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Last Updated: March 29, 2024

Claims for Patent: 9,616,137


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Summary for Patent: 9,616,137
Title:Nanoparticle-based tumor-targeted drug delivery
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.
Inventor(s): Reisfeld; Ralph A. (LaJolla, CA), Xiang; Rong (San Diego, CA), Luo; Yunping (San Diego, CA), Liao; Debbie (San Diego, CA), Liu; Ze (Beijing, CN), Chen; Tingmei (Chongqing, CN), Chen; Si (Tianjin, CN), Lu; Dan (San Diego, CA)
Assignee: The Scripps Research Institute (La Jolla, CA)
Application Number:13/224,399
Patent Claims: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): ##STR00004## 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): ##STR00005## 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): ##STR00006## 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.

Details for Patent 9,616,137

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Genentech, Inc. RITUXAN rituximab Injection 103705 11/26/1997 ⤷  Try a Trial 2030-09-02
Idec Pharmaceuticals Corp. RITUXAN rituximab Injection 103737 02/19/2002 ⤷  Try a Trial 2030-09-02
Genentech, Inc. HERCEPTIN trastuzumab For Injection 103792 09/25/1998 ⤷  Try a Trial 2030-09-02
Genentech, Inc. HERCEPTIN trastuzumab For Injection 103792 02/10/2017 ⤷  Try a Trial 2030-09-02
Genzyme Corporation CAMPATH alemtuzumab Injection 103948 05/07/2001 ⤷  Try a Trial 2030-09-02
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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