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Nucleic acid-drug conjugate, drug delivery system, preparation method and application thereof

A technology of delivery system and conjugate, which is applied in the field of biomedicine, can solve the problems of complex synthesis process, low degradability, limitation, etc., and achieve the effect of simple synthesis process, reasonable and simple construction, and low biodegradability in vivo

Active Publication Date: 2022-01-25
SHANGHAI JIAO TONG UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0008] The first purpose of the present invention is to provide a nucleic acid-drug conjugate based on phosphorothioate modification of nucleic acid to achieve accurate and controllable grafting and efficient delivery of chemotherapeutic drugs, and to solve the following shortcomings of the current drug conjugate delivery system : (1) cannot meet the three requirements of biocompatibility, in vivo degradability and low immunogenicity of carrier materials at the same time; (2) it is difficult to precisely control the drug grafting site and drug loading; (3) the grafting Due to the limitation of drugs, it is impossible to realize the universality of nucleic acid as a carrier material, and it is difficult to reduce the cost of nucleic acid drug loading; (4) it requires a relatively complicated synthesis process; (5) it is impossible to realize a reasonable and simple construction of a multifunctional drug loading system

Method used

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  • Nucleic acid-drug conjugate, drug delivery system, preparation method and application thereof
  • Nucleic acid-drug conjugate, drug delivery system, preparation method and application thereof
  • Nucleic acid-drug conjugate, drug delivery system, preparation method and application thereof

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preparation example Construction

[0087] The present invention provides a nucleic acid-drug combination, a drug delivery system based on a nucleic acid phosphate skeleton, a pharmaceutical delivery system, and a method and application thereof.

[0088] The present invention belongs to the field of biomedicine, and is specifically disclosed, a nucleic acid-drug binding, a drug delivery system, a drug delivery system, and a method of preparing a phosphate phosphate-modified nucleic acid. The nucleic acid-drug conjugate is a thiophosphate in a thiophosphate skeleton in a nucleic acid phosphoric acid by a pharmaceutical molecule that can be modified with a pro-electron reaction group that can react with it, there is a different goal. Select a nucleic acid sequence including a functional nucleic acid, in addition, the nucleic acid-drug binding can be self-assembled into a pharmaceutically acceptable nano carrier for drug delivery. Compared with the prior art, the phosphorothioate nucleic acid skeleton employed by the p...

Embodiment 1

[0092] 1.1 Synthesis of the prodrug of bromoate cooked, see figure 1 (A), the synthesis is two steps:

[0093] (1), the synthesis of oxidatively sensitive prodrug compound 1: Under argon, the gratichum (1G) is dissolved in 150 ml of water gas (313 mg) in 150 ml of anhydrous dichloromethane, slowly add 4-dimethyl. Aminopyridine (DMAP, 1.12 g is dissolved in 20 ml of dichloromethane), stirred at room temperature for half an hour, 2,2'-dithiosis (4.43 g), room temperature to react overnight.

[0094] After the reaction, the mixture was washed with 80 ml of 0.1 m HCl solution, layered, discarded, and then washed three times, washed with 80 ml of saturated NaCl solution, stratified, discarded, and finally washed with 80 mL of distilled water, layered Abandon the supernatant, with anhydrous MGSO 4 Drying, the crude product was separated and purified by column chromatography gradient elution, separated polarity is methanol: dichloromethane = 1: 100.

[0095] This step is 64.5% of the pro...

example 2

[0107] Example 2 Synthesis of nucleic acid - paclitaxel grafting

[0108] 2.1 Synthesis of benzyl bromide-modified paclitaxel drug (PTX-BZ-BR), see figure 1 (B), its synthesis is divided into two steps:

[0109](1) 4-bromomethylmethyl alcohol (500 mg, 1 equivalent) and dithiocaronucleic acid (DTDP, 2.6 g, 5 equivalents) are dissolved in super drying dichloromethane and tetrahydrofuran (1 / 1) , V / V); then add DMAP (91 mg, 0.3 equivalents), stirred for a few minutes, add 2 cyclohexyl carbon diimide (DCC, 615 mg, 1.2 equivalents, dissolved in super-dry dichloromethane), room temperature reaction After overnight, the solvent was evaporated by a rotary evaporator, and a benzy bromide structure (DTPA-BZ-BR) containing disulfide bond was isolated by silica gel column, and the eluent was an ethyl acetate. Product nuclear magnetic map and attribution Figure 9 .

[0110] (2) The paclitaxel (500 mg, 1 equivalent) and DTPA-BZ-BR (230 mg, 1 equivalent) were dissolved in dichloromethane, then ...

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Abstract

The invention belongs to the field of biomedicine, and specifically discloses a phosphorothioate-modified nucleic acid-based nucleic acid-drug conjugate, a drug delivery system and a preparation method thereof. The nucleic acid-drug conjugate is formed by reacting a phosphorothioate group in a phosphorothioate-modified nucleic acid with a group modified on a drug molecule that can undergo an electrophilic reaction with a phosphorothioate group , and, by selecting different nucleic acid sequences including functional nucleic acids, the nucleic acid-drug conjugates can be self-assembled into various forms of drug-containing nanocarriers for drug delivery. Compared with the prior art, the present invention can be achieved by simple solid-phase synthesis technology, and can precisely control the grafting site and assembly form of the drug molecule on the nucleic acid backbone, and this method has universal applicability to chemotherapeutic drugs ; The present invention can significantly improve the physicochemical properties and in vivo distribution properties of chemotherapeutic drugs and promote their therapeutic effects, and can also realize the combined treatment of gene therapy and chemotherapy.

Description

Technical field [0001] The present invention belongs to the field of biomedicine, and more particularly to a nucleic acid-drug combination, a drug delivery system thereof, and a preparation method thereof, based on a nucleic acid-drug binding, a drug delivery system thereof. Background technique [0002] Chemotherapy is one of the important means of tumor treatment. However, due to the defects such as poisonous side effects such as moisture, non-targeted, blood removal rate or even severe poisonous side effects, resulting in lower bioavailability (Nat.Rev.cancer2006) 6,789.), And long-term use can cause drug resistance, bringing certain limitations to their clinical applications. [0003] In order to overcome this problem, the researchers have designed a series of nano-drug delivery systems based on polymer or inorganic nanoparticles in the past few decades, to improve chemotherapeutic drugs and promote their therapeutic effects, including micelles, vesicles, and grease. Mass, al...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/54A61K45/00A61P35/00C07H1/00C07H21/02A61K31/4745A61K31/337
CPCA61K45/00A61K47/548A61K47/549A61P35/00A61K31/337A61K31/4745C07H1/00C07H21/02A61K2300/00
Inventor 张川张娇郭园园
Owner SHANGHAI JIAO TONG UNIV
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