# US 10,765,636 B2 · Mesoporous silica nanoparticles with a lipid bilayer coating for cargo delivery

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- Number: US 10,765,636 B2
- Document ID: US10765636B2
- Status: Granted
- Kind: B2
- Application number: 16/164,030
- Filed: 2018-10-18
- Published: 2019-05-30
- Granted: 2020-09-08
- Earliest claimed: 2016-01-08
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: Andre E. Nel; Huan Meng; Xiangsheng Liu
- Web page: https://patentgrep.com/patent/US10765636B2

## CPC

- A61K 9/5115: {Inorganic compounds}
- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K 9/5123: {Organic compounds, e.g. fats, sugars}
- A61K 9/5192: {Processes}
- 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 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/62: the modifying agent being a protein, peptide or polyamino acid
- 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}
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/1278: Post-loading, e.g. by ion or pH gradient
- 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

A nanocarrier including a silica body having a surface and defining a plurality of pores that are suitable to receive molecules therein is described. The nanocarrier also includes a lipid bilayer coating the surface, and a cargo-trapping agent within the phospholipid bilayer. The phospholipid bilayer stably seals the plurality of pores. The cargo-trapping reagent can be selected to interact with a desired cargo, such as a drug.

## Claims

### Claim 1

A method of treating cancer, comprising administering to a subject in need thereof an effective amount of a nanoparticle drug carrier, wherein the nanoparticle drug carrier comprises:
a) a silica nanoparticle having a surface and defining a plurality of pores;
b) a lipid bilayer coating the surface;
c) a protonating agent disposed within the plurality of pores where said protonating agent is an ammonium salt, a trimethylammonium salt, a triethylammonium salt, or an ionophore combined with a metal salt; and
d) a drug disposed within the plurality of pores, wherein said drug consists of irinotecan, and wherein the nanoparticle drug carrier has a drug loading capacity of at least about 40% w/w.

### Claim 2 (depends on 1)

The method of claim 1, wherein the nanoparticle drug carrier has less than about 15% leakage of the drug over 20 hours in a biological buffer with pH of 7.4 at 37° C.

### Claim 3 (depends on 1)

The method of claim 1, wherein a plurality of nanoparticle drug carriers has a median diameter of less than one micron.

### Claim 4 (depends on 1)

The method of claim 1, wherein the nanoparticle drug carrier comprises a remote loading agent disposed within the plurality of pores.

### Claim 5 (depends on 1)

The method of claim 1, wherein the protonating agent converts the drug into a hydrophilic derivative that is incapable of back diffusion across the lipid bilayer.

### Claim 6 (depends on 1)

The method of claim 1, wherein the protonating agent comprises at least one anionic group.

### Claim 7 (depends on 1)

The method of claim 1, wherein the protonating agent before reaction with the drug comprises an ammonium salt, a trimethylammonium salt, or a triethylammonium salt.

### Claim 8 (depends on 7)

The method of claim 7, wherein the drug is protonated by the protonating agent and trapped in the plurality of pores as a gel-like precipitate.

### Claim 9 (depends on 7)

The method of claim 7, wherein the ammonium salt is selected from the group consisting of ammonium sulfate, ammonium sucrose octasulfate, ammonium α-cyclodextrin sulfate, ammonium β-cyclodextrin sulfate, ammonium γ-cyclodextrin sulfate, ammonium phosphate, ammonium α-cyclodextrin phosphate, ammonium β-cyclodextrin phosphate, ammonium γ-cyclodextrin phosphate, ammonium citrate, and ammonium acetate.

### Claim 10 (depends on 7)

The method of claim 7, wherein the trimethylammonium salt is selected from the group consisting of trimethylammonium sulfate, trimethylammonium sucrose octasulfate, trimethylammonium α-cyclodextrin sulfate, trimethylammonium β-cyclodextrin sulfate, trimethylammonium γ-cyclodextrin sulfate, trimethylammonium phosphate, trimethylammonium α-cyclodextrin phosphate, trimethylammonium β-cyclodextrin phosphate, trimethylammonium γ-cyclodextrin phosphate, trimethylammonium citrate, and trimethylammonium acetate.

### Claim 11 (depends on 7)

The method of claim 7, wherein the triethylammonium salt is selected from the group consisting of triethylammonium sulfate, triethylammonium sucrose octasulfate, triethylammonium α-Cyclodextrin sulfate, triethylammonium β-Cyclodextrin sulfate, triethylammonium γ-Cyclodextrin sulfate, triethylammonium phosphate, triethylammonium α-Cyclodextrin phosphate, triethylammonium β-Cyclodextrin phosphate, triethylammonium γ-Cyclodextrin phosphate, triethylammonium citrate, and triethylammonium acetate.

### Claim 12 (depends on 7)

The method of claim 7, wherein the protonating agent before reaction with the drug comprises triethylammonium sucrose octasulfate (TEA8SOS).

### Claim 13 (depends on 1)

The method of claim 1, wherein the nanoparticle drug carrier is a primary therapy in a chemotherapeutic regimen.

### Claim 14 (depends on 1)

The method of claim 1, wherein the nanoparticle drug carrier is a component in a multi-drug chemotherapeutic regimen.

### Claim 15 (depends on 14)

The method of claim 14, wherein the multi-drug chemotherapeutic regimen comprises at least two drugs selected from the group consisting of irinotecan (IRIN), oxaliplatin (OX), 5-fluorouracil (5-FU), and leucovorin (LV).

### Claim 16 (depends on 1)

The method of claim 1, wherein the cancer is pancreatic cancer, colorectal cancer, breast cancer, lung cancer, liver cancer, glioma, or melanoma.

### Claim 17 (depends on 1)

The method of claim 1, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).