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Methotrexate-containing medicine, preparation method, medicinal composition and application thereof

A methotrexate and drug technology, applied in the field of medicine, can solve problems such as the contradiction between toxicity and transfection activity, the difficulty of non-toxic degradation of connection, and the limited clinical application of small molecule drug methotrexate delivery reliability

Active Publication Date: 2020-04-07
BAI YAO ZHI DA BEIJING NANOBIO TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Cationic liposomes have high transfection activity in vivo and in vitro, however, because the positive charge on the surface affects their normal distribution in vivo, at the same time, cationic lipids can cause immunogenicity and inflammatory responses in animal experiments
The development of polycationic gene carriers has been relatively mature. However, it is difficult to ensure that the targeting group is on the surface of the structure in the structural design, and there is a self-design contradiction between toxicity and transfection activity. At the same time, its connection is difficult to achieve non-toxic degradation in vivo.
[0006] Therefore, how to improve the delivery reliability of the existing small molecule drug methotrexate is one of the difficulties in solving the current limited clinical application of methotrexate.

Method used

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  • Methotrexate-containing medicine, preparation method, medicinal composition and application thereof
  • Methotrexate-containing medicine, preparation method, medicinal composition and application thereof
  • Methotrexate-containing medicine, preparation method, medicinal composition and application thereof

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preparation example Construction

[0156] According to the second aspect of the present application, there is also provided a method for preparing the above-mentioned methotrexate-containing drug, which includes the following steps: providing any one of the above-mentioned nucleic acid nanoparticles; by means of physical connection and / or covalent connection The methotrexate is mounted on the nucleic acid nanoparticles to obtain the methotrexate-containing medicine.

[0157] When physically linked, methotrexate is usually physically intercalated between GC base pairs. In the case of covalent linkage, methotrexate usually undergoes a chemical reaction with the amino group outside the G ring to form a covalent linkage. The methotrexate-containing drug prepared by the above method can have better targeting after the target head is modified, can stably deliver methotrexate, and has high reliability.

[0158]In a preferred embodiment, the step of mounting methotrexate through physical connection includes: mixing an...

Embodiment 1

[0182] 1. RNA and DNA nanoparticle carriers:

[0183] (1) The base sequences of the three polynucleotides that make up the RNA nanoparticles are shown in Table 1 below:

[0184] Table 1:

[0185]

[0186] (2) Three polynucleotide base sequences of DNA nanoparticles

[0187] The DNA uses the same sequence as the above RNA, except that T is substituted for U. Among them, the molecular weight of chain a is 8802.66, the molecular weight of chain b is 8280.33, and the molecular weight of chain c is 9605.2.

[0188]The a, b, and c strands of the above-mentioned RNA nanoparticles and DNA nanoparticles were all synthesized by Sangon Bioengineering (Shanghai) Co., Ltd.

[0189] 2. Self-assembly experimental steps:

[0190] (1) RNA or DNA single strands a, b, and c are simultaneously mixed and dissolved in DEPC water or TMS buffer at a molar ratio of 1:1:1;

[0191] (2) Heat the mixed solution to 80°C / 95°C (the RNA assembly temperature is 80°C, and the DNA assembly temperature i...

Embodiment 2

[0202] 1. Seven groups of short-sequence RNA nanoparticle carriers:

[0203] (1) The base sequences of the three polynucleotides of the seven groups of RNA nanoparticles are shown in Table 2 to Table 8 below:

[0204] Table 2: Three polynucleotide base sequences of R-1

[0205]

[0206]

[0207] Table 3: Three polynucleotide base sequences of R-2

[0208]

[0209] Table 4: Three polynucleotide base sequences of R-3

[0210]

[0211] Table 5: Three polynucleotide base sequences of R-4

[0212]

[0213]

[0214] Table 6: Three polynucleotide base sequences of R-5

[0215]

[0216] Table 7: Three polynucleotide base sequences of R-6

[0217]

[0218] Table 8: Three polynucleotide base sequences of R-7

[0219]

[0220]

[0221] The single strands of the above seven groups of short-sequence RNA nanoparticle carriers were all synthesized by Sangon Bioengineering (Shanghai) Co., Ltd.

[0222] 2. Self-assembly experimental steps:

[0223] (1) RNA ...

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Abstract

The invention provides a methotrexate-containing medicine, a preparation method, a medicinal composition and application thereof. The medicine comprises nucleic acid nanoparticles and methotrexate, wherein the methotrexate is mounted on the nucleic acid nanoparticles; the nucleic acid nanoparticles comprise nucleic acid structural domains, including a sequences, b sequences and c sequences; each asequence contains an a1 sequence or a sequence having at least one basic group inserted, lost or substituted on the a1 sequence; each b sequence contains a b1 sequence or a sequence having at least one basic group inserted, lost or substituted on the b1 sequence; and each c sequence contains a c1 sequence or a sequence having at least one basic group inserted, lost or substituted on the c1 sequence. After the nucleic acid structural domains are subjected to target head modification, the methotrexate-containing medicine has relatively good target performance, can be used for stably deliveringthe methotrexate and has high reliability.

Description

technical field [0001] The application relates to the field of medicine, in particular, to a medicine containing methotrexate, its preparation method, pharmaceutical composition and application. Background technique [0002] Methotrexate (Methotrexate, CSA: 133073-73-1, molecular formula: C 20 h 22 N 8 o 5 , Molecular weight: 454.45) is an anti-folate anti-tumor drug, mainly through the inhibition of dihydrofolate reductase to hinder the synthesis of tumor cells, and inhibit the growth and reproduction of tumor cells. It is mainly applicable to acute leukemia, breast cancer, choriocarcinoma and malignant mole, head and neck tumors, bone tumors, leukemic meningospinal infiltration, lung cancer, reproductive system tumors, liver cancer, refractory psoriasis vulgaris, systemic lupus erythematosus and Dermatomyositis and other autoimmune diseases. [0003] Currently, antitumor antibiotics, including methotrexate, must be administered in large doses of chemotherapy drugs in ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/54A61K47/69A61K31/519A61K9/51A61P35/00A61P35/02
CPCA61K47/549A61K47/6929A61K31/519A61K9/5123A61P35/00A61P35/02
Inventor 王力源王萌
Owner BAI YAO ZHI DA BEIJING NANOBIO TECH CO LTD
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