# US 2014/0155577 A1 · Self-assembly of therapeutic agent-peptide nanostructures

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- Number: US 2014/0155577 A1
- Document ID: US20140155577A1
- Status: Published application
- Kind: A1
- Application number: 14/095,816
- Filed: 2013-12-03
- Published: 2014-06-05
- Earliest claimed: 2012-12-03
- Assignees: Ohio State Innovation Foundation
- Applicants: Ohio State Innovation Foundation
- Inventors: Jonathan R. Parquette; Se Hye Kim; Mark W. Grinstaff; Jonah A. Kaplan
- Web page: https://patentgrep.com/patent/US20140155577A1

## CPC

- A61K 47/62: the modifying agent being a protein, peptide or polyamino acid
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Disclosed are conjugates of hydrophobic drugs linked to protected or unprotected amino acids or peptides. The disclosed conjugates are amphiphilic and can self assemble into nanotubes. Nanotubes comprising the conjugates are also described and can have high loading of the drug and protect it from degradation or elimination. The nanotubes are well suited to deliver hydrophobic and unstable drugs to individuals.

## Claims

### Claim 1

A conjugate for forming a self assembled nanotube; comprising: a hydrophobic drug, a hydrophilic amino acid residue or peptide; and a linker moiety joining the hydrophobic drug to the hydrophilic amino acid or peptide, wherein the conjugate forms a self assembled nanotube.

### Claim 2 (depends on 1)

The conjugate of claim 1, wherein the hydrophobic drug has a water solubility of less than about 10 mg/mL.

### Claim 3 (depends on 1)

The conjugate of claim 1, wherein the hydrophobic drug has a cLogP of five or more.

### Claim 4 (depends on 1)

The conjugate of claim 1, wherein the hydrophobic drug is Camptothecin, Topotecan, Ionotecan, Exatecan, Lurtotecan, DB 67, DNP 1350, ST 1481, CKD 602, 5-fluorouracil, taxol, or vinblastin.

### Claim 5 (depends on 1)

The conjugate of claim 1, wherein the peptide is a dipeptide comprising at least one arginyl, histidyl, lysyl, protected or unprotected aspartyl, glutamyl, seryl, threonyl, cystyl, asparagyl, glutaminyl, prolyl, tyrosyl, methionyl, and or tryptophanyl.

### Claim 6 (depends on 1)

The conjugate of claim 1, wherein the peptide is a tetrapeptide comprising the formula Xaa-Xaa-Xbb-Xbb, Xaa-Xbb-Xaa-Xbb, Xbb-Xbb-Xaa-Xaa, or Xbb-Xaa-Xbb-Xaa, where each Xaa is independent of the other, a protected or unprotected arginyl, histidyl, lysyl, aspartyl, glutamyl, seryl, threonyl, cystyl, asparagyl, glutaminyl, prolyl, tyrosyl, methionyl, and tryptophanyl; and wherein each Xbb is, independent of the others, a protected or unprotected alanyl, allosoleucyl, arginyl asparagyl, aspartyl, cystyl, glutamyl, glutaminyl, glycyl, histidyl, isolelucyl, leucyl, lysyl, methionyl, phenylalanyl, prolyl, pyroglutamyl, seryl, threonyl, tyrosyl, tryptophanyl, or valyl.

### Claim 7 (depends on 1)

The conjugate of claim 1, wherein the conjugate does not contain 9 or more amino acid residues.

### Claim 8 (depends on 1)

The conjugate of claim 1, wherein the peptide is protected at an N terminus or an amino acid residue side chain with a benzoyloxycarbonyl, tert-butoxycarbonyl, acetate, trifluoroacetate, 9-fluorenylmethyloxycarbonyl, or 2-bromobenzyloxycarbonyl, or N-hydroxysuccinimide.

### Claim 9 (depends on 1)

The conjugate of claim 1, wherein the linker moiety is from 1 to 20 atoms in length.

### Claim 10 (depends on 1)

The conjugate of claim 1, wherein the linker moiety is substituted or unsubstituted, branched or unbranched, alkyl, alkenyl, alkynyl, ether, ester, polyether, polyester, polyalkylene, polyamine, heteroatom substituted alkyl, alkenyl, or alkynyl group, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, where the point of attachment to the hydrophobic drug and/or amino acid residue is an ester, ether, carboxylate, amine, or amide bond.

### Claim 11 (depends on 1)

The conjugate of claim 1, wherein the linker moiety comprises —(CH2)m—, wherein m is from 1 to 10, and where the point of attachment to the hydrophobic drug and/or amino acid is an ester, ether, carboxylate, amine, or amide bond.

### Claim 12 (depends on 1)

The conjugate of claim 1, wherein the linker moiety comprises —X1—(CH2)m—X2—, wherein m is from 1 to 10, and X1 and X2 are, independent of one another, C(O), C(O)O, C(O)N, NH, or O.

### Claim 13 (depends on 1)

The conjugate of claim 1, wherein the peptide is protected or unprotected lysyl-lysyl, or protected or unprotected lysyl-phenylalanyl-lysyl-lysyl, and the linker moiety is C1-C6 alkyldiester.

### Claim 14 (depends on 1)

The conjugate of claim 1, wherein the conjugate has Formula II:
where n is from 1 to 4,
each R1 and R2 are, independent of one another, H, OH, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen or deuterium, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, or CO2H, or together two R1 or R1 and R2 can form a fused cycloalkyl or cycloheteroalkyl;
L is a linker moiety having from 1 to 20 atoms; and
AA is a single hydrophilic amino acid residue or peptide.

### Claim 15 (depends on 14)

The conjugate of claim 14, wherein the conjugate has Formula II-A, II-B, II-C, II-D, or II-E:

### Claim 16 (depends on 15)

The conjugate of claim 15, wherein L is C(O)—(CH2)m—C(O), where m is from 1 to 6.

### Claim 17 (depends on 16)

The conjugate of claim 16, wherein AA is protected or unprotected lysyl, lysyl-lysyl, lysyl-phenylalanyl-lysyl-lysyl.

### Claim 18 (depends on 1)

A nanotube comprising a wall, wherein the wall comprises a conjugate of claim 1.

### Claim 19 (depends on 18)

The nanotube of claim 18, wherein the wall comprises a hydrophilic domain comprising the peptide portion of the conjugate and a hydrophobic domain comprising the hydrophobic drug portion of the conjugate.

### Claim 20 (depends on 18)

The nanotube of claim 18, wherein the hydrophobic drug is at least about 50 wt. % of the nanotube.

### Claim 21 (depends on 18)

The nanotube of claim 18, wherein the nanotube has a zeta potential of about zero.