates. Nearly 40% Nearly of all 40% novel of drugall novel candidates drug candidates are lipophilic are lipophilic and demonstrate and demonstrate low water solubilitylow water [solubility3,4]. Following [3,4]. Following oral administration, oral administration, drugs encounter drugs encounter various obstaclesvarious obstacles on their on way their to theway blood to the circulation. blood circulation. Absorption Absorption is a process, is a process, in which in which orally o administeredrally administered compounds compounds travel travel from thefrom gastrointestinal the gastrointestinal (GI) lumen (GI) into lumen the intestinal into the membrane intestinal and entermembrane systemic and circulation enter systemic/become bioavailable.circulation/become Following bioavailable. ingestion Following and prior ingestion to permeation, and prior the drugto permeation, has to be dissolvedthe drug has in the to GIbe milieudissolved and in turn the GI into milieu a molecular and turn form into closea molecular to the form intestinal closemembrane. to the intestinal This membrane. can be diffi Thiscult can for lipophilicbe difficult compounds for lipophilic with compounds poor solubility with inpoor water, solubility thereby in presenting water, thereby a limiting presenting step in a the limiting absorption step process.in the absorption The presence process. of lipids The derivedpresence from of lipids food orderived lipid-based from formulationsfood or lipid- inbased the intestinalformulations lumen in canthe intestinal influence lumen the oral can absorption influence of the highly oral absorption lipophilic drugs of highly in many lipophilic different drugs ways. in many Thesolubility different ofways. the drugThe solubility can be increased, of the drug due can to be the increased, creation of due various to the colloidalcreation of formations various colloidal (vesicles, formations micelles). 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(NHR) Additionally, were shown nuclear to play hormone an important receptors role in(NHR) lipid trawerefficking shown and to metabolism play an important and, thus, role in intestinal in lipid lipid trafficking and drug and absorption, metabolism since and, they thus, control in aintestinal number lipid of proteins and drug (e.g., absorption, fatty-acid-binding since they proteins) control a that number are involved of proteins in lipid (e.g./drug, fatty transport-acid-binding and metabolismproteins) that [8– 10are]. Followinginvolved oralin administration,lipid/drug transport in many and cases metabolism drugs pass through[8–10]. theFollowing hepatic veinoral onadministration, their way to thein many systemic cases blood, drugs whereas pass through highly the lipophilic hepatic compounds vein on their may way be to transported the systemic through blood, thewhereas intestinal highly lymphatic lipophilic system. compounds Lipids canmay also be stimulatetransported intestinal through lymphatic the intestinal drug transport,lymphatic in system. which theLipids drugs can can also bypass stimulate the first-passintestinal hepaticlymphatic metabolism drug transport, and go in directly which tothe the drugs systemic can bypass circulation the first [11].- Afterpass hepatic solubilization, metabolism drugs and permeate go directly through to the the systemic intestinal circulation membrane [11]. via After passive solubilization, diffusion/ activedrugs transportpermeate throughthrough thethe enterocytes.intestinal membrane For hydrophilic via passive drugs diffusion/active with poor solubility transport in lipids, through this stepthe canenterocytes. be the rate-limiting For hydrophilic in the drugs absorption with poor cascade, solubili whereas,ty in lipids, for lipophilic this step drugs,can be thethe unstirredrate‐limiting water in layerthe absorption (UWL) in cascade, the proximity whereas, of the for intestinal lipophilic membrane drugs, the is anunstirred obstacle water for e fflayerective (UWL) permeability. in the Theproximity diffusion of the of FA, intestinal monoglycerides membrane (MG), is an and obstacle many for other effective lipophilic permeability. molecules (includingThe diffusion drugs of andFA, prodrugs)monoglyce throughrides (MG), UWL and is many significantly other lipophilic increased molecules through micellar(including solubilization, drugs and prodrugs) prior to arrivingthrough UWL is significantly increased through micellar solubilization, prior to arriving to the enterocytes. It is likely these lipophilic molecules dissociate from the micelles prior to going into enterocytes or Int. J. Mol. Sci. 2020, 21, 3248 3 of 15 to the enterocytes. It is likely these lipophilic molecules dissociate from the micelles prior to going into enterocytes or through binding to the transporter or vesicular-mediated