Vitamin B6-coupled poly(ester amine) as gene carrier and application in cancer gene therapy

Patent metadata

Field	Value
Publication number	US-9872925-B2
Application number	US-201414182031-A
Country	US
Kind code	B2
Filing date	Feb 17, 2014
Priority date	Jul 26, 2013
Publication date	Jan 23, 2018
Grant date	Jan 23, 2018

Abstract

The present invention relates to a vitamin B6-coupled poly(ester amine) (VBPEA) as a gene carrier and a method for preparing the gene carrier. Moreover, the present invention relates to a gene delivery complex comprising a therapeutic gene coupled to the gene carrier and a pharmaceutical formulation for gene therapy, which comprises the gene delivery complex as an active ingredient. In addition, the present invention relates to gene therapy utilizing the gene carrier, the gene delivery complex or the pharmaceutical formulation. The VBPEA of the invention has a significantly high gene delivery rate compared to existing gene carriers and a complex of the VBPEA with DNA has little or no cytotoxicity and shows a very high in vivo transfection efficiency. In addition, a complex of the VBPEA with siRNA shows high gene silencing efficiency and can induce a high rate of cell death and the inhibition of cell proliferation in cancer cells, suggesting that it can be used for anticancer gene therapy. Thus, the gene carrier VBPEA of the invention can be used as an experimental gene carrier and can also be widely used in gene therapy against various diseases depending on the kind of therapeutic gene.

First claim

The invention claimed is:

1. A gene delivery complex capable of targeting a cancer cell comprising a therapeutic gene coupled to vitamin B6-coupled poly(ester amine) (VBPEA) having the formula of Formula 1:

wherein n is an integer between 1 and 50,
wherein the therapeutic gene inhibits expression of serine hydroxymethyltransferase 1 (SHMT 1), and the gene delivery complex is capable of delivering the therapeutic gene to a cancer cell;
wherein the therapeutic gene and the VBPEA are coupled at a molar ratio of 1:5 to 1:40, and the therapeutic gene coupled to the VBPEA shows a zeta potential of 1 mV to 100 mV;
and wherein the therapeutic gene comprises a polynucleotide selected from the group consisting of small interfering RNAs (siRNAs), small hairpin RNAs (shRNAs), endoribonuclease-prepared siRNAs (esiRNAs), and antisense oligonucleotides.

2. The gene delivery complex of claim 1 , which has an average particle size of 100 to 250 nm.

3. The gene delivery complex of claim 1 , which shows a zeta potential of 25 to 50 mV.

4. A pharmaceutical formulation for gene therapy cancer treatment, comprising the gene delivery complex of claim 1 as an active ingredient.

5. The formulation of claim 4 , wherein the gene delivery complex is formulated as a form for administration by inhalation or injection.

6. A method for treating cancer by administration of the pharmaceutical formulation of claim 4 to a subject in need thereof.

7. The method of claim 6 , wherein the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck carcinoma, melanoma, uterine cancer, ovarian cancer, rectal cancer, colorectal cancer, colon cancer, breast cancer, uterine sarcoma, fallopian tube carcinoma, endometrial cancer, cervical cancer, vaginal carcinoma, vulva cancer, esophageal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, soft tissue sarcoma, urethral cancer, penis cancer, prostate cancer, chronic or acute leukemia, pediatric solid tumors, differentiated lymphoma, bladder cancer, renal cancer, renal cell carcinoma, renal pelvic carcinoma, primary central nervous system lymphoma, spinal cord tumor, brain stem glioma, and pituitary adenoma.

Assignees

• Snu R&Db Foundation

Inventors

• Chung Jong Hoon
• Pandey Shambhavi
• Garg Pankaj
• Choung Pill Hoon

Classifications

• A61K47/551 Primary

  one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid · CPC title

• A61K47/6921

  the form being a particulate, a powder, an adsorbate, a bead or a sphere · CPC title

• C12Y201/02001

  Glycine hydroxymethyltransferase (2.1.2.1) · CPC title

• C12N2310/351

  Conjugate · CPC title

• C12N15/111

  General methods applicable to biologically active non-coding nucleic acids · CPC title