Nanoparticle-based tumor-targeted drug delivery

Patent metadata

Field	Value
Publication number	US-9616137-B2
Application number	US-201113224399-A
Country	US
Kind code	B2
Filing date	Sep 2, 2011
Priority date	Sep 2, 2010
Publication date	Apr 11, 2017
Grant date	Apr 11, 2017

Abstract

The present invention provides an aqueous tumor-targeting liposome nanoparticle composition comprising an aqueous dispersion of liposome nanoparticles. The nanoparticles preferably encapsulate an anti-cancer chemotherapeutic agent, which can be added to a pre-formed liposome composition or can be incorporated in the liposomes during the formation of the liposomes. The liposome nanoparticles comprise a legumain-targeting lipid admixed with one or more other micelle or vesicle-forming lipid materials in the form of nanoparticulate liposomes dispersed in an aqueous carrier. A preferred tumor-targeting liposome nanoparticle composition comprises (a) a legumain-targeting lipid component, (b) a zwitterionic lipid component; (c) an amino-substituted lipid component; (d) a neutral lipid component; and (e) polyethylene glycol-conjugated lipid component. The legumain-targeting lipid component comprising a hydrophobic lipid portion covalently attached to a legumain-binding moiety.

First claim

We claim:

1. A nanoparticle composition comprising lipid nanoparticles in which the nanoparticles include a lipid comprising a lipid component covalently bound to a legumain-binding moiety; wherein the lipid comprises a compound of Formula (II):

wherein the lipid is admixed with one or more micelle or vesicle-forming lipid materials in the nanoparticles; and the legumain-binding moiety comprises an aza-Asn legumain inhibitor.

2. The nanoparticle composition of claim 1 wherein the nanoparticles comprise (a) the lipid, (b) a zwitterionic lipid component, (c) an amino-substituted lipid component, (d) a neutral lipid component, and (e) a polyethylene glycol-conjugated lipid component; and wherein the components (a), (b), (c), (d) and (e) are present in the nanoparticles in a molar ratio of (a):(b):(c):(d):(e) of about 1.1:6.7:6.7:2.2:1.

3. The nanoparticle composition of claim 2 wherein at least one of components (a), (b), (c), (d), and (e) is selected from the group consisting of:
(A) a lipid (a) comprising an aza-Asn legumain inhibitor bound to the amine group of a 1,2-diacylglycero-phosphoalkanolamine,
(B) a zwitterionic lipid component (b) comprising a 1,2-diacylglycero-phosphocholine compound,
(C) a amino-substituted lipid component (c) comprising a 1,2-diacylglycero-phosphoalkanolamine compound,
(D) a neutral lipid component (d) comprising cholesterol, and
(E) a polyethylene glycol-conjugated lipid component (e) comprising a polyethylene glycol-conjugated 1,2-diacylglycero-phosphoalkanolamine compound.

4. The nanoparticle composition of claim 2 wherein at least one of components (a), (b), (c), (d) and (e) is selected from the group consisting of:
(A) a lipid (a) comprising an aza-Asn Michael acceptor legumain inhibitor bound to the amine group of a 1,2-diacylglycero-phosphoalkanolamine;
(B) a zwitterionic lipid component (b) comprising 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine;
(C) a amino-substituted lipid component (c) comprising 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine;
(D) a neutral lipid component (d) comprising cholesterol; and
(E) a polyethylene glycol-conjugated lipid component (e) comprising 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol] wherein the polyethylene glycol portion of the compound has an average molecular weight of about 2000 atomic mass units (amu).

5. A nanoparticle composition comprising lipid nanoparticles in which the nanoparticles include a lipid comprising a lipid component covalently bound to a legumain-binding moiety; wherein the lipid comprises a compound of Formula (II):

wherein the lipid is admixed with one or more micelle or vesicle-forming lipid materials in the nanoparticles; and the legumain-binding moiety comprises an aza-Asn legumain inhibitor; wherein a cancer therapeutic agent is encapsulated within the nanoparticles.

6. The nanoparticle composition of claim 5 wherein the nanoparticles comprise (a) the lipid, (b) a zwitterionic lipid component, (c) an amino-substituted lipid component, (d) a neutral lipid component, and (e) a polyethylene glycol-conjugated lipid component; and wherein the components (a), (b), (c), (d) and (e) are present in the nanoparticles in a molar ratio of (a):(b):(c):(d):(e) of about 1.1:6.7:6.7:2.2:1.

7. The nanoparticle composition of claim 6 wherein at least one of components (a), (b), (c), (d), and (e) is selected from the group consisting of:
(A) a lipid (a) comprising an aza-Asn legumain inhibitor bound to the amine group of a 1,2-diacylglycero-phosphoalkanolamine,
(B) a zwitterionic lipid component (b) comprising a 1,2-diacylglycero-phosphocholine compound,
(C) an amino-substituted lipid component (c) comprising a 1,2-diacylglycero-phosphoalkanolamine compound,
(D) a neutral lipid component (d) comprising cholesterol, and
(E) a polyethylene glycol-conjugated lipid component (e) comprising a polyethylene glycol-conjugated 1,2-diacylglycero-phosphoalkanolamine compound.

8. The nanoparticle composition of claim 6 wherein at least one of components (a), (b), (c), (d) and (e) is selected from the group consisting of:
(A) a lipid (a) comprising an aza-Asn Michael acceptor legumain inhibitor bound to the amine group of a 1,2-diacylglycero-phosphoalkanolamine;
(B) a zwitterionic lipid component (b) comprising 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine;
(C) an amino-substituted lipid component (c) comprising 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine;
(D) a neutral lipid component (d) comprising cholesterol; and
(E) a polyethylene glycol-conjugated lipid component (e) comprising 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol] wherein the polyethylene glycol portion of the compound has an average molecular weight of about 2000 atomic mass units (amu).

9. The nanoparticle composition of claim 5 wherein the cancer therapeutic agent comprises at least one compound selected from the group consisting of cisplatin; carboplatin; oxaliplatin; mechlorethamine; cyclophosphamide; chlorambucil; ifosfamide; 5-fluorouricil; floxuridine; cytosine arabinoside; mercaptopurine; thioguanine; azathioprine; fludarabine; pentostatin; cladribine; etoposide; etoposide phosphate; teniposide; amsacrine; paclitaxel; methotrexate; trimethoprim; pyrimethamine; pemetrexed; vitaxin; anecorvate; angiostatin; endostatin; squalamine; an antiangiogenic tryptophanyl-t-RNA sythetase peptide fragment; bevacizumab; tivozanib; vandetanib; vatalanib; alemtuzumab; cetuximab; gemtuzumab; ibritumomab; pantitumumab; rituximab; tositumomab; trastuzumab; actinomycin; bleomycin; plicamycin; mitomycin; doxorubicin; epirubicin; daunorubicin; valrubicin; idarubicin); ursolic acid; a 2-cyano-3,12-dioxooleana-1,9-dien-28-oic ester, a 2-cyano-3,12-dioxooleana-1,9-dien-28-oic amide; 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (also known as CDDO-Im); as well as physiologically acceptable salts and prodrugs thereof.

10. The nanoparticle composition of claim 5 wherein the cancer therapeutic agent comprises a Stat3 inhibitor, an anti-tumor agent, or a compound that is an agonist or antagonist of a receptor or a receptor ligand known to effect tumor growth.

11. A lipid comprising a lipid component covalently bound to a legumain-binding moiety, wherein the lipid comprises a compound of Formula (II):

wherein the legumain-binding moiety comprises an aza-Asn legumain inhibitor, the lipid component comprises a 1,2-diacylglycero-phosphoalkanolamine, and the legumain-binding moiety is bound to the amine group of the 1,2-diacylglycero-phosphoalkanolamine.

12. A method of targeting and treating a legumain-expressing cancer disease comprising administering to a subject with a legumain-expressing cancer disease an effective amount of a legumain-targeting nanoparticle composition of claim 5 .

13. A method of targeting and treating a legumain-expressing tumor comprising administering to a subject with a legumain-expressing tumor an effective amount of a legumain-targeting nanoparticle composition of claim 5 .

14. A method of delivering a cancer therapeutic agent to a legumain-expressing tumor comprising contacting the tumor wwith the legumain-targeting nanoparticle composition of claim 5 .

Assignees

• Reisfeld Ralph A
• Xiang Rong
• Luo Yunping
• Liao Debbie
• Liu Ze
• Chen Tingmei
• Chen Si
• Lu Dan
• Scripps Research Inst

Inventors

• Reisfeld Ralph A
• Xiang Rong
• Luo Yunping
• Liao Debbie
• Liu Ze
• Chen Tingmei
• Chen Si
• Lu Dan

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4164

  1,3-Diazoles · CPC title

• A61K9/1272

  comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543}) · CPC title

• A61K31/704

  attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)} · CPC title

• B82Y5/00

  Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery · CPC title