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
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[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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