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A kind of small interfering nucleic acid and pharmaceutical composition and application thereof

A composition and drug technology, applied in the field of biomedicine, can solve the problems of high frequency of administration, large amount of administration, high frequency of administration, etc., and achieve the effects of prolonging the interval of administration, reducing the amount of administration, and high biological activity

Active Publication Date: 2020-01-17
SUZHOU RIBO LIFE SCIENCE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Moreover, it has been found that RRM2 is highly expressed in tumors; although there are documents (CN200680018408.5) reporting that siRNA pharmaceutical compositions containing RRM2 can be used to treat liver cancer, the siRNA activity in vivo is not high; Due to its own defects, it can only be administered locally within the tumor. The dosage of the cocktail composed of 2 siRNAs is still 2.5mg / kg, and the administration frequency is high, which is once a day for 3 consecutive administrations
This intrahepatic arterial administration method has high administration frequency and large dosage, which is difficult to meet clinical needs.

Method used

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  • A kind of small interfering nucleic acid and pharmaceutical composition and application thereof
  • A kind of small interfering nucleic acid and pharmaceutical composition and application thereof
  • A kind of small interfering nucleic acid and pharmaceutical composition and application thereof

Examples

Experimental program
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Embodiment approach

[0047] Among them, as a particularly preferred embodiment of the present invention, in the pharmaceutical composition, the molar ratio between the organic amine, cholesterol and the pegylated phospholipid is (50-70): (20 -40): (3-20).

[0048] The liposome particle formed by the siRNA of the present invention and the above-mentioned carrier has an average diameter of about 30 nm to about 200 nm, usually about 40 nm to about 135 nm, more usually, the average diameter of the liposome particle is about 50 nm to about 120 nm, From about 50 nm to about 100 nm, from about 60 nm to about 90 nm, or from about 70 nm to about 90 nm, for example, the liposome particles have an average diameter of about 30, 40, 50, 60, 70, 75, 80, 85, 90, 100, 110, 120, 130, 140, 150 or 160nm.

[0049] In a pharmaceutical composition in the form of a liposome formulation, the weight ratio (weight / weight ratio) of siRNA of the present invention to total lipids (such as organic amines, helper lipids and / or...

preparation example 1

[0060] The sequence of the siRNA is shown in Table 1, and a single strand of the siRNA has a sequence represented by SEQ ID NO:2, which is identical to the corresponding RNA interference target nucleic acid (as shown in SEQ ID NO:4) in the mRNA sequence of RRM2, The other single strand has a sequence represented by SEQ ID NO: 3, and is complementary to the corresponding RNA interference target nucleic acid in the mRNA sequence of RRM2.

[0061]The oligonucleotide single strand of siRNA is chemically synthesized according to methods known in the art. During synthesis, two deoxythymine nucleotides dTdT are added to the 3' end of the single-stranded oligonucleotide. Complementary oligonucleotide single strands anneal to form double strands, and the two ends of the double strands respectively have 3' overhangs of dTdT. The sequences of the synthesized oligonucleotides are listed in Table 1.

[0062] Table 1

[0063]

Embodiment 1

[0065] This example is used to detect the inhibitory efficiency of siRNA on the expression level of RRM2 mRNA in vitro.

[0066] The human liver cancer cell line HepG2 was inoculated in a 24-well plate with DMEM complete medium containing 10% fetal bovine serum, 2mM L-glutamine, 100U / mL penicillin, and 100g / mL streptomycin, at a cell density of 4×10 5 / well, 0.5mL per well, culture overnight at 37°C.

[0067] The specific operation steps of transfection are as follows: Dilute 100 ng of siRNA in Preparation Example 1 into 50 μL of DEME serum-free medium, and at the same time, add 1 μL of Lipofectamine TM 2000 (Invitrogen Company) was diluted in 50 μL DEME serum-free medium, and the above two solutions were incubated at room temperature for 5 minutes and then mixed. After the mixed solution was left to stand at room temperature for 20 minutes, 100 μL of the above mixed solution was added to a 24-well plate seeded with PANC-1 cells. The final concentration of siRNA was approxi...

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Abstract

Provided is a siRNA that inhibits RRM2 gene expression. A sense-strand base sequence of the siRNA is as shown in SEQ ID NO:2, an antisense-strand base sequence of the siRNA is as shown in SEQ ID NO:3, and a phosphate-sugar backbone of the siRNA may further have a modified group; also provided is a pharmaceutical composition comprising the siRNA, which can inhibit tumor cell proliferation and facilitate tumor cell apoptosis, thereby inhibiting growth of tumor tissues.

Description

technical field [0001] The present invention relates to the technical field of biomedicine, in particular, to a siRNA (small interfering nucleic acid), an RNA interference target nucleic acid of the siRNA, a pharmaceutical composition and uses thereof. Background technique [0002] The main treatment methods for tumors are still surgery, radiotherapy and chemotherapy. Although the current treatment methods improve the survival rate of patients compared with the past, there are still blindness and poor pertinence. With the continuous emergence of new chemotherapy drugs, drug resistance has become an important problem that cannot be ignored. Taking pancreatic cancer as an example, at present, surgical resection is the first choice for the treatment of pancreatic cancer, but only 15-20% of patients can be treated surgically when diagnosed, and the 5-year survival rate of pancreatic cancer patients is less than 5%. Pancreatic cancer is not very sensitive to radiotherapy and ch...

Claims

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Application Information

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IPC IPC(8): C12N15/11C12N15/113A61K48/00A61K31/713A61P35/00
CPCA61K31/713A61K48/00C12N15/11C12N15/113
Inventor 张鸿雁高山黄渊余
Owner SUZHOU RIBO LIFE SCIENCE CO LTD
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