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US 2004/0018962 A1Published application
Lipid-conjugated polyamide compounds
AssigneeChiron Corporation
InventorsRonald N. Zuckermann, Chin-Yi Huang, John E. Murphy, Tetsuo Uno
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Abstract
In accordance with the present invention, there are provided lipid-conjugated polyamide compounds and related compositions and methods thereof. Lipid-conjugated polyamide compounds of the present invention are particularly useful as vehicles for delivering biologically active agents to a target site. In particular, the invention compounds are effective at facilitating the delivery of polynucleotides to cells. The present invention also provides a method for producing stable formulations of polynucleotides complexed with a delivery vehicle.
Claims36
A compound having the formula:
- 15
- wherein n is an integer selected from 1 to about 48 and m is an integer selected from about 2 to about 48,
- wherein R1 for each monomeric unit,
- 16
- and Ra are independently selected from the group consisting of a hydrogen atom;
- a hydroxy group;
- an amino group;
- a carboxyl group;
- a sulfonyl group;
- —SH;
- an optionally substituted, branched or straight chain aliphatic group having from 1 to about 8 carbon atoms in a backbone structure that optionally contains nitrogen, oxygen, sulfur, and phosphorus, wherein said aliphatic group optionally has one or more double or triple bonds;
- an optionally substituted aryl group having from about 3 to about 12 carbon atoms in a backbone structure that optionally contains nitrogen, oxygen, sulfur, and phosphorus;
- an optionally substituted arylalkyl group having from about 3 to about 12 carbon atoms in a backbone structure that optionally contains nitrogen, oxygen, sulfur, and phosphorus, wherein the alkyl component of said arylalkyl optionally has one or more double or triple bonds;
- and a lipid moiety that is optionally bonded to linker moiety,
- wherein R1 is not a hydrogen atom for at least one monomeric unit,
- wherein Rc is selected from a hydrogen atom;
- a hydroxy group;
- an amino group;
- a hydrazine group;
- a sulfonyl group;
- —SH;
- an optionally substituted, branched or straight chain aliphatic group having from 1 to about 8carbon atoms in a backbone structure that optionally contains nitrogen, oxygen, sulfur, and phosphorus, wherein said aliphatic group optionally has one or more double or triple bonds;
- an optionally substituted aryl group having from 3 to about 12 carbon atoms in a backbone structure that optionally contains nitrogen, oxygen, sulfur, and phosphorus;
- an optionally substituted arylalkyl group having from about 3 to about 12 carbon atoms in a backbone structure that optionally contains nitrogen, oxygen, sulfur, and phosphorus, wherein the alkyl component of said arylalkyl optionally has one or more double or triple bonds;
- and a lipid moiety that is optionally bonded to a linker moiety,
- wherein when R1, Ra, or Rc is an aryl or arylalkyl group having fewer than about 5 carbon atoms in a backbone structure, said backbone structure further comprises one or more heteroatoms atoms,
- wherein W for each monomeric unit is independently selected from an optionally substituted, branched or straight chain divalent moiety having from 1 to about 50 atoms and optionally, one or more double or triple bonds in a backbone that contains carbon and optionally contains nitrogen, oxygen, sulfur, and phosphorus,
- wherein said lipid moiety is a hydrophobic or amphipathic moiety selected from the group consisting of:
- (i) optionally substituted aryl or arylalkyl moieties having from about 14 to about 50 carbon atoms in a backbone structure that optionally contains nitrogen, oxygen, sulfur, and phosphorus, wherein the alkyl component of said arylalkyl optionally has one or more double or triple bonds;
- and
- (ii) optionally substituted, branched or straight chain aliphatic moieties having from about 10 to about 50 carbon atoms in a backbone structure that optionally contains nitrogen, oxygen, sulfur, and phosphorus, wherein said aliphatic moieties optionally have one or more double or triple bonds, and
- wherein at least one of Ra, Rc, W for a single monomeric unit and R1 for a single monomeric unit comprises a lipid moiety.
29 more elements
A method of synthesizing lipid-conjugated polyamide compounds, said method comprising:
- a) contacting
- (1) a lipid reactant, with
- (2) an oligomer reactant, wherein said oligomer reactant has the general formula:
- 20
- wherein n is an integer selected from 1 to about 48, and m is an integer from about 2 to about 48,
- wherein each Ta and Tc is independently selected from a terminal group and a reactive moiety that is capable of further reaction with said lipid reactant,
- wherein R1 for each monomeric unit,
- 21
- in said oligomer reactant is selected from the group consisting of a hydrogen atom;
- a hydroxy group;
- an amino group;
- a carboxyl group;
- a sulfonyl group, —SH;
- an optionally substituted, branched or straight chain aliphatic group having from 1 to about 8 carbon atoms in a backbone structure that optionally contains nitrogen, oxygen, sulfur, and phosphorus, wherein the aliphatic group optionally has one or more double or triple bonds;
- an optionally substituted aryl group having from about 3 to about 12 carbon atoms in a backbone structure that optionally contains nitrogen, oxygen, sulfur, and phosphorus;
- an optionally substituted arylalkyl group having from about 3 to about 12 carbon atoms in a backbone structure that optionally contains nitrogen, oxygen, sulfur, and phosphorus, wherein the alkyl component of said arylalkyl optionally has one or more double or triple bonds;
- and a reactive moiety that is capable of further reaction with said lipid reactant,
- wherein when R1, Ra, or Rc is an aryl or arylalkyl group having fewer than about 5 carbon atoms in a backbone structure, said backbone structure further comprises one or more heteroatoms,
- wherein R1 is not a hydrogen atom for at least one monomeric unit,
- wherein W for each monomeric unit is selected from an optionally substituted, branched or straight chain divalent moiety having from 1 to about 50 atoms in a backbone that contains carbon, and optionally contains nitrogen, oxygen, sulfur, and phosphorus, and optionally one or more double or triple bonds,
- wherein at least one of Ta, Tc, W for a single monomeric unit, and R1 for a single monomeric unit comprises a reactive moiety that is capable of further reaction with said lipid reactant;
- then
- b) reacting said lipid reactant with said oligomer reactant to conjugate the lipid reactant to the oligomer reactant.
20 more elements
A method for inducing the uptake of a biologically active agent by a cell, said method comprising:
- providing a composition comprising an effective amount of a biologically active agent and a lipid-conjugated polyamide compound;
- then
- contacting a biological sample with an effective dose of said composition,
- wherein said biological sample comprises a cell.
1 more element
A method of making a stable preparation of a polynucleic acid complexed with a delivery vehicle, said method comprising:
- a) providing a polynucleic acid in a first liquid carrier as a dilute polynucleic acid solution that is substantially precipitant-free;
- b) providing a delivery vehicle-forming compound in a second liquid carrier as a delivery vehicle solution that is substantially precipitant-free;
- c) combining said dilute polynucleic acid solution with said delivery vehicle solution to form a dilute preparation of delivery vehicle/polynucleic acid complex;
- then
- d) reducing the volume of said dilute preparation to form a stable preparation of delivery vehicle/polynucleic acid complex,
- wherein the concentration of polynucleic acid in said stable preparation is higher than the concentration of polynucleic acid in said dilute polynucleic acid solution, and
- wherein said stable preparation is substantially precipitant-free.
4 more elements
Dependencies are inferred from the claim text.