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US 6,310,047 B1Granted
High affinity DNA binding compounds as adjuvants in antisense technology
AssigneeVirginia Commonwealth University
InventorsNicholas Farrell, Miriam Kloster
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Abstract
The invention provides an improved method for the delivery and stabilization of antisense oligodeoxynucleotides (ODNs) to cells. The unmodified ODNs are complexed to a polynuclear platinum compound or to a structural derivative thereof. Complexation neutralizes the charge of the ODN and makes possible its passage into the cell, without the addition of other transfection agents. The invention may be used in the treatment any disease which is amenable to treatment by antisense ODNs. In addition, the invention provides a new method specifically for the treatment of cancer.
Claims20
A method for the delivery of an antisense oligodeoxynucleotide to cells, comprising the steps of,
- forming a complex comprising said oligodeoxynucleotide and a polynuclear platinum compound, and
- providing said complex to cells.
A method for the treatment of cancer in a patient in need thereof, comprising the steps of:
- forming a complex comprising an oligodeoxynucleotide and a polynuclear platinum compound, wherein said polynuclear platinum compound is selected from the group consisting of 1,0,1/t,t,t n=6,6 and a structural derivative of 1,0,1/t,t,t n=6,6 and
- administering said complex to said patient.
A composition comprising
- a single-stranded oligodeoxynucleotide, and
- a polynuclear platinum compound complexed with said single-stranded oligodeoxynucleotide wherein said polynuclear platinum compound is selected on the group consisting of
- i) a polynuclear platinum compound having the structural formula:
- wherein X, Y and Z are selected from the group consisting of:
- am(m)ines, mono-dentate diamines, aromatic planar amines, sulfoxides and leaving groups;
- A is selected from the group consisting of:
- NH2(CH2)bH2N, wherein b=2-12
- NH2(CH2)bNR(CH2)cH2N, wherein b and c range from 2 to 12, and R is selected from the group consisting of:
- H2, (C1-C6 alkyl), (C1-C6)acyl, and (C1-C6)alkyloxycarbonyl;
- NH2(CH2)bNR(CH2)cNR(CH2)dH2N wherein b, c and d range from 2 to 12, and R is selected from the group consisting of:
- H2, (C1-C6 alkyl), (C1-C6)acyl, and (C1-C6)alkyloxycarbonyl);
- (NH2(CH2)bH2N)(NH2(CH2)cH2N)Pt(X)(Z) wherein b and c range from 2-12, and X and Z are selected from the group consisting of:
- am(m)ines, mono-dentate diamines, aromatic planar amines, sulfoxides and leaving groups;
- (NH2(CH2)bH2N)Pt(X)(Z)(NH2(CH2)cH2N)Pt(X)(Z)(NH2(CH2)dH2N) and wherein b, c and d range from 2-12, and X and Z are selected from the group consisting of:
- am(m)ines, mono-dentate diamines, aromatic planar amines, sulfoxides and leaving groups;
- (NH2(CH2)bH2N)Pt(X)(Z)(NH2(CH2)cH2N)Pt(X)(Z)(NH2(CH2)dH2N)Pt(X)(Z)(NH2(CH2)eH2N) wherein b, c, d, and e range from 2-12 and X and Z are selected from the group consisting of:
- am(m)ines, mono-dentate diamines, aromatic planar amines, and sulfoxides;
- {(NH2(CH2)aH2N)(NH2(CH2)bH2N)M(L)4}m+ wherein a and b range from 2-12, M is a non-platinum metal, L is a ligand selected from the group consisting of:
- monodentate and bidentate chelates, and m+ is a charge on the non-platinum metal, and n+ is a charge on said polynuclear platinum compound;
- ii) a polynuclear platinum compound having the structural formula:
- wherein A═NH2(CH2)bNR(CH2)cH7N where R═(CH2)dH2N and b, c and d range from 2 to 12;
- X, Y and Z are selected from the group consisting of;
- am(m)ines, mono-dentate diamines, aromatic planar amines, sulfoxides and leaving groups;
- and
- n+ represents an overall charge on said polynuclear platinum compound;
- and
- iii) a polynuclear platinum compound having the structural formula:
- wherein A═NH2(CH2)bNR1(CH2)cNRc(CH2)dH2N, where R1═(CH2)cH2N, R2═(CH2)fH2N and b, c, d, e and f range from 2 to and 12;
- X, Y and Z are selected from the group consisting of:
- am(m)ines, mono-dentate diamines, aromatic planar amines, sulfoxides and leaving groups;
- and
- n+ represents an overall charge on said polynuclear platinum compound.
29 more elements
A polynuclear platinum compound having the structural formula:
- wherein X, Y and Z are selected from the group consisting of:
- am(m)ines, mono-dentate diamines, aromatic planar amines, sulfoxides and leaving groups;
- A is selected from the group consisting of:
- NH2(CH2)bNR(CH2)cH2N, wherein b and c range from 2 to 12, and R is selected from the group consisting of:
- H2, (C1-C6 alkyl), (C1-C6)acyl, and (C1-C6)alkyloxycarbonyl;
- NH2(CH2)bNR(CH2)cNR(CH2)dH2N wherein b, c and d range from 2 to 12, and R is selected from the group consisting of:
- H2, (C1-C6 alkyl), (C1-C6)acyl, and (C1-C6)alkyloxycarbonyl);
- (NH2(CH2)bH2N)(NH2(CH2)cH2N)Pt(X)(Z) wherein b and c range from 2-12, and X and Z are selected from the group consisting of:
- am(m)ines, mono-dentate diamines, aromatic planar amines, sulfoxides;
- (NH2(CH2)bH2N)Pt(X)(Z)(NH2(CH2)cH2N)Pt(X)(Z)(NH2(CH2)dH2N) and wherein b, c and d are sulfoxides;
- (NH2(CH2)bH2N)Pt(X)(Z)(NH2(CH2)cH2N)Pt(X)(Z)(NH2(CH2)dH2N) Pt(X)(Z)(NH2(CH2)eH2N) wherein b, c, d, and e range from 2-12 and X and Z are sulfoxides;
- {(NH2(CH2)aH2N)(NH2(CH2)bH2N)M(L)4}m+ wherein a and b range from 2-12, M is a non-platinum metal, L is a ligand selected from the group consisting of:
- monodentate and bidentate chelates, and m+ is the charge on the non-platinum metal, and n+ is the charge on said polynuclear platinum compound.
10 more elements
A polynuclear platinum compound having the structural formula:
- wherein A═NH2(CH2)bNR(CH2)cH2N where R═(CH2)dH2N and b, c and d range from 2 to 12;
- X, Y and Z are selected from the group consisting of:
- am(m)ines, mono-dentate diamines, aromatic planar amines, sulfoxides;
- and
- n+ represents the overall charge on said polynuclear platinum compound.
2 more elements
A polynuclear platinum compound having the structural formula
- wherein A═NH2(CH2)bNR1(CH2)cNR2(CH2)dH2N, where R1═(CH2)eH2N, R2═(CH2)fH2N and b, c, d, e and f range from 2 to 12;
- X, Y and Z are selected from the group consisting of:
- am(m)ines, monodentate diamines, aromatic planar amines, sulfoxides and leaving groups;
- and
- n+ represents an overall charge on said polynuclear platinum compound.
2 more elements
Dependencies are inferred from the claim text.