# US 9,872,833 B2 · Liposome composite body

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- Number: US 9,872,833 B2
- Document ID: US9872833B2
- Status: Granted
- Kind: B2
- Application number: 14/349,871
- Filed: 2012-10-03
- Published: 2014-12-18
- Granted: 2018-01-23
- Earliest claimed: 2011-10-07
- Assignees: National University Corporation Tottori University; National University Corporation Chiba University
- Applicants: National University Corporation Tottori University; National University Corporation Chiba University
- Inventors: Yoshiharu Okamoto; Yutaka Tamura; Akiko Suganami; Hideki Hayashi; Tomoyuki Madono; Hisahiro Matsubara; Taro Toyota
- Web page: https://patentgrep.com/patent/US9872833B2

## CPC

- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K 31/403: condensed with carbocyclic rings, e.g. carbazole
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 41/0052: {Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy}
- A61K 41/0057: {Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent}
- A61K 49/0021: {the fluorescent group being a small organic molecule}
- A61K 49/0034: {Indocyanine green, i.e. ICG, cardiogreen}
- A61K 49/0052: {Small organic molecules (oligomers, polymers, dendrimers A61K49/0054)}
- A61K 49/0084: {liposome, i.e. bilayered vesicular structure}
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

An object of the present invention is to provide a drug delivery system capable of sustainedly releasing a drug noninvasively at any given point in time. The present invention relates to a liposome complex comprising a liposome membrane-constituting substance bonded to a light-absorbing compound having an absorption wavelength in the near-infrared region, selected from the group consisting of indocyanine green dyes, phthalocyanine dyes, squarylium dyes, croconium dyes, and diimmonium dyes.

## Claims

### Claim 1

A method for treating a tumor comprising:
administering to a subject in need thereof an effective amount of a liposome comprising an anti-cancer agent and a liposome membrane-constituting substance, wherein the liposome membrane-constituting substance is (a) anchored in the hydrophobic membrane region of a liposome and (b) covalently bonded to a light-absorbing compound having an absorption wavelength in the near-infrared region, the light-absorbing compound comprising an indocyanine green dye, the anti-cancer agent being contained in the liposome; and
irradiating an affected area of the subject with light;
wherein the liposome membrane-constituting substance covalently bonded to the light-absorbing compound is represented by formula (I) below:
A-(CH2)a-B1-(CH2)b-B2-D-E1 (I)
wherein A represents the light-absorbing compound;
B1 and B2 each independently represent —CH2—, —CH═CH—, —O—, —S—, —NH—, —CO—, —COO—, —OCO—, —NHCO—, —CONH—, —PO4H—, or —PO4M- (where M represents an alkali metal ion);
D represents —CHE2-, —CH2CH(OCOE2)-CH2OCO—, or —CHE2-CH2OCO—;
E1 represents a substituted or unsubstituted hydrocarbon group having 8 to 18 carbon atoms;
E2 represents hydrogen or a substituted or unsubstituted hydrocarbon group having 8 to 18 carbon atoms; and
a represents an integer of 0 to 4 and b represents an integer of 0 to 6.

### Claim 2 (depends on 1)

The method according to claim 1, comprising irradiating the affected area with light to generate singlet oxygen.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the liposome membrane-constituting substance comprises a lipid.

### Claim 4 (depends on 1)

The method according to claim 1, wherein B1 and B2 each independently represent —CH2—, —CH═CH—, —O—, or —S—; and D represents —CHE2- (where E2 is as described in claim 1).

### Claim 5 (depends on 1)

The method according to claim 1, wherein B1 and B2 each represent —CH2—.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the liposome membrane-constituting substance comprises at least one selected from the group consisting of lipids, membrane stabilizers, antioxidants, and membrane proteins.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the liposome membrane-constituting substance covalently bonded to the light-absorbing compound is represented by formula (II-1) below:
wherein X1 and X2 each represent —C(CH3)2—, O, or S; Y1 and Y3 each represent hydrogen or OCH3 and Y2 and Y4 each represent hydrogen, or Y1 and Y2, and Y3 and Y4 each optionally together form a benzene ring fused with a ring to which they are bound; Q1 and Q2 each represent hydrogen or are optionally bonded to form a 6-membered ring; any one of R1 to R3 represents —(CH2)a-B1-(CH2)b-B2-D-E1 where the symbols have the same meaning as those in the formula (I) in claim 1; P1 represents chloride ion, bromide ion, or iodide ion as a monovalent anion; and R1 to R3 each represent a group selected from the group consisting of the following groups:
where Z1 or Z2 represents —O—, —NH—, —S—, —SO2—, —CH═CH—, —SO2NH—, —NHSO2—, —CONH—, —NHCO—, —CO—, —COO—, —OCO—, or —C6H4—; P2 represents hydrogen ion, lithium ion, sodium ion, or potassium ion as a monovalent cation; M represents hydrogen ion, lithium ion, sodium ion, or potassium ion as a monovalent cation; R4 represents an alkane, an alkene, or an alkyne having 1 to 18 carbon atoms; n or m represents an integer of 0 to 22; 1 represents an integer of 1 to 22; p represents an integer of 0 to 17; and x represents an integer of 2 to 2,000.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the liposome membrane-constituting substance covalently bonded to the light-absorbing compound is represented by formula (5) below:

### Claim 9 (depends on 1)

The method according to claim 1, wherein the liposome membrane-constituting substance covalently bonded to the light-absorbing compound is represented by the formula below: