# US 11,305,024 B2 · Cross-linked polymer modified nanoparticles

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- Number: US 11,305,024 B2
- Document ID: US11305024B2
- Status: Granted
- Kind: B2
- Application number: 17/398,954
- Filed: 2021-08-10
- Published: 2021-12-23
- Granted: 2022-04-19
- Earliest claimed: 2015-03-16
- Assignees: Oregon Health & Science University; PDX Pharmaceuticals, Inc.
- Applicants: Oregon Health & Science University; PDX Pharmaceuticals, Inc.
- Inventors: Wassana Yantasee; Worapol Ngamcherdtrakul; Jingga Morry; David Castro; Joe William Gray
- Web page: https://patentgrep.com/patent/US11305024B2

## CPC

- A61K 49/0093: {Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle}
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 38/16: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof {(enzyme inhibitors A61K38/005)}
- A61K 47/551: {one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid}
- A61K 47/59: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- A61K 47/6923: {the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb}
- A61K 47/6929: {the form being a nanoparticle, e.g. an immuno-nanoparticle}
- A61K 49/1857: {the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA}
- A61K 49/186: {the organic macromolecular compound being polyethyleneglycol [PEG]}
- A61K 49/1875: {coated or functionalised with an antibody}
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- B82Y 30/00: Nanotechnology for materials or surface science, e.g. nanocomposites
- 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)
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES

## Abstract

Disclosed herein are nanoconstructs comprising a nanoparticle, coated with additional agents such as cationic polymers, stabilizers, targeting molecules, labels, oligonucleotides and small molecules. These constructs may be used to deliver compounds to treat solid tumors and to diagnose cancer and other diseases. Further disclosed are methods of making such compounds and use of such compounds to treat or diagnose human disease.

## Claims

### Claim 1

A composition comprising:
a plurality of multilayer nanoconstructs each comprising:
about 10% to about 30% by weight cross-linked polyethylenimine (PEI) bound to an exterior surface of a silica nanoparticle, a silicon nanoparticle, an iron oxide nanoparticle, a silver nanoparticle, or a carbon nanotube; and
polyethylene glycol (PEG) bound to the PEI or to the nanoparticle;
wherein the nanoconstructs have a hydrodynamic size Z-average diameter of about 200 nm or less; and the plurality of nanoconstructs have a polydispersity index (PDI) of no more than about 0.37; and
an oligonucleotide non-covalently attached to the PEI.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the silica nanoparticle is a mesoporous silica nanoparticle (MSNP).

### Claim 3 (depends on 1)

The composition of claim 1, wherein the nanoparticles consist essentially of material(s) selected from the group consisting of: silica, silicon, iron oxide, silver, a carbon nanotube, and a combination of two or more thereof.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the multilayer nanoconstructs each comprise an iron oxide nanoparticle.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the PEI is crosslinked using a cleavable crosslinker.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the PEI has an average size of 1.8 to 25 kDa.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the nanoparticle is from about 5 nm to about 90 nm in diameter.

### Claim 8 (depends on 1)

The composition of claim 1, wherein the hydrodynamic size Z-average diameter of the nanoconstructs is about 80 nm to about 200 nm, or is about 90 nm to about 120 nm.

### Claim 9 (depends on 1)

The composition of claim 1, wherein the oligonucleotide comprises at least one of siRNA, miRNA, an miRNA mimic, DNA, or an antisense oligomer.

### Claim 10 (depends on 1)

The composition of claim 1, wherein the oligonucleotide comprises siRNA.

### Claim 11 (depends on 1)

The composition of claim 1, wherein the PDI of the nanoconstructs is about 0.22.

### Claim 12 (depends on 1)

The composition of claim 1, wherein the hydrodynamic diameter of the nanoconstructs loaded with the oligonucleotide is about 200 nm or less.

### Claim 13 (depends on 1)

The composition of claim 1, wherein the PDI of the nanoconstructs loaded with the oligonucleotide is no more than about 0.2.

### Claim 14 (depends on 1)

The composition of claim 1, wherein the nanoconstructs further comprise one or more of: a small molecule, a protein, or a targeting agent.

### Claim 15 (depends on 14)

The composition of claim 14, wherein the small molecule comprises: a chemotherapeutic agent, a small molecule inhibitor, a label, or a polypeptide.

### Claim 16 (depends on 14)

The composition of claim 14, wherein the targeting agent comprises one or more of: an antibody, a scFv antibody, an affibody, an aptamer, a ligand, a carbohydrate, a peptide, or a small targeting molecule.

### Claim 17 (depends on 1)

The composition of claim 1, further comprising a label attached to the nanoconstructs.

### Claim 18 (depends on 17)

The composition of claim 17, wherein the label comprises at least one of a lanthanide, a fluorescent dye, a gold nanoparticle, a quantum dot, a PET tracer, or a MRI contrast agent.

### Claim 19 (depends on 18)

A method of labeling a target comprising contacting the composition of claim 18 with the target under conditions to bind the nanoconstruct to the target.

### Claim 20 (depends on 19)

The method of claim 19, wherein the contacting occurs ex vivo.

### Claim 21 (depends on 19)

The method of claim 19, wherein the contacting occurs in vivo in a subject.

### Claim 22 (depends on 19)

The method of claim 19, wherein the label comprises at least one of a lanthanide, a fluorescent dye, a gold nanoparticle, a quantum dot, a PET tracer, or a MRI contrast agent.

### Claim 23 (depends on 19)

The method of claim 19, further comprising at least one of:
(1) quantifying the amount of target by detecting the label after the nanoconstruct binds to the target;
(2) administering the labeled nanoconstruct to a subject; and detecting a location of the label after the administering; or
(3) administering the labeled target to a subject; and detecting a location of the labeled target after the administering.

### Claim 24 (depends on 1)

A method of delivering an oligonucleotide to a site in a human or other mammalian subject, the method comprising administering an effective amount of the composition of claim 1 to the human or other mammalian subject under conditions to deliver the nanoconstruct to the site.

### Claim 25 (depends on 24)

The method of claim 24, wherein the site is a cell, or the site is a tumor.

### Claim 26 (depends on 25)

The method of claim 25, wherein the nanoconstruct is administered under conditions that the nanoconstruct is internalized by the cell, or by a cancer or non-cancer cell within the tumor.

### Claim 27 (depends on 24)

The method of claim 24, wherein the oligonucleotide modulates expression of a target protein.

### Claim 28 (depends on 24)

The method of claim 24, wherein the subject is diagnosed with cancer or diagnosed with or is at risk for fibrosis or inflammation, and the effective amount is a therapeutically effective amount.

### Claim 29 (depends on 24)

The method of claim 24, wherein the nanoconstruct further comprises a targeting agent.

### Claim 30 (depends on 24)

The method of claim 24, wherein the nanoconstruct reduces reactive oxygen species, bioavailable copper, and/or NOX expression level in the subject or modulates an adverse effect of one or more cytokines.