Synthesis and self-assembly of ABC triblock bola peptide amphiphiles

• US 7,683,025 B2
• Filed: 11/14/2003
• Issued: 03/23/2010
• Est. Priority Date: 11/14/2002
• Status: Active Grant

• Current Assignee: Northwestern University
• Original Assignee: Northwestern University
• Inventors: Stupp, Samuel I, Rabatic, Bryan M., Claussen, Randal C.
• Primary Examiner(s): Lukton; David
• Application Number:
  US10/534,266
• Publication Number:
  US 20060110437A1
• Time in Patent Office: 2,321 Days
• Field of Search: 514/2, 514 17- 19, 530/345, 424/450
• US Class Current: 514/1.1
• CPC Class Codes: B82Y 30/00 Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C12N 15/88 using microencapsulation, e.g. using amphiphile liposome vesicle

Abstract

The present invention provides for bola amphiphiles compositions which have more than one lyophilic (hydrophilic) head group and a hydrophobic (hydrophobic) moiety capable of hydrogen bonding with other bola amphiphiles. These bola amphiphiles are capable of self assembling into micelles. The advantage of these bola amphiphiles is that they may self-assemble into micelles whose lyophilic head groups are located within the core and on the surface of the micelles. The lyophilic environment at the core and on the surface of the micelles may be different and may be controlled by the choice of head group moieties on the bola amphiphiles. The utility of these compositions is that they can be used to load or encapsulate polar drugs, DNA, mineralizable inorganic salts, or other molecules of interest within the polar interior of the micelle. Such compositions may also provide small water-filled ion-conducting channels within their structure suitable for use in micro electromechanical devices, as templates for nanowires or dielectrics, and as chemical sensors.

Claims

1. A triblock bola amphiphile composition comprising:

a triblock bola amphiphile and a solvent, wherein the triblock bola amphiphile comprises a lyophobic moiety capable of hydrogen bonding and having a first end and a second end;

the first end of said lyophobic moiety chemically coupled to a first lyophilic head group; and

the second end of said lyophobic moiety chemically coupled to a second lyophilic head group, wherein one lyophilic head group is selected from the group consisting of oligo(ethylene glycol) chains or cyclic oligo(ethylene glycols) chains and the other lyophilic head group comprises an amino acid sequence comprising hydroxyl functionalities from L-serine, charged amino or carboxylic acid groups derived from aspartic acid or lysine, or the amino acid sequence selected from glutamic acid-glutamic acid-glutamic acid and lysine-lysine-lysine.

2. The bola amphiphile as in claim 1, wherein one lyophilic head group is oligo(ethylene glycol) chains and the other lyophilic head group comprises an amino acid sequence of glutamic acid-glutamic acid-glutamic acid.

3. A self assembled micelle comprising:

at least one triblock bola amphiphile, said triblock bola amphiphile having a lyophobic moiety capable of hydrogen bonding and having a first end and a second end;

the first end of said lyophobic moiety chemically coupled to a first lyophilic head group; and

the second end of said lyophobic moiety chemically coupled to a second lyophilic head group, wherein one lyophilic head group is selected from the group consisting of oligo(ethylene glycol) chains and cyclic oligo(ethylene glycols) chains, and the other lyophilic head group comprises an amino acid sequence comprising hydroxyl functionalities from L-serine, charged amino or carboxylic acid groups derived from aspartic acid or lysine, or the amino acid sequence, glutamic acid-glutamic acid-glutamic acid or lysine-lysine-lysine.

4. The micelle of claim 3 wherein the lyophilic head groups of the bola amphiphile are different.

5. The micelle of claim 3 wherein the core of the micelle is lyophilic.

6. The micelle of claim 3 wherein the one or more bola amphiphiles comprising the micelle are capable of hydrogen bonding.

17. The micelle as in claim 3, further comprising a composition chosen from the group consisting of:

pharmaceuticals, chemotherapeutics, immunosuppresents, antifungals, antibacterials, growth factors, vaccines, tissue/cell culture factors, and antibiotics.

18. The micelle as in claim 3, further comprising a material chosen from the group consisting of:

carbon nanotubes, colloidal metals, conductive polymers, magnetic colloids, and semiconductors.

7. A method of making a self assembled micelle from triblock bola amphiphile with a lyophobic moiety capable of hydrogen bonding and having a first end and a second end;

the first end of said lyophobic moiety chemically coupled to a first lyophilic head group; and

the second end of said lyophobic moiety chemically coupled to a second lyophilic head group, wherein one lyophilic head group is selected from the group consisting of oligo(ethylene glycol) chains and cyclic oligo(ethylene glycols) chains, and the other lyophilic head group comprises an amino acid sequence comprising hydroxyl functionalities from L-serine, charged amino or carboxylic acid groups derived from aspartic acid or lysine, or the amino acid sequence selected from glutamic acid-glutamic acid-glutamic acid and lysine-lysine-lysine, comprising the steps of;

making a first solution of the triblock bola-amphiphile in a charged ionic form;

mixing the first solution with a second composition which changes the pH of the first solution towards a neutral pH; and

reacting the first and second solutions until a gel forms.

8. A method of encapsulating a therapeutic agent comprising:

providing a therapeutic agent;

exposing said therapeutic agent to a bola amphiphile capable of self assembly, wherein the bola amphiphile comprises a lyophobic moiety capable of hydrogen bonding, the amphiphile having a first end and a second end;

the first end of said lyophobic moiety chemically coupled to a first lyophilic head group; and

the second end of said lyophobic moiety chemically coupled to a second lyophilic head group, wherein one lyophilic head group is selected from the group consisting of oligo(ethylene glycol) chains and cyclic oligo(ethylene glycols) chains, and the other lyophilic head group comprises an amino acid sequence comprising hydroxyl functionalities from L-serine, charged amino or carboxylic acid groups derived from aspartic acid or lysine, or the amino acid sequence selected from glutamic acid-glutamic acid-glutamic acid and lysine-lysine-lysine; and

initiating self assembly.

9. A method of treating a patient in need thereof with a therapeutic agent encapsulated in a self assembled bola amphiphile, wherein the bola amphiphile comprises a lyophobic moiety capable of hydrogen bonding, the amphiphile having a first end and a second end;

the first end of said lyophobic moiety chemically coupled to a first lyophilic head group; and

the second end of said lyophobic moiety chemically coupled to a second lyophilic head group, wherein one lyophilic head group is selected from the group consisting of oligo(ethylene glycol) chains and cyclic oligo(ethylene glycols) chains, and the other lyophilic head group comprises an amino acid sequence comprising hydroxyl functionalities from L-serine, charged amino or carboxylic acid groups derived from aspartic acid or lysine, or the amino acid sequence selected from glutamic acid-glutamic acid-glutamic acid and lysine-lysine-lysine, comprising;

identifying a site on a patient in need of a treatment; and

administering the bola amphiphile encapsulated therapeutic agent to said site.

10. A method of encapsulating a nanotube comprising:

forming a nanotube;

exposing said nanotube to a bola amphiphile capable of self assembly and comprising a lyophobic moiety capable of hydrogen bonding, the bola amphiphile having a first end and a second end;

the first end of said lyophobic moiety chemically coupled to a first lyophilic head group; and

the second end of said lyophobic moiety chemically coupled to a second lyophilic head group, wherein one lyophilic head group is selected from the group consisting of oligo(ethylene glycol) chains and cyclic oligo(ethylene glycols) chains, and the other lyophilic head group comprises an amino acid sequence comprising hydroxyl functionalities from L-serine, charged amino or carboxylic acid groups derived from aspartic acid or lysine, or the amino acid sequence selected from glutamic acid-glutamic acid-glutamic acid and lysine-lysine-lysine, and initiating self assembly of said bola amphiphile.

11. A triblock bola amphiphile composition comprising:

a solvent and a hydrophobic moiety capable of hydrogen bonding and having a first end and a second end;

the first end of said hydrophobic moiety chemically coupled to a first hydrophilic head group; and

the second end of said hydrophobic moiety chemically coupled to a second hydrophilic head group, wherein one hydrophilic head group is selected from the group consisting of oligo(ethylene glycol) chains and cyclic oligo(ethylene glycols) chains and the other hydrophilic head group comprises an amino acid sequence comprising hydroxyl functionalities from L-serine, charged amino or carboxylic acid groups derived from aspartic acid or lysine, or the amino acid sequence selected from glutamic acid-glutamic acid-glutamic acid and lysine-lysine-lysine.

12. A self assembled micelle comprising:

at least one bola amphiphile, said bola amphiphile having a hydrophobic moiety capable of hydrogen bonding and having a first end and a second end;

the first end of said hydrophobic moiety chemically coupled to a first hydrophilic head group; and

the second end of said hydrophobic moiety chemically coupled to a second hydrophilic head group, wherein one hydrophilic head group is selected from the group consisting of oligo(ethylene glycol) chains and cyclic oligo(ethylene glycols) chains—

and the other hydrophilic head group comprises an amino acid sequence comprising hydroxyl functionalities from L-serine, charged amino or carboxylic acid groups derived from aspartic acid or lysine, or an amino acid sequence selected from glutamic acid-glutamic acid-glutamic acid and lysine-lysine-lysine.

13. The micelle of claim 12 wherein the hydrophilic head groups of the bola amphiphile are different.

14. The micelle of claim 12 wherein the core of the micelle is hydrophilic.

15. The micelle of claim 12 wherein the at least one bola amphiphiles comprising the micelle are capable of hydrogen bonding.

19. The micelle as in claim 12, further comprising a composition chosen from the group consisting of:

pharmaceuticals, chemotherapeutics, immunosuppresents, antifungals, antibacterials, growth factors, vaccines, tissue/cell culture factors, and antibiotics.

20. The micelle as in claim 12, further comprising a material chosen from the group consisting of:

carbon nanotubes, colloidal metals, conductive polymers, magnetic colloids, and semiconductors.

16. A method of making a self assembled micelle from bola amphiphile with a hydrophobic moiety capable of hydrogen bonding, wherein the bola amphiphile has a first end and a second end;

the first end of said lyophobic moiety chemically coupled to a first lyophilic head group; and

the second end of said lyophobic moiety chemically coupled to a second lyophilic head group, wherein one lyophilic head group is selected from the group consisting of oligo(ethylene glycol) chains and cyclic oligo(ethylene glycols) chains, and the other lyophilic head group comprises an amino acid sequence comprising hydroxyl functionalities from L-serine, charged amino or carboxylic acid groups derived from aspartic acid or lysine, or the amino acid sequence selected from glutamic acid-glutamic acid-glutamic acid and lysine-lysine-lysine, comprising the steps of;

making a first solution of the triblock bola-amphiphile in a charged ionic form;

mixing the first solution with a second composition which changes the pH of the first solution towards a neutral pH; and

reacting the first and second solutions until a gel forms.