Lipopolyamines of spermine type for construction of liposomal transfection systems
The invention provides new lipopolyamines of spermine type of the general formula I, wherein X is C—N bond or aminopolyethyleneglycolcarboxamide linker or o-hydroxy-alkylcarboxamide linker or ω-hydroxyalkylcarboxamidopolyethyleneglycol-carboxamide linker, and wherein a hydrophobic domain Y is an acyl symmetrically branched in the position C(2) or cholesteryl. The invention further provides a method of preparation of said lipopolyamines and their use for construction of polycationic liposomal drug carriers.
1. Lipopolyamines of spermine type of general formula I
wherein X is selected from the group containing
C—N bond;
aminopolyethyleneglycol carboxamide linker of general formula II
wherein n 1 =1-13;
and a hydrophobic domain Y is selected from an acyl having general formula V
wherein n 5 =5-30.
2. Lipopolyamines of spermine type of general formula I according to claim 1 , characterized in that X is C—N bond or the linker of general formula II wherein n 1 =3, and Y is the acyl of general formula V wherein n 5 =13.
3. A method of preparation of the lipopolyamines of spermine type of general formula I according to claim 1 , characterized in that
in a first step, acids selected from the group containing
fatty acids of general formula VII
wherein n 1 =5-30;
acids of general formula VIII
wherein n 1 =1-13 and n 5 =5-30;
are converted into their pentafluorophenyl esters by reaction with (pentafluorophenyl)carbonate in the presence of organic base in polar aprotic solvent,
in a second step, the acid pentafluorophenyl esters obtained in the first step are converted by reaction with N 2 N 3 N 4 -tri-(tert-butoxycarbonyl)spermine in organic aprotic solvent in the presence of organic base into protected polycationic lipids of general formula XI
wherein X and Y are as defined in claim 1 ,
in a third step, the protected polycationic lipids of general formula XI obtained in the second step are converted by debocylation into lipopolyamines of general formula I as defined in claim 1 .
4. The method according to claim 3 , wherein the acids of general formula VIII are prepared by basic catalysed reaction of pentafluorophenyl esters of the acids of general formula VII with aminopolyethyleneglycol carboxylic acids of formula H 2 N—(CH 2 ) 2 —O—[(CH 2 ) 2 —O] n —(CH 2 )—COOH, wherein n=1-13, in organic aprotic solvent.
5. A method drug delivery, comprising the steps of:
making a polycationic self-assembling system, further comprising the step of providing a lipopolyamine of spermine type of general formula I, as described in claim 1 ;
providing a drug;
using the polycationic self-assembling system as a carrier for the drug; and
delivering the drug to a subject in need thereof.