Supramolecular functionalization of graphitic nanoparticles for drug delivery

Patent metadata

Field	Value
Publication number	US-9233166-B2
Application number	US-201314028353-A
Country	US
Kind code	B2
Filing date	Sep 16, 2013
Priority date	Jul 27, 2007
Publication date	Jan 12, 2016
Grant date	Jan 12, 2016

Abstract

Disclosed are nanoparticles, such as carbon nanotubes or other graphitic sheet materials having extended aromatic surfaces, which are used to deliver active agents such as drugs, labels or dyes (termed for convenience a “drug”) to the interior of cells. The nanoparticles are functionalized by a hydrophilic polymer or adsorption of an amphiphilic molecule to render them stable in suspension. The drug is therefore capable of release in the cell exterior. The drug is more rapidly released at lower pH, as found e.g., in tumor cells. The drug may also be linked to a branched chain hydrophilic polymer, so that each polymer molecule carries more than one drug bound by a cleavable linker.

First claim

What is claimed is:

1. A dispersed nanoparticle complex for delivery of an active agent into a cell, comprising:
(a) a nanoparticle having an extended aromatic structure;
(b) a plurality of hydrophilic polymers bound to the nanoparticle through supramolecular bonding, wherein the hydrophilic polymers are individually covalently bound to a pyrene which is bonded by supramolecular bonding to the nanoparticle and wherein the dispersed nanoparticle complex is in a fluid suspension; and
(c) small molecule chemotherapy cancer drugs, attached to said hydrophilic polymers by a cleavable linkage.

2. The dispersed nanoparticle complex of claim 1 wherein the nanoparticle is a carbon nanotube.

3. The dispersed nanoparticle complex of claim 2 wherein the carbon nanotube is a single-walled carbon nanotube (SWNT).

4. The dispersed nanoparticle complex of claim 1 wherein the nanoparticle comprises boron nitride.

5. The dispersed nanoparticle complex of claim 1 wherein the nanoparticle comprises a graphitic surface.

6. The dispersed nanoparticle complex of claim 5 wherein the nanoparticle is a graphene sheet.

7. The dispersed nanoparticle complex of claim 6 wherein the graphene sheet is a pristine single layer graphene sheet.

8. The dispersed nanoparticle complex of claim 1 wherein the nanoparticle is either (i) a coated nanocrystal, (ii) a nanotube, or (iii) a graphene sheet.

9. The dispersed nanoparticle complex of claim 1 wherein the nanoparticle is a graphitic coated metal core.

10. The dispersed nanoparticle complex of claim 9 wherein the metal core is a nanocrystal and the graphitic coat is a single layer.

11. The dispersed nanoparticle complex of claim 10 wherein the nanocrystal comprises FeCo or Au.

12. The dispersed nanoparticle complex of claim 1 wherein the nanoparticle has an average length of about 50-500 nm.

13. The dispersed nanoparticle complex of claim 1 wherein the nanoparticle is an SWNT having a diameter of between about 1 and 2 nm prior to functionalization.

14. The dispersed nanoparticle complex of claim 1 wherein the hydrophilic polymers comprise polyethylene glycol (PEG) and the PEG is from about 10 to 500 polyethylene oxide units.

15. The dispersed nanoparticle complex of claim 14 wherein the PEG is amine-terminated.

16. The dispersed nanoparticle complex of claim 1 where the hydrophilic polymers comprise two to seven branches.

17. The dispersed nanoparticle complex of claim 16 wherein the hydrophilic polymers have four to six branches.

18. The dispersed nanoparticle complex of claim 17 comprising at least two chemotherapy cancer drug molecules linked to different branches.

19. The dispersed nanoparticle complex of claim 17 wherein the hydrophilic polymers are PEG.

20. The dispersed nanoparticle complex of claim 16 wherein the hydrophilic polymers are dextran.

21. The dispersed nanoparticle complex of claim 16 wherein each of the hydrophilic polymers is further linked to a targeting agent.

22. The dispersed nanoparticle complex of claim 21 wherein the targeting agent is an RGD peptide.

23. The dispersed nanoparticle complex of claim 21 where the targeting agent is an antibody.

24. The dispersed nanoparticle complex of claim 1 further comprising a polar lipid attached to the nanoparticle.

25. The dispersed nanoparticle complex of claim 24 wherein the polar lipid is a phospholipid.

26. The dispersed nanoparticle complex of claim 1 wherein the cleavable linkage is a linkage which is one of hydrazone, ester or disulfide.

27. The dispersed nanoparticle complex of claim 1 wherein the chemotherapy cancer drugs are selected from the group consisting of doxorubicin, camptothecin, daunorubicin, and paclitaxel.

28. The dispersed nanoparticle complex of claim 1 where about 1-40% of the nanoparticle surface area is complexed with the hydrophilic polymers.

29. A preparation of the dispersed nanoparticle complex of claim 1 in an aqueous suspension.

30. A preparation of the dispersed nanoparticle complex of claim 1 in unit dosage form.

31. The dispersed nanoparticle complex of claim 1 wherein the hydrophilic polymers are branched and the small molecule chemotherapy cancer drugs are attached to arms of branches of the branched hydrophilic polymers.

32. A method for preparing a dispersed nanoparticle complex for delivery of an active agent inside a cell, comprising the steps of:
(a) obtaining a nanoparticle, which has an extended aromatic surface, in dispersed form;
(b) attaching through supramolecular bonding to the surface of the nanoparticle a plurality of hydrophilic polymers, wherein the hydrophilic polymers are individually covalently bound to a pyrene through which supramolecular bonding to the surface occurs, and wherein small molecule chemotherapy cancer drugs are attached to said hydrophilic polymers by a cleavable linkage; and
(c) forming a stable aqueous suspension of the complex.

33. A method for delivering an active agent inside a cell, comprising the step of:
contacting the cell with the dispersed nanoparticle complex of claim 1 for a time sufficient to allow internalization of the complex by the cell.

34. The method of claim 33 further comprising a hydrophilic polymer linked to a targeting agent for delivering the active agent to a cell type providing a target for the targeting agent.

35. The method of claim 33 further comprising the step of contacting the complex with serum, whereby the complex does not dissociate in the serum.

36. The method of claim 33 wherein the small molecule chemotherapy cancer drugs are hydrophobic.

Assignees

• Univ Leland Stanford Junior

Inventors

• Dai Hongjie
• Liu Zhuang
• Li Xiaolin
• Sun Xiaoming

Classifications

• A61K9/0092

  Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes · CPC title

• A61K47/48884

  Human Necessities · mapped topic

• A61K39/395

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title

• Y10T428/2982

  Particulate matter [e.g., sphere, flake, etc.] · CPC title

• B82Y5/00

  Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery · CPC title