Abstract
The performance of cationic liposomes for delivery of therapeutic nucleic acids in vivo can be improved and specifically tailored to certain types of cargo and target cells by incorporation of PEG-containing lipoconjugates in the cationic liposome’s composition. Here, we report on the synthesis of novel PEG-containing lipoconjugates with molecular masses of PEG 800, 1500 and 2000 Da. PEG-containing lipoconjugates were used as one of the components in liposome preparation with the polycationic amphiphile 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetra-azahexacosan tetrahydrochloride (2X3) and the lipid-helper dioleoylphosphatidylethanolamine (DOPE). We demonstrate that increasing the length of the PEG chain reduces the transfection activity of liposomes in vitro, but improves the biodistribution, increases the circulation time in the bloodstream and enhances the interferon-inducing activity of immunostimulating RNA in vivo.
Highlights
At present, the prospects of therapeutic preparations based on nucleic acids have been proven and small interfering RNA, microRNA, antisense oligonucleotides, aptamers and genomic editing systems are widely used in experimental biomedicine
We synthesized a series of polyethylene glycol (PEG)-containing lipoconjugates, 3a–c, with PEG spacers of different lengths: from 18 to 52 ethylene glycol units (Figure 1A)
The starting hydrophobic molecule used for the synthesis of PEG-containing lipoconjugates 3a–c was rac-1-O-(4-nitrophenyloxycarbonyl)-2,3-di-O-tetradecylglycerol (1), which was treated with an excess of diamines (O,O0 -bis(2-aminoethyl)-octadecaethylene glycol (MW ~800 Da), bis(3-aminopropyl)polyethylene glycol (MW ~1500 Da) and bis(amino)polyethylene glycol (MW ~2000 Da) to give mono-amino derivatives 2a–c containing PEG spacers [5,15]
Summary
The prospects of therapeutic preparations based on nucleic acids have been proven and small interfering RNA, microRNA, antisense oligonucleotides, aptamers and genomic editing systems are widely used in experimental biomedicine. The use of these biologically active substances in therapy is hampered by the fact that their effective targeted delivery to cells has not been solved to date. Two main approaches are used to ensure the delivery of therapeutic nucleic acids to target cells: the formation of complexes with different particles and polymers [1] and bioconjugation with lipophilic molecules, antibodies, aptamers and amphiphiles [2]. Lipoplexes carrying ligands to specific cellular receptors are used to develop delivery vehicles for therapeutic nucleic acids [3,4,5], which reduces the overall toxic effect on Molecules 2018, 23, 3101; doi:10.3390/molecules23123101 www.mdpi.com/journal/molecules
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
