Nanocarriers and their processing for diagnostics and therapeutics
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.
1. A method of treating joint disease comprising administration to a subject of an effective amount of a nanopiece, wherein said nanopiece comprises i) a compound of Formula I or Formula II or a combination thereof, and ii) a nucleic acid:
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 side chain, amino acid or polypeptide; and
R 1 is hydrogen or aliphatic, wherein the nanopiece has a size in at least one dimension between 0.1 nm and 150 nm,
wherein a ratio of the compound to nucleic acid ranges from 4.4 to 30 μg compound per to 0.1 nmol of the nucleic acid;
wherein the nanopiece is positively charged at pH 7-7.5.
2. The method of claim 1 , wherein said joint disease comprises autoimmune, degenerative, inflammatory, infectious, cancerous, viral, fungal, injured, trauma, genetic, trauma, mechanical, nutritional or mal-alignment derived.
3. The method of claim 1 , wherein said joint disease comprises rheumatoid arthritis, osteoarthritis, juvenile onset of rheumatoid arthritis (JRA), reactive arthritis (RA), septic arthritis, tendinitis, or herniation.
4. The method of claim 1 , wherein the nucleic acid is a diagnostic agent or a therapeutic agent.
5. The method of claim 1 , wherein the nanopiece has a net positive charge of a Zeta potential>+8 mV.
6. The method of claim 1 , wherein the compound is selected from:
7. The method of claim 1 , wherein R 2 comprises an amino acid side chain or is selected from:
wherein Y is absent.
8. The method of claim 1 , wherein the compound is selected from
9. The method of claim 1 , wherein R 1 is C 1 to C 10 alkyl.
10. The method of claim 1 , wherein the nucleic acid comprises siRNA.
11. The method of claim 10 , wherein the nucleic acid comprises an IL-1 receptor siRNA, ADAMTS-5 siRNA, Matrilin-3 siRNA or a siRNA targeting a FGF receptor.
12. The method of claim 1 , wherein the nucleic acid comprises a molecular probe or a molecular beacon.
13. The method of claim 12 , wherein the nucleic acid is the molecular beacon detecting MMP-13 or ADAMTS-5.
14. The method of claim 1 , further comprising administering one or more analgesic agents, anti-inflammatory agents, immunosuppressive agents, antifungal agents, antibiotic agents, lubricants, anti-cancer agents, NMDA receptor antagonists, or antiviral agents.
15. The method of claim 1 , wherein the nanopiece comprises a size of <30 nm in at least one dimension.
16. The method of claim 1 , wherein the nanopiece has a size of 1 to 30 nm in at least one dimension.
17. The method of claim 1 , wherein a ratio of the compound to nucleic acid ranges from 4.4 to 30 μg compound per to 0.1 nmol of the nucleic acid.
18. The method of claim 1 , wherein the nucleic acid comprises microRNA-365.
19. The method of claim 1 , wherein the nucleic acid comprises microRNA-146a.
20. The method of claim 1 , wherein the nucleic acid comprises microRNA-140.
21. The method of claim 1 , wherein the nucleic acid comprises an anti-microRNA.
22. The method of claim 1 , wherein the joint disease is selected from polymyalgia rheumatica, rheumatoid arthritis, multiple sclerosis, Charcot's Joint, osteoarthritis, juvenile onset of rheumatoid arthritis (JRA), system lupus erythematosus (SLE), psoriatic arthritis, inflammatory bowel disease (IBS) arthritis, Whipple's disease, intestinal lipodystrupjy, ankylosing spondylitis (AS), reactive arthritis (RA), Still's disease, avascular necrosis, bursitis, fibromyalgia, gout, hemochromatosis, hypothyroidism, lupus, Lyme disease, Fifths disease, osteomalacia, osteomyelitis, Paget's disease of bone, pseudogout, rickets, septic arthritis, tendinitis, diabetes, Ehlers-Danlos syndrome, costochondritis, Perthes' disease, Marfan syndrome, rheumatic fever, tubercular arthritis, pigmented villonodular synovitis, scleroderma, polymyositis, erythema nodosum, neuropathic arthropathy, sickle-cell disease, acromegaly, amyloidosis, acute crystal synovitis, pyogenic bacterial infection, scurvy, hemophilia, achondroplasia, herniation, diffuse iodophatic skeletal hyperostosis (DISH), ganglion, lumbar spinal stenosis, sacrolilac joint pain, SAPHO syndrome, polycythemia, Raynaud's phenomenon, hydroxyapatite, Behcet's syndrome, Felt's syndrome, hepatitis B, primary Sjoegrens, and polychondritis.
23. The method of claim 1 , wherein the joint disease is resulted from genetics, trauma, mechanical injury, nutrition deficiencies, or joint mal-alignment.
24. The method of claim 1 , wherein the effective amount of the nanopiece is administered by injection or infusion into a localized tissue site, inhalation, transdermally, orally, rectally, transmucosally, intestinally, parenterally, intramuscularly, intra-articularly, subcutaneously, or intravenously.
25. The method of claim 1 , wherein the joint disease comprises arthritis.
26. The method of claim 1 , wherein the joint disease comprises osteoarthritis.
27. The method of claim 1 , wherein the joint disease comprises rheumatoid arthritis.
28. The method of claim 1 , wherein the joint disease comprises osteosarcoma.
29. The method of claim 1 , wherein the nanopiece is administered intravenously.
30. A method of treating a joint disease comprising
(i) providing a cell from a subject;
(ii) introducing siRNA into a cell by contacting the cell with a nanopiece comprising the siRNA and a compound of Formula I or Formula II or a combination 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 side chain, amino acid or poly peptide; and
R 1 is hydrogen or aliphatic; and
(iii) reintroducing the cell into the subject,
wherein the nanopiece has a size in at least one dimension between 0.1 nm and 150 nm,
wherein a ratio of the compound to the siRNA ranges from 4.4 to 30 μg compound per to 0.1 nmol of the siRNA;
wherein the nanopiece is positively charged at pH 7-7.5.
31. The method of claim 1 , wherein the nanopiece is positively charged at pH 7.4.
32. The method of claim 30 , wherein the nanopiece is positively charged at pH 7.4.