# US 10,478,506 B2 · Fucoidan nanogels and methods of their use and manufacture

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- Number: US 10,478,506 B2
- Document ID: US10478506B2
- Status: Granted
- Kind: B2
- Application number: 16/241,954
- Filed: 2019-01-07
- Published: 2019-05-16
- Granted: 2019-11-19
- Earliest claimed: 2014-04-17
- Assignees: Memorial Sloan Kettering Cancer Center
- Applicants: Memorial Sloan Kettering Cancer Center
- Inventors: Adriana Haimovitz-Friedman; Daniel A. Heller; Yosef Shamay
- Web page: https://patentgrep.com/patent/US10478506B2

## CPC

- A61K 47/61: the organic macromolecular compound being a polysaccharide or a derivative thereof
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 9/5146: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides}
- A61K 9/5161: {Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin}
- A61K 9/5169: {Proteins, e.g. albumin, gelatin}
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/4412: having oxo groups directly attached to the heterocyclic ring
- A61K 31/475: having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine (vincamine A61K31/4375)
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/737: Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate (A61K31/727 takes precedence)
- A61K 41/0038: {Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy (radiotherapy per se A61N5/10)}
- A61K 47/585: {Ion exchange resins, e.g. polystyrene sulfonic acid resin}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- 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 47/643: {Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]}
- A61K 47/6935: {the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol}
- A61K 47/6939: {the polymer being a polysaccharide, e.g. starch, chitosan, chitin, cellulose or pectin}
- A61K 49/00: Preparations for testing in vivo
- A61K 51/065: {conjugates with carriers being macromolecules}
- A61P 35/00: Antineoplastic agents
- 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

Described herein are polymeric drug-carrying nanogels that are capable of targeting to P-selectin for the treatment of cancer and other diseases and conditions associated with P-selectin. Furthermore, in certain embodiments, the nanogels presented here offer a drug release mechanism based on acidic pH in the microenvironment of a tumor, thereby providing improved treatment targeting capability and allowing use of lower drug doses, thereby reducing toxicity.

## Claims

### Claim 1

A polymeric nanoparticle with affinity to P-selectin, the nanoparticle comprising a non-covalent assembly of
a sulfated polymer species comprising free hydroxyl moieties and free sulfate moieties capable of targeting P-selectin, the sulfated polymer species comprising one or more of a sulfated polysaccharide, a protein, or a fucoidan;
a hydrophobic drug; and
a dye comprising a fluorophore;
wherein
the nanoparticle has an intensity-weighted average diameter as determined by dynamic light scattering of about 20 nm and about 200 nm; and
the non-covalent assembly is a self-assembly of the sulfated polymer species around the hydrophobic drug.

### Claim 2 (depends on 1)

The nanoparticle of claim 1, wherein the sulfated polymer species comprises a fucoidan.

### Claim 3 (depends on 1)

The nanoparticle of claim 1, wherein the hydrophobic drug comprises a member selected from the group consisting of paclitaxel, MEK162, docetaxel, Camptothecin, sorafenib, ispinesib, LY294002, Selumetinib, PD184352, 5-fluorouracil, Cyclophosphamide, Atorvastatin, Lovastatin, etoposide, dexamethasone, gemcitabine, Rapamycin (Sirolimus), and methotrexate.

### Claim 4 (depends on 1)

The nanoparticle of claim 1, wherein the nanoparticle has an intensity-weighted average diameter as determined by dynamic light scattering of about 100 nm to about 200 nm.

### Claim 5 (depends on 1)

The nanoparticle of claim 1, wherein the nanoparticle has an intensity-weighted average diameter as determined by dynamic light scattering of about 150 nm to about 170 nm.

### Claim 6 (depends on 1)

The nanoparticle of claim 1, wherein the dye is a near infra-red dye.

### Claim 7 (depends on 1)

The nanoparticle of claim 1, wherein the dye is IR783.

### Claim 8 (depends on 1)

The nanoparticle of claim 1, wherein the nanoparticle is negatively charged.

### Claim 9 (depends on 1)

A method for manufacturing the nanoparticle of claim 1, the method comprising:
contacting the hydrophobic drug to the sulfated polymer species to form a mixture; and
agitating the mixture to form nanoparticles.

### Claim 10 (depends on 9)

The method of claim 9, wherein agitating the mixture comprises sonicating the mixture.

### Claim 11 (depends on 9)

The method of claim 9, wherein the hydrophobic drug and the sulfated polymer species are precipitated together.

### Claim 12 (depends on 9)

The method of claim 9, wherein the hydrophobic drug and the sulfated polymer species are precipitated together via nano-precipitation.

### Claim 13 (depends on 1)

A method of treating a subject suffering from a P-selectin associated disease, the method comprising
administering to the subject a formulation comprising the nanoparticle of claim 1.

### Claim 14 (depends on 13)

The method of claim 13, wherein the subject is human.

### Claim 15 (depends on 13)

The method of claim 13, wherein the P-selectin associated disease comprises a member selected from the group consisting of carcinoma, sarcoma, lymphoma, leukemia, sickle cell disease, arterial thrombosis, rheumatoid arthritis, ischemia, and reperfusion.

### Claim 16 (depends on 13)

The method of claim 13, wherein the P-selectin associated disease comprises a tumor.

### Claim 17 (depends on 13)

The method of claim 13, the method further comprising administering radiation to a site in the subject comprising the P-selectin associated disease.

### Claim 18 (depends on 17)

The method of claim 17, the radiation comprising ionizing radiation.

### Claim 19 (depends on 17)

The method of claim 17, wherein the P-selectin associated disease comprises a member selected from the group consisting of carcinoma, sarcoma, lymphoma, leukemia, sickle cell disease, arterial thrombosis, rheumatoid arthritis, ischemia, and reperfusion.

### Claim 20 (depends on 17)

The method of claim 17, wherein the P-selectin associated disease comprises a tumor.