In vitro and in vivo intracellular delivery of sirna via self-assembled nanopieces

Patent metadata

Field	Value
Publication number	US-2021023117-A1
Application number	US-201917041399-A
Country	US
Kind code	A1
Filing date	Mar 26, 2019
Priority date	Mar 26, 2018
Publication date	Jan 28, 2021
Grant date	—

Abstract

The compositions and methods of the invention provide compositions and methods for preferential targeting of tissues to delivery therapeutic or diagnostic agents. For example, such compounds are useful in the treatment of joint disorders those affecting articulating joints, e.g., injury-induced osteoarthritis as well as autoimmune diseases affecting joint tissue such as rheumatoid arthritis.

First claim

1 . A system for selective drug delivery to a cell or bodily tissue comprising a rosette nanopiece composition comprising a cargo compound,
wherein a positively-charged nanopiece composition with net positive charge at pH 7-7.5 localizes or penetrates a negatively-charged cell or tissue; wherein a negatively-charged or weakly positively-charged nanopiece composition with net negative charge or weak positive charge at pH 7-7.5 localizes or penetrates a positively-charged cell or tissue.

2 . The system of claim 1 , wherein said cargo compound comprises:
i) tumor necrosis factor-alpha (TNF-α) small interfering ribonucleic acid (siRNA): or ii) a drug, and wherein said drug comprises a diagnostic reagent or a therapeutic compound.

3 . The system of claim 1 , wherein said cell comprises a macrophage, said negatively charged tissue comprises cartilage tissue or a chondrocyte cell, or said positively charged tissue comprises neuronal tissue or comprises a neuron.

4 . (canceled)

5 . The system of claim 1 , wherein said net positive charge comprises a Zeta potential >+8 mV, or said net negative charge comprises a Zeta potential <+30 mV.

6 - 8 . (canceled)

9 . The system of claim 1 , wherein said composition comprises a compound of Formula (I) or (II):

or a salt thereof,
wherein, X is CH or N;
R 2 is hydrogen or a linker group;
Y is absent when R 2 is hydrogen or is an amino acid or polypeptide; and
R 1 is hydrogen or aliphatic,
wherein the amino acid side chain is selected from:

10 . The system of claim 9 , wherein said composition comprises a compound selected from

or a salt thereof.

11 - 15 . (canceled)

16 . The system of claim 9 , wherein compounds of Formula (I), Formula (II), or a salt thereof, or a combination of Formula (I) and Formula (II) self-assemble to form a nanotube.

17 . The system of claim 16 , wherein said nanotube comprises one or more diagnostic agents and said diagnostic agent comprises a molecular probe or a molecular beacon, or, said therapeutic agent comprises an IL-1 receptor antagonist.

18 . The system of claim 16 , wherein said nanotube comprises one or more therapeutic agents, wherein said therapeutic agent comprises nucleic acid, peptide or small molecule.

19 . (canceled)

20 . The system of claim 18 , wherein the nucleic acid comprises siRNA, TNF-α siRNA, or the sequence comprising of: AAG CCT GTA GCC CAC GTC GTA (SEQ ID NO: 229) and GGC ACC ACT AGT TGG TTG TCT TTG (SEQ ID NO: 230).

21 - 25 . (canceled)

26 . A method of treating a joint disease comprising administration of an effective amount of a rosette nanopiece, wherein said nanopiece comprises a compound of Formula I or Formula II,

or a salt thereof,
wherein, X is CH or N;
R 2 is hydrogen or a linker group;
Y is absent when R 2 is hydrogen or is an amino acid or polypeptide, and
R 1 is hydrogen or aliphatic,
Wherein the amino acid side chain is selected from:

27 . The method of claim 26 , wherein said joint disease comprises a TNF-α-mediated autoimmune disease, or said autoimmune disease comprises rheumatoid arthritis.

28 . (canceled)

29 . The method of claim 26 , wherein said nanopiece comprises a TNF-α siRNA.

30 . The method of claim 26 , wherein said nanopiece enters a macrophage cell.

31 . The method of claim 26 , wherein said nanopiece is administered systemically.

32 . A method of diagnosing joint disease comprising administration of rosette nanopiece, wherein said nanopiece comprises a compound of Formula I or Formula II,

or a salt thereof,
wherein, X is CH or N;
R 2 is hydrogen or a linker group;
Y is absent when R 2 is hydrogen or is an amino acid or polypeptide; and
R 1 is hydrogen or aliphatic,
Wherein the amino acid side chain is selected from:

33 . The method of claim 26 , wherein said joint disease comprises autoimmune, degenerative, inflammatory, infectious, cancerous, viral, fungal, injured, trauma, genetic, trauma, mechanical, nutritional or mal-alignment derived, rheumatoid arthritis, osteoarthritis, juvenile onset of rheumatoid arthritis (JRA), reactive arthritis (RA), septic arthritis tendinitis, or herniation.

34 - 36 . (canceled)

37 . The system for selective drug delivery of claim 1 ,
wherein a size of ≤100 nm in at least one dimension localizes or penetrates a phagocytic cell, synovium, ocular tissue, dermatologic tissue, mucosal tissue, or pulmonary tissue; wherein a size of <90 nm in at least one dimension localizes or penetrates cartilage with inflammation or defect; wherein a size of ≤50 nm in at least one dimension localizes or penetrates kidney tissue; wherein a size of <30 nm in at least one dimension localizes or penetrates healthy, intact cartilage; or wherein a size of ≤20 nm in at least one dimension localizes or penetrates heart tissue.

38 . (canceled)

39 . A composition comprising a cargo molecule and a nanostructure comprising Formula I or Formula II,

or a salt thereof,
wherein, X is CH or N;
R 2 is hydrogen or a linker group,
Y is absent when R 2 is hydrogen or is an amino acid or polypeptide; and
R 1 is hydrogen or aliphatic,
Wherein the amino acid side chain is selected from:

or a salt thereof, for selective delivery of a therapeutic drug or diagnostic agent to a target cell or a bodily tissue.

40 . The composition of claim 39 , further comprising a nucleic acid molecule.

41 . The composition of claim 40 , wherein the nucleic acid molecule comprises siRNA, TNF-α siRNA, or the sequence comprising of: AAG CCT GTA GCC CAC GTC GTA (SEQ ID NO: 229) and GGC ACC ACT AGT TGG TTG TCT TTG (SEQ ID NO. 230).

42 - 43 . (canceled)

44 . The composition of claim 39 , wherein said cell comprises a phagocytic cell, or a macrophage.

45 . (canceled)

46 . A method of treating a joint disease comprising administration of a composition comprising a nanopiece and a nucleic acid, wherein

Assignees

• Rhode Island Hospital

Inventors

• Chen Qian
• Chen Yupeng
• Yu Hongchuan

Classifications

• A61K47/6949 Primary

  inclusion complexes, e.g. clathrates, cavitates or fullerenes · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C12N2310/11

  Antisense · CPC title

• C12N15/113

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• C12N2320/31

  Combination therapy · CPC title