Hypoxic/ROS response type prodrug for blocking pancreatic duct adenocarcinoma innervation through deep penetration

Abstract

The invention relates to a hypoxic / ROS (reactive oxygen species) responsive prodrug for deeply penetrating and blocking pancreatic duct adenocarcinoma innervation and a preparation method of the prodrug. The preparation method comprises the following steps: (1) reacting N-alpha-fluorenylmethoxycarbonyl-N-epsilon-t-butyloxycarbonyl-L-lysine with 5-amino-1, 3, 4-thiadiazole-2-sulfonamide to obtain (A); reacting (A) with piperidine to obtain (B); (2) dimethyl dithiopropionic acid methane and thionyl chloride are subjected to a reaction, and (C) is obtained; reacting the compound (C) with camptothecin to obtain a compound (D); (3) azobenzene-4, 4-dicarbonyl chloride and lalotinib are subjected to a reaction, and (E) is obtained; (4) reacting maleimide polyethylene glycol with azobenzene-4, 4-dicarbonyl chloride to obtain (F); (F) reacts with (B) to obtain (G); reacting (G) with trifluoroacetic acid to obtain (H); the reaction product (H) sequentially reacts with N6-carbobenzoxy-L-lysine cyclic anhydride and N5-t-butyloxycarboryl-L-ornithine cyclic anhydride, and (I) is obtained; reacting (I) with trifluoroacetic acid, adding (D), and reacting to obtain (J); reacting (J) with hydrobromic acid and acetic acid, adding (F) and iRGD, and reacting to obtain a polymer prodrug (K); the invention also discloses a method for preparing a nano-drug from the polymer prodrug.

Description

technical field [0001] The present invention relates to a polymer prodrug, in particular to a polymer prodrug that enhances the enrichment and penetration of nanoparticles in pancreatic ductal adenocarcinoma, promotes chemotherapy and blocks the synergistic therapeutic effect of starvation therapy mediated by innervation. The invention also relates to the nano-medicine obtained from the polymer prodrug and its preparation method. Background technique [0002] Pancreatic ductal adenocarcinoma (PDAC), known as the "King of Cancer", is the cancer with the highest mortality rate and the lowest survival rate among all cancers. Treatment methods such as surgical resection, chemotherapy, and radiotherapy are ineffective. The dense fibroblastic matrix around PDAC tumors distorts pancreatic tissue, resulting in poor blood vessel formation and increased intratumoral pressure, which limits the diffusion and penetration of drugs, making most of the existing nanomedicine largely ineffect...

AI Technical Summary

Problems solved by technology

[0002] Pancreatic ductal adenocarcinoma (PDAC), known as the "King of Cancer", is the cancer with the highest mortality rate and the lowest survival rate among all cancers. Treatment methods such as surgical resection, chemotherapy, and radiotherapy are ineffective

The dense fibroblastic matrix around PDAC tumors distorts pancreatic tissue, resulting in poor blood vessel formation and increased intratumoral pressure, which limits the diffusion and penetration of drugs, making most of the existing nanomedicine largely ineffective [Nature Reviews Clinical Oncology, 2016, 13(12), 750-765]

The fibroblast matrix of PDAC further compresses the neovascularization of the tumor, leading to a lack of nutrients, hypoxia and acidic internal microenvironment, which starves the cancer cells inside the PDAC and cannot meet the vigorous metabolic needs of cancer cells [NanoLett, 2019, 19(6 ), 3527-3534]

Images