# US 8,772,472 B2 · SiRNA conjugate and preparation method thereof

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- Number: US 8,772,472 B2
- Document ID: US8772472B2
- Status: Granted
- Kind: B2
- Application number: 13/613,071
- Filed: 2012-09-13
- Published: 2013-04-18
- Granted: 2014-07-08
- Earliest claimed: 2009-05-14
- Assignees: Bioneer Corporation
- Applicants: Bo Ram Han; Han Oh Park; Mi Sik Shin; Sam Young Lee
- Inventors: Bo Ram Han; Han Oh Park; Mi Sik Shin; Sam Young Lee
- Web page: https://patentgrep.com/patent/US8772472B2

## CPC

- C07F 7/0836: {Compounds with one or more Si-OH or Si-O-metal linkage}
- 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 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- C07H 21/02: with ribosyl as saccharide radical
- C08G 65/3356: {having nitrogen in addition to phosphorus}
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- C12N 2310/11: Antisense
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/351: Conjugate
- C12N 2310/3515: Lipophilic moiety, e.g. cholesterol
- C12N 2320/30: Special therapeutic applications
- C12N 2320/51: modulating the chemical stability, e.g. nuclease-resistance
- Y10S 977/773: Nanoparticle, i.e. structure having three dimensions of 100 nm or less
- Y10S 977/906: Drug delivery
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- 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
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS

## Abstract

Provided are an siRNA-polymer conjugate, and a method for preparing the same, and more specifically, to a hybrid conjugate formed by covalently bonding siRNA and a polymeric compound for improving the in vivo stability of siRNA, and to a preparation method of the hybrid conjugate. The conjugate of the present invention can improve the in vivo stability of siRNA, thereby achieving an efficient delivery of therapeutic siRNA into cells and exhibiting the activity of siRNA even with a small dose of a relative low concentration. Therefore, the conjugate can advantageously be used as not only an siRNA treatment tool for cancers and other infectious disease, but also a novel type siRNA delivery system.

## Claims

### Claim 1

A conjugate of survivin-specific siRNA and polymer compound, of the structure below:
A-X—R—Y—B
wherein:
one of A and B is a hydrophilic polymer compound and the other thereof is a hydrophobic compound;
X and Y each are independently a simple covalent bond or a linker-mediated covalent bond; and
R is a survivin-specific siRNA,
wherein the hydrophobic compound is C16˜C50 hydrocarbon or cholesterol which has a molecular weight of 250 to 1,000.

### Claim 2 (depends on 1)

The conjugate of claim 1, wherein a single strand of the survivin-specific siRNA (R) is composed of 19 to 31 nucleotides.

### Claim 3 (depends on 1)

The conjugate of claim 1, wherein the survivin-specific siRNA (R) comprises sense strand having a nucleotide sequence selected from nucleotide sequences of SEQ ID NOs.: 1 to 4 and an antisense strand having a nucleotide sequence complementary to the sequence of the sense strand.

### Claim 4 (depends on 1)

The conjugate of claim 1, wherein the survivin-specific siRNA(R) has chemical modification.

### Claim 5 (depends on 4)

The conjugate of claim 4, wherein the chemical modification includes at least one modification selected from:
modification of a phosphorodiester bond into a phosphorothioate linkage; modification of —OH at the 2′-position of a pentose into 2′-OCH3 or 2′-dioxy-2′-fluouridine; and
modification of —OH at the 2′ position of the pentose into an LNA type formed by linking the 2′ position and the 4′ position of the pentose.

### Claim 6 (depends on 1)

The conjugate of claim 1, wherein:
the hydrophilic polymer compound is a non-ionic polymer compound having a molecular weight of 1,000 to 10,000; and
the simple covalent bond or linker-mediated covalent bond is a non-degradable bond or a degradable bond.

### Claim 7 (depends on 6)

The conjugate of claim 6, wherein the non-degradable bond is an amide bond or a phosphate bond; and the degradable bond is selected from a disulfide bond, an acid-cleavable bond, an ester bond, an anhydride bond, a biodegradable bond and an enzyme-cleavable bond.

### Claim 8 (depends on 6)

The conjugate of claim 6, wherein the hydrophilic polymer compound includes at least one selected from polyethyleneglycol, polyvinylpyrolidone, and polyoxazoline.

### Claim 9 (depends on 1)

A nanoparticle comprising the conjugate of claim 1.

### Claim 10 (depends on 1)

A composition comprising the conjugate of claim 1 as a pharmaceutically effective component.

### Claim 11 (depends on 9)

A composition comprising the nanoparticle of claim 9 as a pharmaceutically effective component.