Target-aiming drug delivery system for diagnosis and treatment of cancer containing liposome labeled with peptides which specifically targets interleukin-4 receptors, and manufacturing method thereof

Patent metadata

Field	Value
Publication number	US-9833464-B2
Application number	US-201013519821-A
Country	US
Kind code	B2
Filing date	Dec 29, 2010
Priority date	Dec 29, 2009
Publication date	Dec 5, 2017
Grant date	Dec 5, 2017

Abstract

The present invention relates to a target-aiming drug delivery system for diagnosis and treatment of cancer containing liposome labeled with peptides which specifically targets interleukin-4 receptors, and a manufacturing method thereof. The liposome which contains anticancer drugs labeled with IL4RPep peptides prepared in accordance with the present invention can deliver drugs to cancer cells in which IL-4 receptors are overexpressed by IL4RPep peptides which specifically bind to IL-4 receptors, and the drug delivery can recognize cancer cells specifically by a label. Thus, IL4RPep peptides can increase the effect of drugs only on cancer tissues and at the same time significantly reduce the side effects on normal tissues, which makes possible in vivo(molecular) imaging and early diagnosis of tumors. Therefore, the liposome which contains anticancer drugs labeled with IL4Pep peptides of the present invention can be applied, as the target-aiming drug delivery system, effectively to the diagnosis and treatment of cancers.

First claim

The invention claimed is:

1. A target-aiming drug delivery composition consisting of as an active ingredient an anticancer agent-loaded liposome that is labeled with a peptide targeting interleukin-4 receptor consisting of the amino acid sequence of SEQ ID NO: 1 conjugated to a maleimide-modified DSPE-PEG 2000 (DSPE-PEG 2000 -maleimide), wherein the peptide is present in an amount of 0.1 to 3 mol %, based on total moles of lipids in the liposome,
wherein the liposome is a multilamellar liposome consisting of:
a first lipid selected from the group consisting of phosphatidyl choline (PC), phosphatidyl glycerol (PG), phosphatidyl serine (PS) and phosphatidyl ethanolamine (PE);
a second lipid, wherein the second lipid is distearoylphosphatidylethanolamine-polyethylenoglycol (DSPE-PEG); and
a cholesterol, and

wherein the first lipid amounts to 60˜70 mol % of total lipids in the liposome, the second lipid amounts to 1˜10 mol % of total lipids in the liposome, and the cholesterol amounts to 1˜40 mol % of total lipids in the liposome.

2. The target-aiming drug delivery composition of claim 1 , wherein the anticancer agent is doxorubicin.

3. A method for manufacturing a target-aiming drug delivery composition consisting of:
1) dissolving a first lipid, a second lipid and a cholesterol in ethanol to assure a lipid mixture, hydrating the mixture in water to form a lipid suspension, and forcing the lipid suspension through a filter to yield homogeneous liposomes,
2) adding an anticancer agent to the liposomes formed in step 1) to afford anticancer agent-loaded liposomes,
3) labeling the anticancer agent-loaded liposomes with at least one marker, and
4) conjugating a peptide targeting interleukin-4 receptor (IL4RPep) consisting of the amino acid sequence of SEQ ID NO: 1 to maleimide-modified DSPE-PEG 2000 (DSPE-PEG 2000 -maleimide) and
5) incubating at 50-70° C. for 1-3 hours the conjugate with the anticancer agent-loaded liposome labeled with the marker to insert the IL4RPep into the surface of the liposomes; and
wherein the first lipid, the second lipid and the cholesterol are mixed at a molar ratio of 60˜70:1˜10:1˜40 in step 1).

4. The method of claim 3 , wherein the anticancer agent loaded within the liposomes in step 2) is present at a concentration of 1 to 5 mg per mL of the liposome.

5. The method of claim 3 , wherein the at least one marker in step 3) is selected from the group consisting of a radioisotope, a chromophore, a luminescent, a fluorescent, a superparamagnetic particle, an ultrasmall paramagnetic particle, and a chromogenic enzyme.

6. The method of claim 3 , wherein the IL4RPep is conjugated at a molar ratio of 1:1 to 1:3 with the maleimidemodified DSPE-PEG 2000 (DSPE-PEG 2000 -maleimide) in step 3.

7. The target-aiming drug delivery composition of claim 1 ,
further comprising at least one marker selected from the group consisting of a radioisotope, a chromophore, a luminescent, a fluorescent, a superparamagnetic particle, an ultrasmall paramagnetic particle, and a chromogenic enzyme.

Assignees

• Kim In San
• Lee Byung Heon
• Lu Maggie J M
• Liang Hsiang-Fa
• Ko Yi-Ju
• Lo Ya-Chin
• Chang Li-Wen
• Wei Ming-Cheng
• Kyungpook National Univ Industry-Academic Cooperation Foundation
• Ind Tech Res Inst

Inventors

• Kim In San
• Lee Byung Heon
• Lu Maggie J M
• Liang Hsiang-Fa
• Ko Yi-Ju
• Lo Ya-Chin
• Chang Li-Wen
• Wei Ming-Cheng

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K9/1271

  Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911}) · CPC title

• A61K47/6911

  the form being a liposome · CPC title

• A61K31/704 Primary

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

• A61P35/00

  Antineoplastic agents · CPC title