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

Abstract

The invention belongs to the field of biological medicine and specifically discloses a nucleic acid-drug conjugate based on phosphorothioate modified nucleic acid, a drug delivery system and a preparation method thereof. Phosphorothioate groups in the phosphorothioate modified nucleic acid react with groups modified on drug molecules and capable of generating electrophilic reaction with the phosphorothioate groups, so as to form the nucleic acid-drug conjugate; the nucleic acid-drug conjugate can be self-assembled into drug-containing nano-carriers in various forms for drug delivery, in the manner of selecting different nucleotide sequences including functional nucleic acid; compared with the prior art, the invention has the advantages that the nucleic acid-drug conjugate can be acquired through a simple solid-phase synthesis technology, grafting sites and assembling forms of drug molecules on nucleic acid skeleton can be accurately controlled and the method has universality to chemotherapeutic drugs; according to the nucleic acid-drug conjugate, the drug delivery system, the preparation method and the application thereof disclosed by the invention, physicochemical properties and in vivo distribution properties of chemotherapeutic drugs are obviously improved, therapeutic effect thereof can be promoted and combination therapy of gene therapy and chemotherapy can be realized.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a nucleic acid-drug conjugate based on nucleic acid phosphorothioate modification, a drug delivery system, a preparation method and application thereof. Background technique [0002] Chemotherapy is one of the important means of tumor treatment. However, due to the defects of poor water solubility, non-targeting, high blood clearance rate and even serious side effects of most chemotherapeutic drugs, their bioavailability is low (Nat.Rev.Cancer2006 ,6,789.), and long-term use will produce drug resistance, which brings certain limitations to their clinical application. [0003] In order to overcome this problem, in the past few decades, researchers have designed a series of nano drug delivery systems based on polymer or inorganic nanoparticles to improve the properties of chemotherapy drugs and promote their therapeutic effects, such as micelles, vesicles, lipids, etc. Plast...

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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

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