# US 9,872,870 B2 · Multifunctional micellar nanoparticle-based drug and targeting agent system

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- Number: US 9,872,870 B2
- Document ID: US9872870B2
- Status: Granted
- Kind: B2
- Application number: 14/356,121
- Filed: 2012-11-05
- Published: 2014-09-25
- Granted: 2018-01-23
- Earliest claimed: 2011-11-04
- Assignees: University of Notre Dame du Lac
- Applicants: University of Notre Dame du Lac
- Inventors: Zihni Basar Bilgicer; Tanyel Kiziltepe Bilgicer; Jonathan Darryl Ashley; Jared Stefanick; Nathan J. Alves; Michael W. Handlogten
- Web page: https://patentgrep.com/patent/US9872870B2

## CPC

- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/351: not condensed with another ring
- A61K 47/62: the modifying agent being a protein, peptide or polyamino acid
- A61K 47/6907: {the form being a microemulsion, nanoemulsion or micelle}
- A61K 47/6909: {Micelles formed by phospholipids}
- A61K 51/0455: {having six-membered rings with one nitrogen as the only ring hetero atom}
- A61P 35/00: Antineoplastic agents
- A61K 9/1075: {Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence)}
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Embodiments provide systems, methods, and compositions for nanoparticle-based drug delivery to target cells or tissues. A drug delivery system may include a nanoparticle with a targeting component and a therapeutic component. The nanoparticle may have a predetermined number or valence of targeting molecules for multivalent interaction with a target cell or tissue. Binding of the targeting molecules to the target cell may result in receptor-mediated uptake of the nanoparticle by the target cell. The therapeutic component may be subsequently released within an endocytic vesicle of the target cell. Nanoparticle-based drug delivery systems as described herein may provide improved efficacy and/or reduced toxicity.

## Claims

### Claim 1

A micellar nanoparticle comprising:
a hydrophobic interior portion surrounded by an outer portion, the outer portion comprising a water-soluble polymer;
a therapeutic agent coupled to, and disposed at least partially within, the outer portion; and
a targeting agent coupled to, and disposed at least partially within, the outer portion, wherein the targeting agent is a low-affinity, high-specificity peptide ligand of a conjugate of the formula:
wherein VLA4-pep is a peptide of SEQ ID NO: 1.

### Claim 2 (depends on 1)

The nanoparticle of claim 1, wherein the water-soluble polymer is coupled to a first lipid, the therapeutic agent is coupled to a second lipid, and the targeting agent is coupled to a third lipid, and the first, second, and third lipids are disposed within the interior portion of the nanoparticle.

### Claim 3 (depends on 2)

The nanoparticle of claim 2, wherein the water-soluble polymer is polyethylene glycol (PEG).

### Claim 4 (depends on 1)

The nanoparticle of claim 1, wherein the therapeutic agent comprises an antibiotic.

### Claim 5 (depends on 4)

The nanoparticle of claim 4, wherein the therapeutic agent is doxorubicin.

### Claim 6 (depends on 1)

The nanoparticle of claim 1, wherein the nanoparticle further comprises one or more targeting agents comprising the peptide sequence CFLDFP (SEQ ID NO: 2), (X)CDPC (SEQ ID NO: 3), XC(Z)PC (SEQ ID NO: 4), XCA(Z)C (SEQ ID NO: 5), (X)CSPC (SEQ ID NO: 6), YC(X)C (SEQ ID NO: 7), or RC(X)PC (SEQ ID NO: 8) where X and Z are variable amino acids.

### Claim 7 (depends on 6)

The nanoparticle of claim 6, wherein the targeting agent comprises the peptide sequence CFLDFP (SEQ ID NO: 2).

### Claim 8 (depends on 1)

The nanoparticle of claim 1, wherein the nanoparticle has a size of about 20 nm and includes 10 to 40 molecules of said targeting agent.

### Claim 9 (depends on 2)

The nanoparticle of claim 2, wherein the water-soluble polymer comprises polyethylene glycol (PEG), and the therapeutic agent is coupled to the second lipid via a pH-sensitive bond.

### Claim 10 (depends on 9)

The nanoparticle of claim 9, wherein the targeting agent is configured to bind to a VLA-4 receptor of a target cell, the therapeutic agent comprises doxorubicin, and the pH-sensitive bond is configured to hydrolyze at the pH of an endocytic vesicle of the target cell.

### Claim 11 (depends on 1)

A method of delivering a therapeutic agent to a cell or tissue of interest in an individual, comprising administering the nanoparticle of claim 1 to a patient in need thereof, wherein the targeting agent of said nanoparticle enhances accumulation of said therapeutic agent in the cell or tissue of interest.

### Claim 12 (depends on 11)

The method of claim 11, wherein the targeting agent binds to a receptor of the cell or tissue of interest, and the targeting agent enhances receptor-mediated endocytosis of the nanoparticle by the cell or tissue of interest.

### Claim 13 (depends on 11)

The method of claim 11, wherein the cell or tissue of interest is a cancerous cell or tissue.

### Claim 14 (depends on 13)

The method of claim 13, wherein the cell or tissue of interest is a multiple myeloma cell.

### Claim 15 (depends on 13)

The method of claim 13, wherein the therapeutic agent is doxorubicin.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising the nanoparticle of claim 1 and a pharmacologically acceptable excipient.

### Claim 17

A micellar nanoparticle comprising:
a hydrophobic interior portion surrounded by an outer portion, the outer portion comprising a water-soluble polymer conjugated to a phospholipid;
a therapeutic agent coupled to, and disposed at least partially within, the outer portion, wherein the therapeutic agent coupled to the outer portion is a phospholipid conjugate of the formula:
and
a targeting agent coupled to, and disposed at least partially within, the outer portion, wherein the targeting agent is a low-affinity, high-specificity peptide ligand of the formula:
wherein VLA4-pep is a peptide of SEQ ID NO: 1.

### Claim 18 (depends on 17)

A pharmaceutical composition comprising the nanoparticle of claim 17 and a pharmacologically acceptable excipient.