# US 10,369,104 B2 · Targeted polymerized nanoparticles for cancer treatment

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- Number: US 10,369,104 B2
- Document ID: US10369104B2
- Status: Granted
- Kind: B2
- Application number: 15/301,020
- Filed: 2015-04-01
- Published: 2017-01-26
- Granted: 2019-08-06
- Earliest claimed: 2014-04-01
- Assignees: Children's Hospital Los Angeles; Nanovalent Pharmaceuticals, Inc.
- Applicants: Children's Hospital Los Angeles; Nanovalent Pharmaceuticals, Inc.
- Inventors: Jon O. Nagy; Tim Triche; Hyung-Gyoo Kang
- Web page: https://patentgrep.com/patent/US10369104B2

## CPC

- A61K 9/1273: Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
- A61K 9/1271: Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911})
- A61K 9/51: Nanocapsules; {Nanoparticles; (nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00)}
- A61K 31/136: having the amino group directly attached to the aromatic ring, e.g. benzeneamine
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/475: having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine (vincamine A61K31/4375)
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 33/243: Platinum; Compounds thereof
- Y10S 977/773: Nanoparticle, i.e. structure having three dimensions of 100 nm or less
- Y10S 977/906: Drug delivery
- Y10S 977/907: Liposome
- 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
- Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS

## Abstract

The invention relates to a novel drug delivery vehicle. Various embodiments of the invention provide a hybrid polymerized liposomal nanoparticle comprising both polymerizable lipids and non-polymerizable lipids. Therapeutic agents can be loaded into the polymerized liposomal nanoparticle and targeting agents can be conjugated to the surface of the polymerized liposomal nanoparticle. Also described in the invention are methods, compositions and kits that utilize the hybrid polymerized liposomal nanoparticle to treat disease conditions such as various cancers.

## Claims

### Claim 1

A hybrid polymerized liposomal nanoparticle, comprising:
a polymerizable lipid, wherein the polymerizable lipid comprises at least one PEGylated polymerizable lipid having a PEG polymer chain, wherein the PEGylated polymerizable lipid having the PEG polymer chain is m-PEG2000-PCDA; and
a non-polymerizable lipid.

### Claim 2 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the nanoparticle comprises:
about 15-40 mol % of the polymerizable lipid; and
the non-polymerizable lipid comprising:
at least about 10 mol % of a zwitterionically charged lipid;
about 20-45 mol % of a neutrally charged molecule;
and about 1-15 mol % of a negatively charged lipid.

### Claim 3 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the nanoparticle comprises:
about 15 mol % of the polymerizable lipid; and
the non-polymerizable lipid comprising:
about 51 mol % of a zwitterionically charged lipid;
about 32 mol % of a neutrally charged molecule; and
about 2 mol % of a negatively charged lipid.

### Claim 4 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, comprising:
about 14 mol % h-PEG1PCDA,
about 51 mol % hydrogenated soy PC,
about 32 mol % cholesterol,
about 2 mol % m-PEG2000-DSPE, and
about 1 mol % m-PEG2000-PCDA.

### Claim 5 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, comprising:
about 14 mol % h-PEG1PCDA,
about 48 mol % hydrogenated soy PC,
about 32 mol % cholesterol,
about 2 mol % m-PEG2000-DSPE,
about 3 mol % mal-PEG2000-DSPE, and
about 1 mol % m-PEG2000-PCDA.

### Claim 6 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, comprising:
about 24 mol % h-PEG1PCDA,
about 41 mol % hydrogenated soy PC,
about 32 mol % cholesterol,
about 2 mol % m-PEG2000-DSPE, and
about 1 mol % m-PEG2000-PCDA.

### Claim 7 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the polymerized liposomal nanoparticle is about 30-200 nm in size.

### Claim 8 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the polymerized liposomal nanoparticle is prepared by cooling at 5-10° C. after extrusion but prior to polymerization.

### Claim 9 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the polymerized liposomal nanoparticle is UV treated for about 1-35 minutes after fabrication to polymerize the polymerizable lipid.

### Claim 10 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the polymerized liposomal nanoparticle has a circulation half-life of at least about 1 to at least about 4 hours.

### Claim 11 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, comprising a neutrally charged molecule selected from cholesterol, ergosterol, hopanoids, phytosterol, stanol, and sterols, and functional derivatives thereof.

### Claim 12 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the PEGylated polymerizable lipid is about 0.1-1, 1-5, 5-10, or 10-15 mol%.

### Claim 13 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the polymerizable lipid is about 15-40 mol%.

### Claim 14 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the polymerizable lipid further comprises a lipid selected from the group consisting of N-(5′-hydroxy-3′-oxypentyl)-10-12-pentacosadiynamide (h-PEG1-PCDA), N-(5′-sulfo-3′-oxypenty 1)-10-12-pentacosadiynamide (sulfo-PEG1-PCDA), N-[methoxy(polyethylene glycol)-750]-10-12-pentacosadiynamide (m-PEG750-PCDA), N-[maleimide(polyethylene glycol)-1500]-10-12-pentacosadiynamide (mal-PEG1500-PCDA), and combinations thereof.

### Claim 15 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the non-polymerizable lipid is about 80-85 mol %.

### Claim 16 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the non-polymerizable lipid is about 30-60 mol %.

### Claim 17 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the non-polymerizable lipid comprises a saturated phospholipid.

### Claim 18 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the non-polymerizable lipid comprises at least one PEGylated non-polymerizable lipid having a PEG polymer chain.

### Claim 19 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the non-polymerizable lipid comprises a lipid selected from the group consisting of L-a-phosphatidylcholine hydrogenated soy (hydrogenated soy PC), distearoylphosphatidylcholine (DSPC), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (m-Peg2000-DSPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)-2000](mal-Peg2000-DSPE), and combinations thereof.

### Claim 20 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the non-polymerizable lipid comprises a lipid selected from the group consisting of L-α-phosphatidylcholine, PE-PEG2000-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000], PE-PEG2000-biotin, and combinations thereof.

### Claim 21 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, comprising a zwitterionically charged lipid at least about 10 mol %.

### Claim 22 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, comprising a zwitterionically charged lipid at about 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, or 80-90 mol %.

### Claim 23 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, comprising a zwitterionically charged lipid at about 10-60 mol %.

### Claim 24 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the zwitterionically charged lipid comprises L-α-distearoylphosphatidylcholine.

### Claim 25 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, further comprising a therapeutic agent loaded into the polymerized liposomal nanoparticle, wherein the therapeutic agent is selected from the group consisting of antineoplastic agents, blood products, biological response modifiers, anti-fungals, hormones, vitamins, peptides, anti-tuberculars, enzymes, anti-allergic agents, anti-coagulators, circulatory drugs, metabolic potentiators, antivirals, antianginal s, antibiotics, antiinflammatories, antiprotozoans, antirheumatics, narcotics, opiates, cardiac glycosides, neuromuscular blockers, sedatives, local anesthetics, general anesthetics, radioactive compounds, radiosensitizers, immune checkpoint inhibitors, monoclonal antibodies, genetic material, antisense nucleic acids, and prodrugs.

### Claim 26 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, further comprising a chemotherapeutic agent loaded into the polymerized liposomal nanoparticle.

### Claim 27 (depends on 26)

The hybrid polymerized liposomal nanoparticle of claim 26, wherein the chemotherapeutic agent is selected from the group consisting of doxorubicin, irinotecan, cis-platin, topotecan, vincristine, mitomycin, paclitaxel, cytarabine, mitoxantrone, etoposide, siRNA, and combinations thereof.

### Claim 28 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, further comprising a targeting agent conjugated to the surface of the polymerized liposomal nanoparticle.

### Claim 29 (depends on 28)

The hybrid polymerized liposomal nanoparticle of claim 28, wherein the targeting agent is selected from the group consisting of an anti-CD 19 antibody, anti-CD34 antibody, anti-CD99 antibody, anti-CD117 antibody, anti-CD 166antibody, anti-CA19-9 antibody, and combinations thereof.

### Claim 30 (depends on 28)

The hybrid polymerized liposomal nanoparticle of claim 28, wherein the targeting agent is a peptide capable of specifically binding to a cell surface molecule.

### Claim 31 (depends on 30)

The hybrid polymerized liposomal nanoparticle of claim 30, wherein the cell surface molecule is a cell membrane protein selected from the group consisting of structural proteins, cell adhesion molecules, membrane receptors, carrier proteins and channel proteins.

### Claim 32 (depends on 30)

The hybrid polymerized liposomal nanoparticle of claim 30, wherein the cell surface molecule is selected from the group consisting of Activated Leukocyte Adhesion Molecule (CD-166), carbohydrate antigen 19-9 (CA19-9), Alphafetoprotein (AFP), Carcinoembryonic antigen (CEA), CA-125, MUC-1, epithelial tumor antigen (ETA), Tyrosinase malignant melanoma antigen, Melanoma-associated antigen (MAGE), abnormal antigenic products of ras, p53, CD-99, CD-19, CD-117, Vascular Endothelial Growth Factor (VEGF), Epithelial Growth Factor Receptor (EGFR), Her2/neu, and prostate-specific membrane antigen (PSMA).

### Claim 33 (depends on 28)

The hybrid polymerized liposomal nanoparticle of claim 28, wherein the targeting agent is selected from a group consisting of diabodies, antibodies, ligands, proteins, peptides, carbohydrates, vitamins, nucleic acids and combinations thereof.

### Claim 34 (depends on 28)

The hybrid polymerized liposomal nanoparticle of claim 28, wherein the targeting agent enhances endocytosis or cell membrane fusion.

### Claim 35 (depends on 28)

The hybrid polymerized liposomal nanoparticle of claim 28 further comprising an agent conjugated to the surface that will elicit an immune response as a treatment for cancer.

### Claim 36 (depends on 35)

The hybrid polymerized liposomal nanoparticle of claim 35, wherein the cell surface molecule is a cell membrane protein selected from the group consisting of E6 and E7 proteins that are detectable in all Human Papilloma Virus (HPV)-positive pre-cancerous and cancer cells or mucin glycoproteins based on tumor associated MUC1 and MUC4 glycoproteins.

### Claim 37 (depends on 1)

A pharmaceutical composition comprising the hybrid polymerized liposomal nanoparticle of claim 1.

### Claim 38 (depends on 37)

The pharmaceutical composition of claim 37, further comprising a pharmaceutically acceptable excipient.

### Claim 39 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the hybrid polymerized liposomal nanoparticle is a non-aggregating hybrid polymerized liposomal nanoparticle.

### Claim 40 (depends on 1)

The hybrid polymerized liposomal nanoparticle of claim 1, wherein the hybrid polymerized liposomal nanoparticle is colloidally stable.

### Claim 41

A non-aggregating hybrid polymerized liposomal nanoparticle, comprising:
a polymerizable lipid, wherein the polymerizable lipid comprises at least one PEGylated polymerizable lipid having a PEG polymer chain, wherein the PEGylated polymerizable lipid having the PEG polymer chain is m-PEG2000-PCDA; and a non-polymerizable lipid.