Targeted delivery of nucleic acids into xenograft tumors mediated by novel folate-equipped liposomes

Novel PEGylated Liposomes Enhance Immunostimulating Activity of isRNA

“…The polydispersity index (PI) values indicated that the presence of PEG lipoconjugate does not influence the homogeneity of the liposomes: liposomes had similar PI values that varied from 0.207 ± 0.015 for P800 to 0.260 ± 0.055 for L (Table 1). These data are in agreement with our recent results [5] showing that the addition of up to 2 M% of folate-based lipoconjugate to liposomal composition did not alter particle size or homogeneity. Liposomes F, containing lipoconjugate in which folate was attached via octadecaethylene glycol spacer, formed particles with a diameter of 60.7 ± 21.7 and a PI of 0.200 ± 0.050, similar to those for P800 .…”

“…It is worth mentioning that working concentration of liposomes for in vitro delivery of NA did not exceed 9 μM. These results are in agreement with our recent data [5,12], showing that very low toxicity of conventional liposome L was not altered by incorporation in liposomal formulation of 2 M% folate lipoconjugate.…”

“…We synthesized a series of 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- О -(4-nitrophenyloxycarbonyl)-2,3-di- O -tetradecylglycerol ( 1 ), which was treated with an excess of diamines ( O , O ′-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]. The free terminal amino group of compounds 2a – c was protected by acetylation to yield the lipoconjugates 3a – c (Figure 1A).…”

“…It has been shown that cationic lipoplexes predominantly accumulate in highly vascularized organs: liver, kidney, heart and lungs, but they do not have any cell or tissue specificity. Therefore, 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 the body and ensures the accumulation of an effective therapeutic dose in the target organ. Cationic lipoplexes, which are highly effective for delivering nucleic acids in cell culture, are less effective in the body due to the toxicity associated with the interactions of a positively charged particle with proteins and blood cells, and also due to the recognition and absorption of these particles by macrophages [6].…”

“…Previously, we developed an effective liposomal nucleic acid delivery system based on the polycationic amphiphile 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosan tetrahydrochloride (2X3) and the lipid-helper dioleoylphosphatidylethanolamine (DOPE) [12,13,14], which effectively delivers nucleic acids in vitro and in vivo and showed that the incorporation of a folic acid-containing lipoconjugate into the lipid composition provides targeted delivery to tumors that express folate receptors at a high level [5].…”