# US 12,649,000 B2 · Use of alginate oligomers to enhance the translocation of micro/nanoparticles across mucus layers

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- Number: US 12,649,000 B2
- Document ID: US12649000B2
- Status: Granted
- Kind: B2
- Application number: 16/982,240
- Filed: 2019-03-19
- Published: 2021-02-04
- Granted: 2026-06-09
- Earliest claimed: 2018-03-19
- Assignees: Algipharma AS
- Applicants: AlgiPharma AS
- Inventors: Aristides Tagalakis; Stephen Hart; Are Kristiansen; Arne Dessen; Philip D. Rye
- Web page: https://patentgrep.com/patent/US12649000B2

## CPC

- 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 47/61: the organic macromolecular compound being a polysaccharide or a derivative thereof
- C12N 15/1131: {against viruses}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- C12N 2750/14123: Virus like particles [VLP]
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- 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)
- 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

## Abstract

A method for translocating a cationic micro/nanoparticle across a mucus layer, the method including (a) contacting the mucus layer with at least one alginate oligomer, the alginate oligomer having at least 70% mannuronate residues, together with the cationic micro/nanoparticle; or (b)(i) contacting the cationic micro/nanoparticle with an alginate oligomer having at least 70% mannuronate residues thereby forming a micro/nanoparticle carrying the alginate oligomer, and (b)(ii) contacting the mucus layer with the micro/nanoparticle prepared in step (b)(i). There is also provided a method for translocating a molecule of interest across a mucus layer including contacting the mucus layer with a micro/nanoparticle which is formed of self-assembling micro/nanoparticle forming components, wherein at least one is a cationic micro/nanoparticle forming agent and at least one is an alginate oligomer which has at least 70% mannuronate residues, and further comprises the molecule of interest, optionally wherein the molecule of interest is covalently bound to one or more of the self-assembling micro/nanoparticle forming components.

## Claims

### Claim 1

A method for translocating a cationic micro/nanoparticle across a mucus layer said method comprising
contacting the mucus layer with at least one alginate oligomer and a cationic micro/nanoparticle, wherein said at least one alginate oligomer has at least 70% mannuronate residues, and wherein said at least one alginate oligomer and said cationic micro/nanoparticle are separate from one another.

### Claim 2 (depends on 1)

The method of claim 1 comprising delivering a molecule of interest to an epithelial cell of a mucosal surface, wherein said mucus layer is the mucus layer of the mucosal surface.

### Claim 3 (depends on 2)

The method of claim 2, wherein said micro/nanoparticle carries the molecule of interest or said molecule is provided in a micro/nanoparticulate form thereof.

### Claim 4 (depends on 3)

The method of claim 3, wherein the molecule of interest is covalently bound to another component of the micro/nanoparticle or may be distinct from other components of the micro/nanoparticle.

### Claim 5 (depends on 2)

The method of claim 2, wherein said molecule of interest is a molecule of therapeutic and/or diagnostic utility.

### Claim 6 (depends on 1)

The method of claim 1, wherein the mucus layer is the mucus layer of a mucosal surface
(i) affected by CFTR dysfunction,
(ii) of the respiratory system,
(iii) of the gastrointestinal tract,
(iv) of the pancreatic and/or bile ducts,
(v) of the female reproductive system, or
(vi) of the male reproductive system.

### Claim 7 (depends on 1)

The method of claim 1, wherein said micro/nanoparticle is
(i) a microparticle of about 1 μm to about 500 μm or
(ii) a nanoparticle of about 1 nm to about 1000 nm.

### Claim 8 (depends on 1)

The method of claim 1, wherein the micro/nanoparticle is a vesicle, micelle, virus, virus like particle, dendrimer, metal/metallic micro/nanoparticle, carbon nanotube, silica micro/nanoparticle, or polymeric micro/nanoparticle.

### Claim 9 (depends on 8)

The method of claim 8, wherein the micro/nanoparticle is a liposome or lipoplex comprising a cationic lipid selected from the group consisting of N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), 2,3-dioleoyloxy trimethylammonium propane (DOTAP), 2,3-di-(oleyloxy) propyl trimethyl ammonium (DOTMA), N-[1-(2,3,-ditetradecyloxy) propyl]-N,N-dimethyl-N-hydroxyethylammonium bromide (DMRIE), N-[1-(2,3,dioleyloxy) propyl]-N,N-dimethyl-N-hydroxy ethylammonium bromide (DORIE), 3B-[N—(N′,N′-dimethylaminoethane) carbamoyl]cholesterol (DC-Choi), dimethyldioctadecylammonium (DDAB), dioctadecylamidoglycyl spermine (DOGS) and 2,3-dioleyloxy-1-(dimethylamino) propane (DODMA).

### Claim 10 (depends on 8)

The method of claim 8, wherein the micro/nanoparticle is a virus carrying a nucleic acid vector or a heterologous peptide or an oncolytic virus.

### Claim 11 (depends on 8)

The method of claim 8, wherein the polymeric micro/nanoparticle comprises polystyrene, polylactic acid, polyacrylamide, melamine, poly(D-L-lactide), poly-D-L-glycolide, polyalkylcyanoacrylate, poly(lactide-co-glycolide) PLA, polycaprolactone, chitosan, gelatine, albumin, dextran, agarose, poly-L-glutamic acid and/or poly L-lysine.

### Claim 12 (depends on 8)

The method of claim 8, wherein the metal/metallic micro/nanoparticle comprises gold, silver, platinum, iron, copper, gadolinium, indium, technetium, gallium, rhenium, lutetium, actinium, yttrium, antimony), tin, dysprosium, cobalt, ruthenium, palladium, cadmium, tellurium, barium, terbium, lanthanum, radium, strontium, samarium, ytterbium, thallium, caesium, iridium and rubidium.

### Claim 13 (depends on 2)

The method of claim 2, wherein the molecule of interest is a therapeutically active agent, a diagnostic agent, an imaging agent, or an agent for engineering the properties of a cell or the products a cell produces.

### Claim 14 (depends on 13)

The method of claim 13, wherein the therapeutically active agent is a small molecule pharmaceutical, a biological therapeutic or a radiopharmaceutical.

### Claim 15 (depends on 14)

The method of claim 14 wherein the biological therapeutic is an antibody, a peptide hormone, a cytokine, a peptide growth factor, a peptide antigen or a nucleic acid.

### Claim 16 (depends on 13)

The method of claim 13, wherein the therapeutically active agent is a CFTR modulator, an antibiotic, an antifungal, an antiviral, a cytotoxic chemotherapy agent, an angiogenesis inhibitor, an anti-cancer monoclonal antibody, a radioimmunotherapeutic, an immunostimulatory agent, an immunosuppressant, a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), a bronchodilator, or an oral antidiabetic drug.

### Claim 17 (depends on 13)

The method of claim 13, wherein the therapeutically active agent is a nucleic acid for use in gene therapy, gene editing, RNA interference therapy, antisense therapy or an in vitro transcribed mRNA therapy.

### Claim 18 (depends on 13)

The method of claim 13, wherein the diagnostic agent is a radiodiagnostic, a contrast agent or a nucleic acid or protein for use as a molecular probe.

### Claim 19 (depends on 13)

The method of claim 13, wherein the cell engineering agent is a nuclease, a protease, a lipase, a co-factor, a precursor compound or a substrate.

### Claim 20 (depends on 1)

The method of claim 1, wherein said alginate oligomer has an average molecular weight of less than 35,000 Daltons.

### Claim 21 (depends on 1)

The method of claim 1, wherein the alginate oligomer has a degree of poplymerization (DP), or a number average degree of poplymerization (DPn) of 2 to 100.

### Claim 22 (depends on 1)

The method of claim 1, wherein the alginate oligomer has at least 80% M residues.

### Claim 23 (depends on 1)

The method of claim 1, wherein the alginate oligomer has a degree of polymerization (DP), or a number average degree of polymerization (DPn) of 2 to 28.