Multifunctional nanodevice platform

• US 6,471,968 B1
• Filed: 05/12/2000
• Issued: 10/29/2002
• Est. Priority Date: 05/12/2000
• Status: Expired due to Fees

• Current Assignee: University of Alabama (University of Alabama System)
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Tomalia, Donald A., Baker, James R. Jr.
• Primary Examiner(s): McGarry, Sean
• Assistant Examiner(s): Lacourciere, Karen A.
• Application Number:
  US09/570,198
• Time in Patent Office: 900 Days
• Field of Search: 536/23.1, 536/24.1, 536/24.5, 514/44, 530/300, 530/351, 530/397, 530/399, 530/402, 424/130.1, 424/184.1, 424/94.1, 424/1.11, 424/277.1, 424/283.1, 424/280.1
• US Class Current: 424/280.1
• CPC Class Codes: A61K 41/0057 Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
• CPC Class Codes: A61K 41/0071 PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
• CPC Class Codes: A61K 47/6949 inclusion complexes, e.g. clathrates, cavitates or fullerenes
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C08G 83/003 Dendrimers
• CPC Class Codes: C08L 101/005 Dendritic macromolecules

Abstract

The present invention relates to novel therapeutic and diagnostic arrays. More particularly, the present invention is directed to dendrimer based multifunctional compositions and systems for use in disease diagnosis and therapy (e.g., cancer diagnosis and therapy). The compositions and systems generally comprise two or more separate components for targeting, imaging, sensing, and/or triggering release of a therapeutic or diagnostic material and monitoring the response to therapy of a cell or tissue (e.g., a tumor).

Claims

1. A composition comprising a dendrimer complex, said dendrimer complex comprising covalently linked first and second dendrimers, said first dendrimer comprising a first agent and said second dendrimer comprising a second agent, wherein said first dendrimer is different from said second dendrimer, and wherein said first agent is different than said second agent.

2. The composition of claim 1, wherein said first and said second agents are selected from the group consisting of therapeutic agents, biological monitoring agests, biological imaging agents, and targeting agents.

3. The composition of claim 1, further comprising a third dendrimer, wherein said third-dendrimer is covalently linked to said first and said second dendrimers.

4. The composition of claim 3, further comprising a third agent complexed with said third dendrimer.

5. The composition of claim 3, further comprising a fourth dendrimer comprising a third agent, wherein said fourth dendrimer is covalently linked to said third dendrimer.

6. The composition of claim 5, further comprising a fifth dendrimer comprising a fourth agent, wherein said fifth dendrimer is complexed with said third dendrimer.

7. The composition of claim 1, wherein said first agent is a therapeutic agent and said second agent is a biological monitoring agent.

8. The composition of claim 7, wherein said therapeutic agent is selected from the group consisting of a chemotherapeutic agent, an anti-oncogenic agent, an anti-vascularizing agent, and an expression construct comprising a nucleic acid encoding a therapeutic protein.

9. The composition of claim 7, wherein said therapeutic agent is protected with a protecting group selected from photo-labile, radio-labile, and enzyme-labile protecting groups.

10. The composition of claim 8, wherein said chemotherapeutic agent is selected from the group consisting of platinum complex, verapamil, podophyllotoxin, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, bisulfan, nitrosurea, adriamycin, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide, tamoxifen, taxol, transplatinum, 5-fluorouracil, vincristin, vinblastin, and methotrexate.

11. The composition of claim 8, wherein said anti-oncogeric agent comprises an antisense nucleic acid.

12. The composition of claim 11, wherein said antisense nucleic acid comprises a sequence complementary to an RNA of an oncogene.

13. The composition of claim 12, wherein said oncogene is selected from the group consisting of abl, Bcl-2, Bcl-x₁, erb, fms, gsp, hst, jun, myc, neu, raf, ras, ret, src, and trk.

14. The composition of claim 8, wherein said nucleic acid encodes a factor selected from the group consisting of tumor suppressors, cytokines, receptors, inducers of apoptosis, and differentiating agents.

15. The composition of claim 14, wherein said tumor suppressor is selected from the group consisting of BRCA1, BRCA2, C-CAM, p16, p21, p53, p73, Rb, and p27.

16. The composition of claim 14, wherein said cytokine is selected fr om the group consisting of GMCSF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, β

-inteferon, γ

-interferon, and TNF.

17. The composition of claim 14, wherein said receptor is selected from the group consisting of CFTR, EGFR, estrogen receptor, IL-2 receptor, and VEGFR.

18. The composition of claim 14, wherein said inducer of apoptosis is selected from the group consisting of AdE1B, Bad, Bak, Bax, Bid, Bik, Bim, Harakid, and ICE-CED3 protease.

19. The composition of claim 2, wherein said biological monitoring agent comprises an agent that measures an effect of a therapeutic agent.

20. The composition of claim 2, wherein said therapeutic agent comprises a short-half life radioisotope.

22. The composition of claim 19, wherein said monitoring agent is capable of measuring the amount of apoptosis caused by said therapeutic agent.

23. The composition of claim 2, wherein said targeting agent is selected from the group consisting of antibody, receptor ligand, hormone, vitamin, and antigen.

24. The composition of claim 23, wherein said antibody is specific for a disease specific antigen.

25. The composition of claim 24, wherein said disease specific antigen comprises a tumor specific antigen.

26. The composition of claim 23, wherein said receptor ligand is selected from the group consisting of a ligand for CFTR, FGFR, estrogen receptor, FGR2, folate receptor, IL-2 receptor, glycoprotein, and VEGPR.

27. The composition of claim 3, wherein said first and second dendrimers comprise PAMAM dendrimers and wherein said third dendrimer comprises a POPAM dendriiner.

21. The composition of claim 21, wherein said biological imaging agent comprises a radioactive label selected from the group consisting of ¹⁴C, ³⁶Cl, ⁵⁷Co, ⁵⁸Co, ⁵¹Cr, ¹²⁵I, ¹³¹I, ¹¹¹ln, ¹⁵²Eu, ⁵⁹Fe, ⁶⁷Ga, ³²P, ¹⁸⁶Re, ³⁵S, ⁷⁵Se, Tc-99m, and ¹⁷⁵Yb.

28. A method of treating a cell comprising:

a) providing;

i) an in vitro or ex vivo cell; and

ii) a composition comprising a dendrimer complex, said dendrimer complex comprising covalently linked first and second dendrimers, said first dendrimer comprising a first agent and said second dendrimer comprising a second agent, wherein said first dendrimer is different from said second dendrimer, and wherein said first agent is different than said second agent; and

b) exposing said cell to said composition.

29. The method of claim 28, wherein said first and said second agents are selected from the group consisting of therapeutic agents, biological monitoring agents, biological imaging agents, and targeting agents.

30. The method of claim 28, further comprising a third dendrimer, wherein said third-dendrimer is covalently linked to said first and said second dendrimers.

31. The method of claim 30, further comprising a third agent complexed with said third dendrimer.

32. The method of claim 30, further comprising a fourth dendrimer comprising a third agent, wherein said fourth dendrimer is covalently linked to said third dendrimer.

33. The method of claim 32, further comprising a fifth dendrimer comprising a fourth agent, wherein said fifth dendrimer is complexed with said third dendrimer.

34. The method of claim 28, wherein said first agent is a therapeutic agent and said second agent is a biological monitoring agent.