Dexamethasone Conjugates: Synthetic Approaches and Medical Prospects
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biomedicines Review Dexamethasone Conjugates: Synthetic Approaches and Medical Prospects Natallia V. Dubashynskaya , Anton N. Bokatyi and Yury A. Skorik * Institute of Macromolecular Compounds of the Russian Academy of Sciences, Bolshoy pr. V.O. 31, 199004 St. Petersburg, Russia; [email protected] (N.V.D.); [email protected] (A.N.B.) * Correspondence: [email protected] Abstract: Dexamethasone (DEX) is the most commonly prescribed glucocorticoid (GC) and has a wide spectrum of pharmacological activity. However, steroid drugs like DEX can have severe side effects on non-target organs. One strategy to reduce these side effects is to develop targeted systems with the controlled release by conjugation to polymeric carriers. This review describes the methods available for the synthesis of DEX conjugates (carbodiimide chemistry, solid-phase synthesis, reversible addition fragmentation-chain transfer [RAFT] polymerization, click reactions, and 2-iminothiolane chemistry) and perspectives for their medical application as GC drug or gene delivery systems for anti-tumor therapy. Additionally, the review focuses on the development of DEX conjugates with different physical-chemical properties as successful delivery systems in the target organs such as eye, joint, kidney, and others. Finally, polymer conjugates with improved transfection activity in which DEX is used as a vector for gene delivery in the cell nucleus have been described. Keywords: dexamethasone; drug conjugate; drug delivery system; gene delivery system; biopoly- mers Citation: Dubashynskaya, N.V.; Bokatyi, A.N.; Skorik, Y.A. Dexamethasone Conjugates: Synthetic Approaches and Medical 1. Introduction Prospects. Biomedicines 2021, 9, 341. Glucocorticoids (GC), including dexamethasone (DEX), are the most potent anti- https://doi.org/ inflammatory drugs available, but they can have quite severe acute and chronic systemic 10.3390/biomedicines9040341 side effects [1]. The local administration of DEX in the eye or the joints, as well as inhalation Academic Editor: Shaker A. Mousa and irrigation applications, can provide the correct dose of the drug directly to the inflamed site and reduce the side effects that can arise with systemic administration. However, these Received: 1 March 2021 local methods need frequent application, which creates inconvenience for patients and Accepted: 24 March 2021 may lead to patient noncompliance with the drug protocol. In addition, the use of intra- Published: 27 March 2021 articular and intravitreal injections is limited by possible complications that can include joint infections and retinal detachment, respectively [1–6]. Publisher’s Note: MDPI stays neutral The administration of drugs using extended release delivery systems can control the with regard to jurisdictional claims in release and increase the residence time of the drug at the target site, thereby reducing the published maps and institutional affil- frequency of doses and the risk of side effects [7–12]. For this reason, much research is iations. focused on the development of DEX delivery systems with a release profile that extends from several days to months [13]. Conjugates that are able to provide prolonged release by hydrolysis of chemical bonds are of particular interest [14]. Many reviews have appeared recently on DEX delivery systems [15,16], especially Copyright: © 2021 by the authors. those aimed at ocular [7,17] and intra-articular [8] therapies. These reviews have discussed Licensee MDPI, Basel, Switzerland. DEX delivery using many nanocarriers, including polymer and lipid particles, dendrimers, This article is an open access article micelles, liposomes, implants, and conjugates. However, these reviews lack a detailed distributed under the terms and description of one particularly important delivery system, namely DEX conjugates. In conditions of the Creative Commons particular, descriptions of the methods for their synthesis and the physicochemical charac- Attribution (CC BY) license (https:// teristics that affect targeted delivery are scarce. For these reasons, this review focuses on creativecommons.org/licenses/by/ the preparation of DEX conjugates with various physicochemical properties and describes 4.0/). Biomedicines 2021, 9, 341. https://doi.org/10.3390/biomedicines9040341 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, 341 2 of 26 Biomedicines 2021, 9, 341 2 of 27 and describes the promise these delivery systems hold for providing more appropriate sustainedthe promise release these profiles. delivery systems hold for providing more appropriate sustained release profiles. 2. DEX as a Pharmaceutical Substance: Chemical, Pharmacological, and Biopharmaceutical2. DEX as a Pharmaceutical Properties Substance: Chemical, Pharmacological, and Biopharmaceutical Properties DEX (9-fluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione, Figure 1A) isDEX a synthetic (9-fluoro-11 GC,β a,17,21-trihydroxy-16 fluorinated homologueα-methylpregna-1,4-diene-3,20-dione, of hydrocortisone, and is includedFigure in 1theA ) Worldis a synthetic Health GC,Organization a fluorinated model homologue list of e ofssential hydrocortisone, medicines. and DEX is includedmimics the in the GC World hor- moneHealth that Organization is secreted modelby the listadrenal of essential cortex medicines.mainly to regulate DEX mimics carbohydrate the GC hormone and protein that metabolism.is secreted by The the presence adrenal cortexof a fluorine mainly atom to regulate in the DEX carbohydrate molecule and makes protein this metabolism.GC about 7 timesThe presence more potent of a fluorinethan prednisolone atom in the and DEX abou moleculet 35 times makes more this potent GC aboutthan cortisone, 7 times more alt- houghpotent DEX than has prednisolone practically and no aboutmineralocorticoid 35 times more activity. potent The than duration cortisone, of althoughDEX action DEX is has practically no mineralocorticoid activity. The duration of DEX action is 36–72 h, far 36–72 h, far longer than cortisone and hydrocortisone (only 5–12 h), and prednisone (12– longer than cortisone and hydrocortisone (only 5–12 h), and prednisone (12–30 h) [7,18–21]. 30 h) [7,18–21]. Figure 1. Chemical structure of dexamethasone (A) and dexamethasone sodium phosphate (B). Essential structures for Figure 1. Chemical structure of dexamethasone (A) and dexamethasone sodium phosphate (B). Essential structures for pharmacological activity are highlighted in red (anti-inflammatory), in green (carbohydrate regulation), in blue (adreno- pharmacological activity are highlighted in red (anti-inflammatory), in green (carbohydrate regulation), in blue (adrenocor- corticosteroid function), in light blue (Na+ retention), and in violet (Na+ elimination) [22,23]. ticosteroid function), in light blue (Na+ retention), and in violet (Na+ elimination) [22,23]. DEX is a lipophilic substance with a solubility in water of 100 μg/mL; accordingly, DEX is a lipophilic substance with a solubility in water of 100 µg/mL; accordingly, DEX is soluble in acetone, ethanol, and chloroform. The water-soluble form, DEX sodium DEX is soluble in acetone, ethanol, and chloroform. The water-soluble form, DEX sodium phosphate (Figure 1B), is transformed within the organism into active DEX; it has a lower phosphate (Figure1B), is transformed within the organism into active DEX; it has a lower lipidlipid membrane membrane permeability permeability and and is isused used as asa more a more soluble soluble form form of the of theactive active pharmaceu- pharma- ticalceutical ingredient ingredient in intravenous in intravenous drugs drugs [24,25]. [24 DEX,25]. mimics DEX mimics natural natural GCs in GCs terms in termsof phar- of macologicalpharmacological effects, effects, such as such anti-inflammatory, as anti-inflammatory, anti-allergic, anti-allergic, immunosuppressive, immunosuppressive, anti- shock,anti-shock, and anti-toxicity and anti-toxicity actions actions [26,27]. [26 ,27]. TheThe mechanism mechanism of of DEX DEX action action can can be be re realizedalized in in both genomic and non-genomic waysways [28]. [28]. The The genomic genomic mechanism mechanism is is as as follows follows (Figure (Figure 2A):2A): lipophilic lipophilic DEX DEX easily easily pene- pen- tratesetrates the the cell cell membrane membrane and and binds binds to tointracellular intracellular cytoplasmic cytoplasmic GCGC receptors receptors that that are arelo- catedlocated in inalmost almost all all organs organs and and tissues. tissues. The The resulting resulting receptor-GC receptor-GC complex complex interacts interacts with with aa specific specific DNA DNA site site and and activates activates the the transcription transcription of of specific specific genes. genes. As As a result, a result, mRNA mRNA is synthesizedis synthesized and and acts acts as a as matrix a matrix for the for thesynthesi synthesiss of specific of specific proteins proteins that thatthen then change change cell functions.cell functions. For Forexample, example, the thesynthesized synthesized pr proteinotein lipocortin lipocortin blocks blocks phospholipase phospholipase A2 A2 (PLA2),(PLA2), therebythereby blockingblocking the the phospholipid phospholipid destruction destruction and and the arachidonicthe arachidonic acid formationacid for- mationtypically typically carried outcarried by PLA2. out by This PLA2. then This prevents then prevents the synthesis the synthesis of inflammatory of inflammatory mediators mediators(prostaglandins (prostaglandins [PG], thromboxanes [PG],