Tubular nanostructure targeted to cell membrane

• US 10,683,365 B2
• Filed: 03/08/2017
• Issued: 06/16/2020
• Est. Priority Date: 09/15/2008
• Status: Active Grant

• Current Assignee: Enterprise Science Fund, LLC (Intellectual Ventures LLC)
• Original Assignee: Deep Science LLC (Intellectual Ventures LLC)
• Inventors: Bangera, Mahalaxmi Gita, Harlow, Ed, Hyde, Roderick A., Ishikawa, Muriel Y., Jung, Edward K. Y., Leuthardt, Eric C., Myhrvold, Nathan P., Rivet, Dennis J., Sweeney, Elizabeth A., Tegreene, Clarence T., Wood, Jr., Lowell L., Wood, Victoria Y. H.
• Primary Examiner(s): Babic, Christopher M
• Assistant Examiner(s): Leonard, Arthur S
• Application Number:
  US15/453,103
• Publication Number:
  US 20170173177A1
• Time in Patent Office: 1,196 Days
• Field of Search: None
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/1703 from vertebrates
• CPC Class Codes: A61K 38/1732 Lectins
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/6871 the antibody targeting an enzyme
• CPC Class Codes: A61K 47/6901 Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B82Y 15/00 Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
• CPC Class Codes: B82Y 30/00 Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: B82Y 40/00 Manufacture or treatment of nanostructures
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C01B 21/0648 After-treatment, e.g. grinding, purification transformation of hexagonal into cubic or wurtzitic boron nitride C04B35/5831
• CPC Class Codes: C01B 2202/02 Single-walled nanotubes
• CPC Class Codes: C01B 2202/34 Length
• CPC Class Codes: C01B 2202/36 Diameter
• CPC Class Codes: C01B 32/168 After-treatment
• CPC Class Codes: C01B 32/174 Derivatisation; Solubilisation; Dispersion in solvents
• CPC Class Codes: C01P 2004/13 Nanotubes
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
• CPC Class Codes: Y10S 977/743 : having specified tube end structure, e.g. close-ended shell or open-ended tube
• CPC Class Codes: Y10S 977/75 : Single-walled
• CPC Class Codes: Y10S 977/762 : Nanowire or quantum wire, i.e. axially elongated structure having two dimensions of 100 nm or less
• CPC Class Codes: Y10S 977/788 : Of specified organic or carbon-based composition
• CPC Class Codes: Y10S 977/795 : Composed of biological material
• CPC Class Codes: Y10S 977/848 : Tube end modifications, e.g. capping, joining, splicing
• CPC Class Codes: Y10S 977/896 : Chemical synthesis, e.g. chemical bonding or breaking
• CPC Class Codes: Y10S 977/915 : Therapeutic or pharmaceutical composition

Abstract

Devices, compositions, and methods are described which provide a tubular nanostructure or a composite tubular nanostructure targeted to a lipid bilayer membrane. The tubular nanostructure includes a hydrophobic surface region flanked by two hydrophilic surface regions. The tubular nanostructure is configured to interact with a lipid bilayer membrane and form a pore in the lipid bilayer membrane. The tubular nanostructure may be targeted by including at least one ligand configured to bind to one or more cognates on the lipid bilayer membrane of a target cell.

Claims

1. A tubular nanostructure comprising:

a hydrophobic surface region flanked by two hydrophilic surface regions configured to form a pore in a lipid bilayer membrane of a cell, at least one cell type specific ligand attached to the tubular nanostructure and configured to bind one or more cell type specific cognates on the membrane, and a binding moiety associated with one or both ends of the tubular nanostructure, the binding moiety having a structure to reversibly bind an agent, wherein controlled dissociation of the agent from the binding moiety results in passage of the agent through the pore formed by the tubular nanostructure in the lipid bilayer of the cell, and wherein the agent includes at least one of a therapeutic agent or a toxin.

2. The nanostructure of claim 1, wherein the tubular nanostructure includes one or more of a carbon nanotube, cyclic peptide nanotube, crown ether nanotube, polymer nanotube, polymer/carbon nanotube, DNA nanotube, or inorganic nanotube.

3. The nanostructure of claim 1, wherein the hydrophilic surface region includes one or more of amines, amides, charged or polar amino acids, alcohols, carboxylic groups, oxides, ester groups, ether groups, or ester-ether groups, ketones, aldehydes, or derivatives thereof.

4. The nanostructure of claim 1, wherein the at least one cell type specific ligand is configured to bind one or more cell surface receptors or cell surface markers in the lipid bilayer membrane of the cell.

5. The nanostructure of claim 1, wherein the at least one cell type specific ligand is configured to bind at least one of a protein, a carbohydrate, a glycoprotein, a glycolipid, a sphingolipid, a glycerolipid or a metabolite thereof.

6. The nanostructure of claim 1, wherein one or both of the hydrophilic surface regions are at the end of the tubular nanostructure.

7. The nanostructure of claim 1, having a length of about 1 nm to about 1500 nm.

8. The nanostructure of claim 1, having a diameter of about 0.5 nm to about 5 nm.

9. The nanostructure of claim 7, having a length of about 20 Å

to about 40 Å

.

10. The nanostructure of claim 8, having a diameter of about 5 Å

to about 20 Å

.

11. The nanostructure of claim 1, wherein the at least one cell type specific ligand includes at least a portion of an antibody, antibody-coated liposome, polynucleotide, polypeptide, receptor, viral plasmid, polymer, protein, small chemical compound, carbohydrate, lipid, toxin, pore-forming toxin, or lectin.

12. The nanostructure of claim 11, wherein the at least one cell type specific ligand is a therapeutic compound configured to affect a cell or process or to treat at least one of a disease, condition, or symptom.

13. The nanostructure of claim 1, further comprising at least one second cell type specific ligand configured to bind one or more cell type specific cognates on the lipid bilayer membrane of the cell.

14. The nanostructure of claim 1, wherein the tubular nanostructure induces cell death.

15. The nanostructure of claim 1, further comprising a constitutively activatable marker attached to the tubular nanostructure.

16. The nanostructure of claim 15, wherein the constitutively activatable marker is an activatable fluorescent marker having a chemical structure that constitutively fluoresces in response to a lipid environment.

17. The nanostructure of claim 15, wherein the constitutively activatable marker is a molecular beacon having a chemical structure that constitutively fluoresces in response to interacting with a target on the membrane.

18. The nanostructure of claim 15, wherein the constitutively activatable marker is a pH sensitive fluorescent dye.

19. The nanostructure of claim 1, wherein the hydrophobic surface region is extended in diameter.

20. The nanostructure of claim 19, wherein the hydrophobic surface region is extended in diameter by a disk, a stub, or a graphene sheet.

38. The nanostructure of claim 1, wherein the binding moiety is a bifunctional antibody having a first portion and a second portion, the first portion capable of binding at one or both ends of the tubular nanostructure and the second portion capable of reversibly binding to the agent.

39. The nanostructure of claim 1, further comprising one or more elements associated with one or both ends of the tubular nanostructure, the one or more elements having a size and a structure configured to physically and reversibly block the pore formed by the tubular nanostructure in the lipid bilayer membrane of the cell.

40. The nanostructure of claim 39, wherein the one or more elements associated with one or both ends of the tubular nanostructure include one or more nanoparticles associated with one or both ends of the tubular nanostructure, the one or more nanoparticles having a size and shape to physically and reversibly block the pore formed by the tubular nanostructure in the lipid bilayer of the cell.

41. The nanostructure of claim 40, wherein the one or more nanoparticles associated with one or both ends of the tubular nanostructure include one or more microbeads associated with one or both ends of the tubular nanostructure, the one or more microbeads having a size and shape to physically and reversibly block the pore formed by the tubular nanostructure in the lipid bilayer of the cell.

42. The nanostructure of claim 39, wherein the one or more elements associated with one or both ends of the tubular nanostructure include one or more microbeads tethered to one or both ends of the tubular nanostructure and having a size and shape to physically and reversibly block the pore formed by the tubular nanostructure in the lipid bilayer of the cell.

43. The nanostructure of claim 39, wherein the one or more elements associated with one or both ends of the tubular nanostructure include one or more magnetic nanoparticles associated with one or both ends of the tubular nanostructure, the one or more magnetic nanoparticles having a size and shape to physically and reversibly block the pore formed by the tubular nanostructure in the lipid bilayer of the cell in response to a magnetic field.

21. A composite tubular nanostructure comprising:

two or more nanotubes wherein at least one nanotube includes a hydrophobic surface region, each hydrophobic surface region flanked by two hydrophilic surface regions configured to form a pore in a lipid bilayer membrane of a cell;

at least one cell type specific ligand attached to the tubular nanostructure and configured to bind one or more cell type specific cognates on the lipid bilayer membrane of the cell;

a binding moiety associated with one or both ends of the at least one nanotube, the binding moiety having a structure to reversibly bind an agent, wherein controlled dissociation of the agent from the binding moiety results in passage of the agent through the pore formed by the at least one nanotube, and wherein the agent includes at least one of a therapeutic agent or a toxin; and

one or more active transport polypeptide elements configured to reversibly block the pore to control transport of molecules through the tubular nanostructure.

22. The composite tubular nanostructure of claim 21 including three or more nanotubes.

23. The composite tubular nanostructure of claim 22, wherein at least one nanotube includes a completely hydrophobic surface region.

24. The composite tubular nanostructure of claim 23, wherein the at least one nanotube including the completely hydrophobic surface region is surrounded by at least six nanotubes including the hydrophobic surface region flanked by two hydrophilic surface regions configured to form the pore in the lipid bilayer membrane.

25. The composite tubular nanostructure of claim 21, wherein at least two of the nanotubes have different diameters.

26. The composite tubular nanostructure of claim 21, wherein at least two of the nanotubes have different lengths.

27. The composite tubular nanostructure of claim 21, wherein at least two of the two or more nanotubes are substantially parallel.

28. The composite tubular nanostructure of claim 21, wherein at least two of the two or more nanotubes are substantially orthogonal.

29. The composite tubular nanostructure of claim 21, wherein the hydrophobic surface region includes a single wall carbon nanotube surface region.

30. The composite tubular nanostructure of claim 21, wherein the at least one cell type specific ligand is configured to bind one or more cell surface receptors or cell surface markers in the lipid bilayer membrane of the cell.

31. The composite tubular nanostructure of claim 21, wherein one or both of the hydrophilic surface regions are at the end of the one or more nanotubes.

32. The composite tubular nanostructure of claim 21, wherein the at least one cell type specific ligand is at least a portion of an antibody, antibody-coated liposome, polynucleotide, polypeptide, receptor, viral plasmid, polymer, protein, carbohydrate, lipid, toxins, pore-forming toxins, or lectin.

33. The composite tubular nanostructure of claim 21, wherein two or more cell type specific ligands are configured to bind to the one or more cell type specific cognates on the lipid bilayer membrane of the cell.

34. The composite tubular nanostructure of claim 21, further comprising a cytotoxic agent or antimicrobial agent.

35. The composite tubular nanostructure of claim 21, wherein the one or more active transport polypeptide elements are on the extracellular end of the nanostructure.

36. The composite tubular nanostructure of claim 21, wherein the one or more active transport polypeptide elements are on the cytoplasmic end of the nanostructure.

37. The composite tubular nanostructure of claim 21, further comprising a marker attached to the nanostructure, wherein the marker includes a fluorescent marker, a radioactive marker, quantum dot, metal, or magnetic resonance imaging marker.