CYCLODEXTRIN CONJUGATES

• US 20190321487A1
• Filed: 12/14/2017
• Published: 10/24/2019
• Est. Priority Date: 12/14/2016
• Status: Active Application

• Current Assignee: University College Cork (Higher Education Authority)
• Original Assignee: University College Cork (Higher Education Authority)
• Inventors: DARCY, Raphael, O'DRISCOLL, Caitriona, MALHOTRA, Meenakshi
• Application Number:
  US16/469,248
• Publication Number:
  US 20190321487A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/6929 the form being a nanoparticle, e.g. an immuno-nanoparticle
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40

Abstract

A cyclodextrin-RNA conjugate is described in which the cyclodextrin molecule is conjugated at its glucosyl 6-, 2- or 3-positions, optionally via a linker, to at least one RNA molecule at the RNA 3′ terminal base. The at least one RNA molecule may be an siRNA molecule.

Claims

1. A cyclodextrin-RNA conjugate in which the cyclodextrin molecule is conjugated at its glucosyl 6-, 2- or 3-positions, optionally via a linker, to at least one RNA molecule at the RNA 3′

terminal base.

2. The cyclodextrin-RNA conjugate according to claim 1 in which at least one of the RNA molecules is a siRNA.

3. The cyclodextrin-RNA conjugate according to claim 1 in which the cyclodextrin is an amphiphilic cyclodextrin.

4. An amphiphilic cyclodextrin-RNA conjugate which has the following formula:

5. The cyclodextrin-RNA conjugate according to claim 4 in which R₁ is a lipophilic group and in which R₂ and R₃ are independently selected from polar groups and/or groups capable of hydrogen bonding.

6. The cyclodextrin-RNA conjugate according to claim 4 in which the cyclodextrin has a primary side that is hydrophilic and comprises the R₁X₁ groups and a secondary side that is lipophilic and comprises the R₂X₂ and R₃X₃ groups, wherein R₁ and one of R₂, R₃ are independently a polar group and/or group capable of hydrogen bonding, and in which the other of R₂, R₃ is a lipophilic group.

7. The cyclodextrin-RNA conjugate according to claim 4 in which the groups that are polar and/or capable of hydrogen-bonding are selected from:

H;

OH;

(CH₂)_2-4OH;

CH₂CH(OH)CH₂OH;

CH₂CH(OH)CH₂NH₂;

an amine group;

a cationic group;

an anionic group;

a polyamino acid;

a peptide;

an oligosaccharide;

a polyethylene glycol (PEG) group; and

a hydrophilic group.

8. The cyclodextrin-RNA conjugate according to claim 4 in which the targeting ligand is selected from a group comprising:

a polyaminoacid, a peptide, an oligosaccharide, a steroid, —

P(Y)(Z)O-nucleoside, —

P(Y)(Z)O-oligonucleotide, —

P(Y)(Z)O-Linker-OP(Y′

)(Z′

) O-oligonucleotide, a nucleotide, an oligonucleotide, wherein Y, Z, Y′ and

Z′

are independently O, or S.

9. The cyclodextrin-RNA conjugate according to claim 4 in which the lipophilic group is selected from an aliphatic chain, an alicyclic, aromatic or heterocyclic group, or combinations thereof.

10. The cyclodextrin-RNA conjugate according to claim 4 wherein X₁, X₂, X₃ are independently selected from an ether, ester, methylene, methylenoxy, ethylene, ethylenoxy, carbonyl, thioether, thioester, thiocarbonyl, sulfanyl, disulfide, sulfonyl, sulfoxy, amido, amino, phosphate, thiophosphate, triazolyl.

11. The cyclodextrin-RNA conjugate according to claim 4 wherein the amine group is selected from the group comprising NH₂, NHR where R is one or more of a methyl group, ethyl group, a branched or dendrimeric group comprising one to ten amine groups or a peptide containing basic amino acids, where one or more of the amino groups is optionally in its protonated form, preferably as a hydrohalide salt or trifluoroacetic acid salt.

12. The cyclodextrin-RNA conjugate according to claim 7, wherein the polyethylene glycol (PEG) group is a straight-chain or branched group with one or more independently of a glycosyl, an oligosaccharide, a peptide, a glycopeptide, a protein, an antibody and/or a targeting ligand attached thereto.

13. The cyclodextrin-RNA conjugate according to claim 4 in which the targeting ligand is selected from folate, anisamide, an antibody fragment, a fusogenic peptide, a cell penetrating peptide, rabies virus glycoprotein (RVG), a galactosylated group such as GalNAc (N-acetyl galactosamine)-derivatised group, and prostate surface membrane antigen.

14. A nanoparticulate molecular complex comprising a cyclodextrin-RNA conjugate according to claim 4.

15. The nanoparticulate molecular complex according to claim 14 which is self-assembling and in which the cyclodextrin-RNA conjugate is an amphiphilic cyclodextrin-RNA conjugate of claim 4.

16. The nanoparticulate molecular complex according to claim 14 additionally comprising a complexity amphiphile.

17. The molecular complex according to claim 14 additionally comprising a complexing amphiphile and in which the complexing amphiphile is an amphiphilic cyclodextrin.

18. The nanoparticulate molecular complex according to claim 14 in which the cyclodextrin-RNA conjugate is complexed with a polycation chosen from the following:

a polycationic cyclodextrin, a polycationic lipid, a polycationic oligosaccharide, a polycationic polysaccharide, a polycationic peptide, a polycationic polymer.

19. The nanoparticulate molecular complex according to claim 14, incorporating additionally, by host-guest inclusion or by amphiphilic or electrostatic interaction, a lipophile such as a cholesterol or adamantane derivative and/or other lipid derivative.

20. The nanoparticulate molecular complex according to claim 14, coated, by host-guest inclusion or by amphiphilic or electrostatic interaction, with a polyamine, peptide, protein, oligosaccharide, modified cyclodextrin, polysaccharide, antibody and/or antibody fragment.

21-36. -36. (canceled)