Lipid bilayer coated mesoporous silica nanoparticles with a high loading capacity for one or more anticancer agents

Patent metadata

Field	Value
Publication number	US-11918686-B2
Application number	US-202016948498-A
Country	US
Kind code	B2
Filing date	Sep 21, 2020
Priority date	Mar 5, 2013
Publication date	Mar 5, 2024
Grant date	Mar 5, 2024

Abstract

A submicron structure comprising a silica body defining a plurality of pores that are suitable to receive molecules therein, and having a surface, and a phospholipid bilayer coating the surface, wherein said submicron structure has a maximum dimension of less than one micron, and wherein the phospholipid bilayer stably seals the plurality of pores; and wherein the submicron structure is a member of a monodisperse population of submicron structures.

First claim

We claim:

1. A drug delivery carrier comprising:
a silica body having a plurality of pores suitable to receive a therapeutic agent therein, and having a surface;
an intact lipid bilayer coating the surface and encapsulating the silica body and stably sealing the plurality of pores, wherein the encapsulating is performed without lipid phase exchange and without contacting a preformed liposome with the silica body;
a first therapeutic agent within the pores of the silica body, wherein the first therapeutic agent comprises gemcitabine; and
a second therapeutic agent disposed in the lipid bilayer, wherein the second therapeutic agent comprises paclitaxel.

2. The drug delivery carrier of claim 1 , wherein the drug delivery carrier provides a predetermined dose and ratio of first therapeutic agent to second therapeutic agent.

3. The drug delivery carrier of claim 1 , wherein the first therapeutic agent and the second therapeutic agent act synergistically.

4. The drug delivery carrier of claim 1 , wherein the drug delivery carrier includes about 20% w/w or greater of gemcitabine molecules within the pores of the silica body.

5. The drug delivery carrier of claim 1 , wherein the drug delivery carrier includes about 30% w/w or greater of gemcitabine molecules within the pores of the silica body.

6. The drug delivery carrier of claim 1 , wherein the drug delivery carrier includes about 40% w/w or greater of gemcitabine molecules within the pores of the silica body.

7. The drug delivery carrier of claim 1 , wherein the lipid bilayer is formed from a lipid film containing the second therapeutic agent.

8. The drug delivery carrier of claim 1 , wherein the drug delivery carrier is configured to retain the first therapeutic agent within the silica body without substantial loss for at least 1 week prior to administration to a subject.

9. The drug delivery carrier of claim 1 , wherein the drug delivery carrier is configured to retain the first therapeutic agent within the silica body with 10% or less loss for at least 1 week prior to administration to a subject.

10. The drug delivery carrier of claim 1 , wherein the drug delivery carrier is a member of a monodisperse population of drug delivery carriers.

11. The drug delivery carrier of claim 1 , wherein the drug delivery carrier is a submicron structure with a maximum dimension of between 20 nm and 300 nm.

12. The drug delivery carrier of claim 1 , wherein the drug delivery carrier has a submicron structure with a maximum dimension of between 50 nm and 200 nm.

13. The drug delivery carrier of claim 1 , wherein the lipid bilayer comprises a phospholipid bilayer.

14. The drug delivery carrier of claim 13 , wherein the phospholipid bilayer comprises 2-dioleoyl-3-trimethylammonium-propane (DOTAP), 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS),1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), or any combination thereof.

15. A composition comprising a plurality of drug delivery carriers, each drug delivery carrier comprising:
a silica body having a plurality of pores suitable to receive a therapeutic agent therein, and having a surface;
an intact lipid bilayer coating the surface and encapsulating the silica body and stably sealing the plurality of pores, wherein the encapsulating is performed without lipid phase exchange and without contacting a preformed liposome with the silica body;
a first therapeutic agent within the pores of the silica body, wherein the first therapeutic agent comprises gemcitabine; and
a second therapeutic agent disposed in the lipid bilayer, wherein the second therapeutic agent comprises paclitaxel.

16. The composition of claim 15 , wherein the composition comprises a stable colloidal suspension.

17. The composition of claim 15 , wherein the plurality of drug delivery carriers provides a predetermined dose and ratio of the first therapeutic agent to the second therapeutic agent.

18. The composition of claim 15 , wherein the plurality of drug delivery carriers form a monodisperse population having a deviation in average diameter of 10% or less.

19. The composition of claim 15 , wherein the composition is formulated for systemic administration to a subject for treating cancer.

20. The composition of claim 15 , wherein the composition is formulated for intravenous, intra-arterial, intraperitoneal, intramuscular, or subcutaneous administration.

Assignees

• Univ California

Inventors

• Nel Andre E
• Zink Jeffrey I
• Meng Huan

Classifications

• A61K9/127 Primary

  Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant · CPC title

• A61K9/5115

  Inorganic compounds · CPC title

• A61K31/337

  having four-membered rings, e.g. taxol · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• A61K31/7068

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title