Complexes comprising a nucleic acid bound to a cationic polyamine having an endosome disruption agent

Claim 1

A multifunctional molecular complex for the transfer of a nucleic acid composition to a target cell comprising in combination: A) said nucleic acid composition non-covalently bonded to B) a transfer moiety, wherein said transfer moiety comprises one or more cationic polyamine components bound to said nucleic acid composition, each independently comprising a cationic polyamine of the formula (1): NR(R.sup.3)-- --(CR.sup.1 R.sup.2).sub.m --N(R.sup.3)--!.sub.n --(CR.sup.1 R.sup.2).sub.m --NR(R.sup.3) (1) wherein: R, R 1 and R 2 are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; m in each occurrence is independently selected from the integers 2 through 5 inclusive; n is selected from the integers 1 through 10 inclusive; R 3 is independently selected from the group consisting of hydrogen; C 1-6 alkyl; and one or more endosome membrane disruption promoting components independently selected from the group consisting of: a) --B--(CR 1 R 2 ) j --C(R) 3 , where R, R 1 and R 2 are each independently defined as above; j is an integer from 6 to 24 inclusive; and B is optionally absent, or is a bridging group of the formula: --(CR.sup.1 R.sup.2).sub.k --C(═O)--Z--; i) --(CR.sup.1 R.sup.2).sub.k --N(R)--C(═O)--Z--; ii) --(CR.sup.1 R.sup.2).sub.k --N(R)--{--C(═O)--CH.sub.2 --O-- --(CH.sub.2).sub.2 --O--!.sub.1 --(CH.sub.2).sub.2 --N(R)}.sub.p --C(═O)--Z--; or iii) --(CR.sup.1 R.sup.2).sub.k --C(═O)--{--N(R)-- --(CH.sub.2).sub.2 --O--!.sub.1 --CH.sub.2 --C(═O)}.sub.p --Z--; iv) where k is an integer from 1 to 6 inclusive, l is an integer from 0 to 4 inclusive, and p is an integer from 1 to 3 inclusive; R, R 1 and R 2 are each independently defined as above; and Z is O, S, N(R), or is absent; b) --B--(R 4 )R, where R, R 1 and R 2 are each independently defined as above; B cannot be absent and is a bridging group independently selected from groups i) through iv) above, and the group of the formula: --(CR.sup.1 R.sup.2).sub.j' --X--, v) where j' is an integer from 1 to 8 inclusive; R 1 and R 2 are each independently defined as above; X is O, S, N(R), or absent; and R 4 is independently selected from the group consisting of: i) fusogenic peptides comprising spike glycoproteins of enveloped animal viruses; ii) cholic acid derivatives of the formula (2): ##STR5## where: represents a bond of unspecified stereochemistry; - - - represents a single or double bond, forming a saturated or unsaturated portion of the ring system, provided that they cannot both be unsaturated at the same time, whereby the ring system must be either Δ4 or Δ5; R 6 is --H, --OH, --CO 2 H, --C(═O)NH 2 , --OC(═O)NH 2 , --NH 2 , or --O(CH 2 CH 2 O) n' H, where n' is an integer from 1 to 6 inclusive; R 7 is a radical that forms the point of attachment of the cholic acid derivative, comprising --C 1-6 alkyl-- or --C 1-6 alkylcarbonyl--; and R 8 is C 1-6 alkyl; and iii) cholesteryl derivatives of the formula (3): ##STR6## where: represents a bond of unspecified stereochemistry; - - - represents a single or double bond, forming a saturated or unsaturated portion of the ring system, provided that they cannot both be unsaturated at the same time, whereby the ring system must be either Δ4 or Δ5; R 6a is a radical that forms the point of attachment of the cholesteryl derivative, comprising --C 1-6 alkyl--, --OC(═O)--, or --OCH 2 C(═O)--; R 7a is C 1-6 alkyl; and R 8a is C 1-6 alkyl; PROVIDED THAT R 3 is one or more endosome membrane disruption promoting components attached to at least one nitrogen atom of at least one of said cationic polyamine components; and OPTIONALLY, R 3 may be one or more groups defined below, attached either to a further nitrogen atom of at least one of said cationic polyamine components to which said one or more endosome membrane disruption promoting components is attached, or to a nitrogen atom of at least one further polyamine component which does not have attached thereto any endosome membrane disruption promoting component: c) --B--(R 5 )R, where B cannot be absent, and is a bridging group independently selected from groups i) through v) inclusive; R is independently defined as above; and R 5 is a receptor specific binding component independently selected from the group consisting of: i) D-biotin; ii) β-3'-propionyl galactosyl-β1-4-thioglucoside; iii) N 2 ,N 6 -bis(β-3'-propionyl galactosyl-β1-4-thioglucoside)lysine; iv) N 2 ,N 6 -bis(β1-3'-propionyl galactosyl-β1-4-thioglucoside)lysyl-N 6 -(β-3'-propionyl galactosyl-β1 -4-thioglucoside)lysine; v) 5-methyitetrahydrofolate; vi) folic acid; vii) folinic acid; viii) α-3'-propionyl thiomannoside; and ix) α-3'-propionyl thiomannoside-6-phosphate.