# US 10,765,637 B2 · RGD and transferrin nanoparticle composition

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- Number: US 10,765,637 B2
- Document ID: US10765637B2
- Status: Granted
- Kind: B2
- Application number: 16/087,557
- Filed: 2017-03-23
- Published: 2019-04-04
- Granted: 2020-09-08
- Earliest claimed: 2016-03-24
- Assignees: Toyo University
- Applicants: Toyo University
- Inventors: Toru Maekawa; Sakthikumar Dasappan Nair; Sheikh Mohamed Mohamed; Srivani Veeranarayanan
- Web page: https://patentgrep.com/patent/US10765637B2

## CPC

- A61K 9/5123: {Organic compounds, e.g. fats, sugars}
- A61K 9/1271: Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911})
- A61K 9/16: Agglomerates; Granulates; Microbeadlets {; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction (A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51)}
- A61K 9/5169: {Proteins, e.g. albumin, gelatin}
- A61K 9/5192: {Processes}
- A61K 38/168: {from plants}
- A61K 45/00: Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/24: containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
- A61K 47/42: Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34)
- A61K 47/62: the modifying agent being a protein, peptide or polyamino acid
- A61K 47/6929: {the form being a nanoparticle, e.g. an immuno-nanoparticle}
- A61K 49/00: Preparations for testing in vivo
- A61K 49/0056: {Peptides, proteins, polyamino acids}
- A61K 49/0067: {quantum dots, fluorescent nanocrystals}
- A61P 35/00: Antineoplastic agents
- A61K 49/0004: {Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions}
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- 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
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES

## Abstract

Provided is a composition which can be utilized for drug delivery systems that can penetrate the blood brain barrier, and has low cytotoxicity. A nanoparticle composition comprises nanoparticles to the surface of which a first substance and a second substance each having specificity to a tumor cell are bound, wherein the first substance having specificity to the tumor cell is a peptide comprising an amino acid sequence of arginine-glycine-aspartic acid, and wherein the second substance having specificity to the tumor cell is an iron-binding protein, and wherein the nanoparticles each comprise an outer layer and vesicles enveloped by the outer layer and the nanoparticles each comprise, as membrane components, a PEGylated phospholipid, a fatty acid with a melting point of 30° C. or more, and a non-PEGylated phospholipid.

## Claims

### Claim 1

A nanoparticle composition comprising nanoparticles to the surface of which a first substance and a second substance each having specificity to a tumor cell are bound,
wherein the first substance having specificity to the tumor cell is a peptide comprising an amino acid sequence of arginine-glycine-aspartic acid,
wherein the second substance having specificity to the tumor cell is transferrin,
wherein the nanoparticle composition comprises the first substance and the second substance at a mass ratio of 2:8 to 8:2, and
wherein the nanoparticles each comprise an outer layer and vesicles enveloped by the outer layer, and the nanoparticles comprise membrane components that comprising a PEGylated phospholipid, stearic acid, and phosphatidylcholine,
wherein the PEGylated phospholipid is phosphatidylethanolamine to which PEG is bound and the PEG is modified with the amino group.

### Claim 2 (depends on 1)

The nanoparticle composition according to claim 1, wherein the phosphatidylethanolamine is DSPE.

### Claim 3 (depends on 1)

The nanoparticle composition according to claim 1, wherein the nanoparticle further comprises a drug.

### Claim 4 (depends on 3)

The nanoparticle composition according to claim 3, wherein the drug is an anti-cancer agent.

### Claim 5 (depends on 1)

The nanoparticle composition according to claim 1, wherein the nanoparticle further comprises an imaging agent.

### Claim 6 (depends on 1)

A method for producing the nanoparticle composition comprising nanoparticles to the surface of which a first substance and a second substance each having specificity to a tumor cell are bound according to claim 1, comprising:
(i) removing a volatile organic solvent from a solution comprising a PEGylated phospholipid, stearic acid, and phosphatidylcholine in the volatile organic solvent to form a membrane,
wherein the PEGylated phospholipid is phosphatidylethanolamine to which PEG is bound and the PEG is modified with an amino group,
(ii) sonicating the membrane formed in the step (i) in a buffer to produce nanoparticles, and
(iii) binding the first substance and the second substance each having specificity to the tumor cell to the surface of the nanoparticles produced in the step (ii) at a mass ratio of 2:8 to 8:2,
wherein the first substance having specificity to the tumor cell is a peptide comprising an amino acid sequence of arginine-glycine-aspartic acid, and
wherein the second substance having specificity to the tumor cell is transferrin.

### Claim 7 (depends on 6)

The method according to claim 6, wherein in the step (ii), the buffer comprises a drug, and nanoparticles comprising the drug are produced.

### Claim 8 (depends on 7)

The method according to claim 7, wherein the drug is an anti-cancer agent.

### Claim 9 (depends on 6)

The method according to claim 6, further comprising introducing an imaging agent into the nanoparticle.

### Claim 10 (depends on 4)

A pharmaceutical composition for treating cancer, comprising the nanoparticle composition according to claim 4.

### Claim 11 (depends on 10)

The pharmaceutical composition according to claim 10, wherein the cancer is a brain tumor.

### Claim 12 (depends on 5)

A composition for imaging a tumor cell, comprising the nanoparticle composition according to claim 5.

### Claim 13 (depends on 5)

A method for detecting a brain tumor, comprising administering the composition according to claim 5 to a subject in need thereof and detecting a localization of the imaging agent in a brain.

### Claim 14 (depends on 5)

A method for monitoring the effect of a therapy against a brain tumor, comprising administering the composition according to claim 5 to a subject in need thereof and detecting a localization of the imaging agent in a brain.

### Claim 15 (depends on 1)

The nanoparticle composition according to claim 1, wherein the nanoparticles are produced by (i) removing a volatile organic solvent from a solution comprising the PEGylated phospholipid, stearic acid, and phosphatidylcholine in the volatile organic solvent to form a membrane, (ii) sonicating the membrane formed in the step (i) in a buffer to produce nanoparticles, and (iii) binding said first substance and said second substance each having specificity to the tumor cell to the surface of the nanoparticles produced in the step (ii) at a mass ratio of 2:8 to 8:2.

### Claim 16 (depends on 15)

The nanoparticle composition according to claim 15, wherein the sonicating in the step (ii) is carried out at 43 kHz for 1 to 2 minutes.

### Claim 17 (depends on 6)

The method according to claim 6, wherein the sonicating in the step (ii) is carried out at 43 kHz for 1 to 2 minutes.