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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