Drug-containing protein-bonded liposome

• US 5,264,221 A
• Filed: 05/22/1992
• Issued: 11/23/1993
• Est. Priority Date: 05/23/1991
• Status: Expired due to Term

• Current Assignee: Mitsubishi Kasei Corp. (Mitsubishi Chemical Group Corp.)
• Original Assignee: Mitsubishi Kasei Corp. (Mitsubishi Chemical Group Corp.)
• Inventors: Nagaike, Kazuhiro, Hosokawa, Saiko, Tagawa, Toshiaki
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): KISHORE, GOLLAMUDI S
• Application Number:
  US07/886,846
• Time in Patent Office: 550 Days
• Field of Search: 424/450, 424/417, 436/829, 428/402.2, 264/4.1, 530/402, 530/403, 530/810, 530/812, 935/54
• US Class Current: 424/450
• CPC Class Codes: A61K 47/6913 the liposome being modified on its surface by an antibody
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: Y10S 436/829 Liposomes, e.g. encapsulation
• CPC Class Codes: Y10S 530/812 Peptides or proteins is immobilized on, or in, an organic carrier
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]

Abstract

A drug-containing protein-bonded liposome comprising a liposome containing a drug and having maleimide residues on its surface, and a protein and residues of a compound having a polyalkylene glycol moiety, bonded via respective thiol groups to the maleimide residues.

Claims

1. A drug containing, protein-bonded liposome, which comprises a liposome containing a drug, said liposome having maleimide groups on the surface thereof, wherein a portion of the maleimide groups are bonded to a thiol group-containing protein and a remaining portion of the maleimide groups are bonded to a thiol group-containing polyethylene glycol moiety;

said liposome comprising phosphatidyl choline, cholesterol and maleimide-modified phosphatidyl ethanolamine.

2. The drug-containing, protein-bonded liposome of claim 1, wherein the protein is selected from the group consisting of an antibody, FGF and EGF.

3. The drug-containing, protein-bonded liposome of claim 2, wherein said protein is an antibody selected from the group consisting of animal polyclonal antibodies, mouse monoclonal antibodies, human-mouse chimeric antibodies and human monoclonal antibodies.

4. The drug-containing, protein-bonded liposome of claim 3, wherein said protein is a human monoclonal antibody.

5. The drug-containing, protein-bonded liposome of claim 1, wherein the liposome comprises dipalmitoylphosphatidyl choline, cholesterol and maleimide-modified dipalmitoylphosphatidyl ethanolamine.

6. The drug-containing, protein-bonded liposome of claim 5, wherein the maleimide-modified dipalmitoylphosphatidyl ethanolamine is obtained by reacting N-(ε

-maleimidocaproyloxy) succinimide and dipalmitoylphosphatidyl ethanolamine.

7. The drug-containing, protein-bonded liposome of claim 1, wherein the thiol group-containing protein having maleimide groups bonded thereto is obtained by reacting maleimide residues on the liposome surface and a thiol group-containing protein.

8. The drug-containing, protein-bonded liposome of claim 1, wherein said thiol-group containing polyethylene glycol moiety having maleimide groups bonded thereto is obtained by reacting maleimide residues on the liposome surface and a thiol-group containing polyethylene glycol.

9. The drug-containing, protein-bonded liposome of claim 1, wherein said drug comprises an antitumor drug, a β

-lactam antibiotic, a toxin, an aminoglucoside, antisense RNA or actinoplane.

10. The drug-containing, protein-bonded liposome of claim 9, wherein the antitumor drug is selected from the group consisting of adriamycin, daunomycin, mitomycin, cisplatin, vincristine, epirubicin, methotrexate, 5-FU and aclacinomycin.

11. The drug containing, protein-bonded liposome of claim 9, wherein said aminoglucoside is gentamicin.

12. The drug containing, protein-bonded liposome of claim 9, wherein said β

-lactam antibiotic is sulpenisillin.

13. The drug containing, protein-bonded liposome of claim 9, wherein said toxin is ricin A or diphtheria toxin.

14. The drug containing, protein-bonded liposome of claim 9, wherein said antisense RNA is antisense RNA against HIV or ras gene.

15. An antitumor drug, comprising a liposome containing a drug, said liposome having maleimide groups on the surface thereof, wherein a portion of the maleimide groups are bonded to a thiol group-containing protein and a remaining portion of the maleimide groups are bonded to a thiol group-containing polyethylene glucol moiety;

said liposome comprising phosphatidyl choline, cholesterol and maleimide-modified phosphatidyl ehtanolamine.