Intraperitoneally-administered nanocarriers that release their therapeutic load based on the inflammatory environment of cancers

Patent metadata

Field	Value
Publication number	US-9532949-B2
Application number	US-201214233527-A
Country	US
Kind code	B2
Filing date	Jul 18, 2012
Priority date	Jul 19, 2011
Publication date	Jan 3, 2017
Grant date	Jan 3, 2017

Abstract

In one embodiment, the invention provides a new design of nanocarrier compositions that release their therapeutic load specifically at intraperitoneal cancers' site. These nanocarriers are administered intraperitoneally and comprise a plurality of porous nanoparticulates that (a) are loaded with one or more pharmaceutically-active agents alone or in combination with imaging agents thus providing a theranostic value and (b) that are encapsulated by and that support a lipid bilayer which is disrupted upon contact with a reactive oxygen species generated within the environment of the cancer. In other embodiments, the invention provides methods of treatment and pharmaceutical compositions comprising nanocarriers as described herein.

First claim

What claimed is:

1. A method of treating a subject who suffers from a cancer, the method comprising intraperitoneally administering to the subject a pharmaceutically effective amount of a nanocarrier composition, comprising a plurality of porous nanoparticulates that are loaded with one or more pharmaceutically active anticancer agents and are encapsulated by and support a lipid bilayer which is disrupted upon contact with a reactive oxygen species, wherein the lipid bilayer comprises 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC).

2. The method of claim 1 , wherein:
(a) the subject suffers from peritoneal cancer and the composition comprising nanocarriers is administered intraperitoneally to the subject's uterus;
(b) the nanoparticulates are selected from the group consisting of silica nanoparticles, a biodegradable polymer, a sol-gel, a metal-based nanoparticle and an oxide-based nanoparticle;
(c) subsequent to administration, the lipid bilayer of said nanocarriers is disrupted upon contact with a reactive oxygen species (ROS) selected from the group consisting of ozone (O 3 ), hydrogen peroxide, hypochlorite ion, hydroxyl radical, superoxide anion (O 2 − ), and peroxynitrite; and
(d) the nanocarriers' one or more anti-cancer agents are selected from the group consisting of doxorubicin, melphalan, bevacizumab, dactinomycin, cyclophosphamide, amifostine, etoposide, gemcitabine, altretamine, topotecan, a taxane, a platinum based chemotherapeutic agent, and combinations thereof.

3. The method of claim 1 , wherein the subject is co-administered one or more additional anti-cancer agents or anti-cancer treatments along with the nanocarrier composition.

4. The method of claim 3 , wherein the one or more additional anti-cancer agents or anti-cancer treatments and nanocarrier composition are administered concomitantly to the subject.

5. The method according to claim 1 wherein said composition is administered directly into the cancer/tumor.

6. The method of claim 1 , wherein the reactive oxygen species is selected from the group consisting of ozone (O 3 ), hydrogen peroxide, hypochlorite ion, hydroxyl radical, superoxide anion (O 2 − ), and peroxynitrite.

7. The method of claim 1 , wherein the lipid bilayer further comprises one or more lipids selected from the group consisting of phospholipids, cholesterol, a phosphatidyl-choline, a phosphatidyl-serine, a phosphatidyl-diethanolamine, a phosphatidylinosite, a sphingolipid, and an ethoxylated sterol, and mixtures thereof.

8. The method of claim 1 , wherein the lipid bilayer further comprises one or more phospholipids selected from the group consisting of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), egg phosphatidyl-choline (PC), a lipid mixture comprising between about 40 to 60% by weight of one or more unsaturated phosphatidyl-choline, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) [16:0], 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) [18:0], 1,2-dioleoyl-sn-glycero-3-phosphocholine, and combinations thereof.

9. The method of claim 1 , wherein the lipid bilayer comprises a mixture of (1) egg PC, and (2) 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC).

10. The method of claim 9 , wherein the molar concentration of egg PC in the mixture is between about 40% to about 60% of the lipid bilayer.

11. The method of claim 9 , wherein the molar concentration of DMPC is between about 40% to about 60% of the lipid bilayer.

12. The method of claim 1 , wherein the lipid bilayer further comprises phospholipid selected from the group consisting of monoacyl or diacylphosphoglyceride.

13. The method of claim 1 , wherein the lipid bilayer further comprises one or more phospholipids selected from the group consisting of PEG-poly(ethylene glycol)-derivatized distearoylphosphatidylethanolamine (PEG-DSPE), poly(ethylene glycol)-derivatized ceramides (PEG-CER), hydrogenated soy phosphatidylcholine (HSPC), egg phosphatidylcholine (EPC), phosphatidyl ethanolamine (PE), phosphatidyl glycerol (PG), phosphatidyl insitol (PI), monosialogangolioside, spingomyelin (SPM), distearoylphosphatidylcholine (DSPC), and dimyristoylphosphatidylglycerol (DMPG).

14. The method of claim 1 , wherein the one or more anticancer agents are selected from the group consisting of doxorubicin, melphalan, bevacizumab, dactinomycin, cyclophosphamide, amifostine, etoposide, gemcitabine, altretamine, topotecan, a taxane, and a platinum based chemotherapeutic agent.

15. A method of treating a subject suffering from peritoneal cancer, the method comprising intraperitoneally administering to the subject a pharmaceutically effective amount of a nanocarrier composition, said nanocarrier composition comprising a plurality of porous silica nanoparticulates that:
(a) are loaded with one or more pharmaceutically-active agents selected from the group consisting of doxorubicin, melphalan, bevacizumab, dactinomycin, cyclophosphamide, amifostine, etoposide, gemcitabine, altretamine, topotecan, a taxane or a platinum based chemotherapeutic agent, and
(b) that are encapsulated by and that support a lipid bilayer comprising 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) to form a nanocarrier;
wherein subsequent to administration, the lipid bilayer is disrupted in vivo upon contact with a reactive oxygen species (ROS) selected from the group consisting of ozone (O 3 ), hydrogen peroxide, hypochlorite ion, hydroxyl radical, superoxide anion (O 2 − ), and peroxynitrite.

Assignees

• Zeineldin Reema
• Stc Unm

Inventors

• Zeineldin Reema

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K9/0019

  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) · CPC title

• A61K9/127 Primary

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

• Y10S977/773

  Nanoparticle, i.e. structure having three dimensions of 100 nm or less · CPC title

• Y10S977/907

  Liposome · CPC title