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Lipophilic Polyamines As Promising Components of Liposomal Gene Delivery Systems

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Lipophilic Polyamines As Promising Components of Liposomal Gene Delivery Systems pharmaceutics Review Lipophilic Polyamines as Promising Components of Liposomal Gene Delivery Systems Pavel A. Puchkov and Michael A. Maslov * Lomonosov Institute of Fine Chemical Technologies, MIREA—Russian Technological University, Vernadsky Ave. 86, 119571 Moscow, Russia; [email protected] * Correspondence: [email protected]; Tel.: +7-499-600-8202 Abstract: Gene therapy requires an effective and safe delivery vehicle for nucleic acids. In the case of non-viral vehicles, including cationic liposomes, the structure of compounds composing them deter- mines the efficiency a lot. Currently, cationic amphiphiles are the most frequently used compounds in liposomal formulations. In their structure, which is a combination of hydrophobic and cationic domains and includes spacer groups, each component contributes to the resulting delivery efficiency. This review focuses on polycationic and disulfide amphiphiles as prospective cationic amphiphiles for gene therapy and includes a discussion of the mutual influence of structural components. Keywords: polyamines; spermine; cationic amphiphiles; cationic liposomes; disulfide groups; gemini amphiphiles; gene delivery 1. Introduction Citation: Puchkov, P.A.; Maslov, M.A. Gene therapy is a modern and promising method for treating severe hereditary and Lipophilic Polyamines as Promising acquired diseases, including COVID-19 immunization, through the delivery of therapeutic Components of Liposomal Gene nucleic acids (NAs) that can replace a damaged gene (pDNA), provide a new one, or block Delivery Systems. Pharmaceutics 2021, the expression of an unwanted protein (antisense oligonucleotides, siRNA) [1,2]. The direct 13, 920. https://doi.org/10.3390/ administration of therapeutic NAs is an inefficient process due to multiple external and pharmaceutics13060920 internal limiting factors [3]. External factors lead to the instability of NAs in biological Academic Editors: María Luisa Moyá fluids (degradation by nucleases or interaction with albumin or low-density lipoproteins, and Manuel López-López causing the aggregation and rapid clearance of NAs) and a low degree of interaction with target cells. Internal factors are determined by the presence of membrane barriers (plasma, Received: 18 May 2021 endosomal, and nuclear membranes) that present a challenge to NAs as they attempt to Accepted: 17 June 2021 reach the cytosol and nucleus [4]. Published: 21 June 2021 Overcoming these factors requires the development of special delivery vehicles. At present, viruses [5,6], which are highly effective but present some serious disadvantages, Publisher’s Note: MDPI stays neutral primarily associated with the induction of inflammatory and immune responses in the with regard to jurisdictional claims in body, fill this role. However, alternative non-viral delivery vehicles, such as cationic published maps and institutional affil- liposomes (CLs) based on cationic amphiphiles (CAs) [6–9], are being developed. The most iations. recent success is development of an mRNA vaccine [10] against COVID-19, where lipid nanoparticles deliver nucleoside-modified mRNA encoding a mutated form of the spike protein of SARS-CoV-2 [11]. Generally, CA structure is a combination of hydrophobic and cationic domains linked together by various spacer groups [12]. The positive charge of Copyright: © 2021 by the authors. CAs enables the “packing” of NAs due to electrostatic interactions with the formation Licensee MDPI, Basel, Switzerland. of lipoplexes (complexes of NAs with liposomes) and facilitates their interaction with a This article is an open access article negatively charged plasma membrane. distributed under the terms and In addition to CAs, liposomes can include helper lipids (for example, 1,2-dioleoyl-sn- conditions of the Creative Commons glycero-3-phosphoethanolamine, DOPE) [13–15], which promote the formation of a certain Attribution (CC BY) license (https:// lipid phase and favor cell transfection. Liposomes may also contain additional lipophilic creativecommons.org/licenses/by/ molecules that permit them to target certain cells [16] or increase their circulation time in 4.0/). Pharmaceutics 2021, 13, 920. https://doi.org/10.3390/pharmaceutics13060920 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2021, 13, 920 2 of 27 Pharmaceutics 2021, 13, 920 certain lipid phase and favor cell transfection. Liposomes may also contain additional2 oflip- 27 ophilic molecules that permit them to target certain cells [16] or increase their circulation time in the bloodstream (for example, lipophilic derivatives of polyethylene glycol, PEG) [17]. If it is not stated below, CAs were used without additional components. the bloodstreamThe CA structure (for example, significantl lipophilicy affects derivatives the efficiency of polyethylene of NA delivery glycol, PEG)to eukaryotic [17]. If it cells.is not In stated recent below, years, CAs many were monocationic used without amphiphiles additional components. have been obtained [18–28] that form Theliposomes CA structure for NA significantly delivery. affectsIn this the review, efficiency we ofwill NA consider delivery topolycationic eukaryotic cells.am- phiphiles,In recent years,which, many compared monocationic to monocationic amphiphiles analogs, have enable been the obtained more efficient [18–28] thattransport form ofliposomes NAs into forcells NA due delivery. to the formation In this review, of a system we will of distributed consider polycationic charges in the amphiphiles, polyamine which, compared to monocationic analogs, enable the more efficient transport of NAs into matrix and their ability to facilitate NA release from endosomes. This ability is strongly cells due to the formation of a system of distributed charges in the polyamine matrix and affected by the high H+ buffer capacity of polyamines containing titratable amines results their ability to facilitate NA release from endosomes. This ability is strongly affected by the in endosomal Cl− accumulation during acidification with presumed osmotic endosome high H+ buffer capacity of polyamines containing titratable amines results in endosomal disruption and enhanced lipoplex escape [29]. Cl− accumulation during acidification with presumed osmotic endosome disruption and enhanced lipoplex escape [29]. 2. Cationic Amphiphiles Based on Polyamines or Amino Acids 2.1.2. Cationic Cationic AmphiphilesAmphiphiles Ba Basedsed on onLinear Polyamines Polyamines or Amino Acids 2.1. CationicEnhancement Amphiphiles of NA Based transport on Linear by polycationic Polyamines amphiphiles may be related not only to distributedEnhancement charges. of NA On transportthe cell surface, by polycationic polyamine amphiphiles recognition may sites—for be related example, not only PAT to [30],distributed a polyamine charges. transporter—selectively On the cell surface, polyamine transport recognition both polyamines sites—for example,and their PAT deriva- [30], tives.a polyamine Moreover, transporter—selectively cancer cells have more transport such sites both on polyaminestheir surfaces, and which their derivatives.means that amphiphilesMoreover, cancer based cells on havepolyamines more such can sites transfect on their cancer surfaces, cells which more meansefficiently. that amphiphilesParticularly importantbased on polyaminesfactors in NA can delivery transfect are cancer the number cells more and efficiently.distribution Particularly of positive charges important in thefactors polyamine in NA delivery molecule. are theTransfection number and activity distribution (TA) has of positive been shown charges to in increase the polyamine as the numbermolecule. of Transfectionamino groups activity in the (TA)polyamine has been structure shown increases. to increase Compound as the number 1e (Figure of amino 1) exhibitedgroups in the the highest polyamine transfection structure efficiency increases. Compoundamong the synthesized1e (Figure1) lipopolyamines exhibited the highest 1a–g [31],transfection which suggests efficiency that among 1e can the use synthesized PAT and compete lipopolyamines with other1a– polyamines,g [31], which for suggests exam- ple,that spermine,1e can use PATfor binding and compete to certain with otherrecognition polyamines, sites foron example,the cell surface spermine, (in forparticular, binding withto certain the same recognition PAT). sites on the cell surface (in particular, with the same PAT). Figure 1. LipopolyaminesLipopolyamines with with benzyl benzyl linker. AnotherAnother factor factor affecting affecting the the efficiency efficiency of transfection is the hydrophobicity of the amphiphilicamphiphilic molecule. molecule. A A study study of of compounds compounds 22 andand 3a3a––dd,, which which contain contain sterols sterols (cortisol (cortisol andand its derivatives) asas hydrophobichydrophobic domainsdomains (Figure (Figure2), 2), revealed revealed that that TA TA increases increases with with an anincrease increase in thein the hydrophobicity hydrophobicity of theof the molecule molecule [32 [32].]. While While liposomes liposomes with with compound compound3d 3dwere were shown shown to beto be incapable incapable of deliveringof delivering NAs, NAs, possibly possibly due due to theto the lower lower hydrophobicity hydrophobi- cityof the of amphiphilethe amphiphile3d and 3d and ineffective ineffective formation formation of lipoplexes, of lipoplexes, compounds compounds3b and 3b and3c had 3c hadthe highestthe highest transfection transfection efficiencies. efficiencies. Notably, Notably, the contributionthe contribution
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