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CN-122005464-A - Paclitaxel precursor nano-drug and preparation method and application thereof

CN122005464ACN 122005464 ACN122005464 ACN 122005464ACN-122005464-A

Abstract

The application provides a taxol precursor nano-drug and a preparation method and application thereof, belonging to the technical field of pharmaceutical chemistry. Including paclitaxel dimer prodrug and supported 7-ethyl 10-hydroxy-camptothecin. The application uses taxol dimer prodrug as self-assembled monomer to construct PTX-SN38 cooperative treatment nanometer system, and has the advantages of water dispersibility, biocompatibility, tumor specific response, cooperative treatment and the like, and can effectively solve the limitation of taxol and SN38 in anti-tumor treatment.

Inventors

  • Jin Jinghuai
  • ZHANG ZHIJUN
  • ZHU QIMING
  • HAO LI
  • SHEN YONGMIAO
  • YANG XINGDI
  • XU MINGKAI

Assignees

  • 浙江理工大学
  • 浙江理工大学嵊州创新研究院有限公司

Dates

Publication Date
20260512
Application Date
20260413

Claims (10)

  1. 1. A taxol precursor nano-drug is characterized by comprising taxol dimer prodrug and 7-ethyl 10-hydroxy-camptothecine loaded by the taxol dimer prodrug.
  2. 2. The method of claim 1, wherein the paclitaxel prodrug is PTX 2 -SS or PTX 2 -C8.
  3. 3. The paclitaxel prodrug according to claim 1, wherein the mass ratio of paclitaxel dimer prodrug to 7-ethyl 10-hydroxy-camptothecin is 100-4:1.
  4. 4. The paclitaxel prodrug according to claim 1, wherein the mass ratio of paclitaxel dimer prodrug to 7-ethyl 10-hydroxy-camptothecin is 100-10:1.
  5. 5. A process for preparing the nano-medicine of taxol precursor, as claimed in claim 1, characterized in that taxol dimer prodrug is assembled with bovine serum albumin and directly doped with 7-ethyl 10-hydroxy-camptothecine to obtain the nano-medicine loaded with 7-ethyl 10-hydroxy-camptothecine.
  6. 6. The method for preparing the taxol precursor nano-drug according to claim 5, wherein the taxol dimer prodrug is dissolved in tetrahydrofuran, 7-ethyl 10-hydroxy-camptothecin solution is added, and after uniform mixing, the taxol dimer prodrug is slowly dripped into bovine serum albumin aqueous solution, and then stirring and dialysis are continued to obtain the 7-ethyl 10-hydroxy-camptothecin loaded nano-drug.
  7. 7. The method for preparing a taxol prodrug according to claim 5, wherein taxol is dissolved in methylene chloride, a connecting agent, EDC, HCl and DMAP are sequentially added, EDC, HCl and DMAP are added again after stirring reaction, stirring reaction is continued until complete, methylene chloride is removed by rotary evaporation, the obtained solid is redissolved, column purification, rotary evaporation, redissolution and precipitation in ice water are carried out, and taxol dimer prodrug is obtained.
  8. 8. The method of claim 7, wherein the linker is 3, 3-dithiodipropionic acid, and the reaction temperature is room temperature, and the obtained paclitaxel dimer prodrug is designated PTX 2 -SS.
  9. 9. The method of claim 7, wherein the linker is suberic acid, the temperature of the stirring reaction is 30-40 ℃, and the obtained paclitaxel dimer prodrug is designated as PTX 2 -C8.
  10. 10. Use of the paclitaxel prodrug of claim 1 in the preparation of an anti-tumor formulation.

Description

Paclitaxel precursor nano-drug and preparation method and application thereof Technical Field The application relates to a taxol precursor nano-drug, a preparation method and application thereof, belonging to the technical field of pharmaceutical chemistry. Background Paclitaxel (PTX) is a natural tumor chemotherapeutic drug widely used clinically, has high anti-tumor activity and low toxicity, but has poor water solubility and biological stability, is difficult to gather in tumor areas, and greatly reduces the anti-cancer effect. The microenvironment of high ROS and GSH concentrations within tumor cells can be used as an ideal stimulus response condition for designing prodrugs. Disulfide bonds can simultaneously respond to ROS and GSH, convert to sulfones or sulfhydryls, which in turn initiate hydrolysis of the linker, releasing PTX. However, single chemotherapy treatment is easy to cause drug resistance of tumor cells and affects the treatment effect. Camptothecine (CPT) has antitumor activity, and camptothecine and its derivative have antitumor mechanism different from that of taxol, and can be used as topoisomerase I (TOPOI) inhibitor to combine with TOPOI to form CPT-TOPO I-DNA ternary complex for tissue DNA synthesis and finally inducing cancer cell death. 7-ethyl-10-hydroxycamptothecin (SN 38) is a main active metabolite of camptothecin clinical anticancer drug irinotecan (CPT-11), and has been formally effective in treating various cancers such as rectal cancer, small cell lung cancer, lymphoma, etc., and the biological activity of the 7-ethyl-10-hydroxycamptothecin is 100-1000 times that of CPT-11. However, SN38 has hydrophobicity (almost insoluble in water and most medical oily solvents) and instability at physiological pH, which limits its clinical transformation. Disclosure of Invention In view of the above, the application provides a paclitaxel precursor nano-drug, which realizes the treatment effect by cooperating with the load, solves the problems of poor water solubility, difficult tumor delivery and the like of the drug chemotherapeutic drugs PTX and SN38, has tumor targeting property, and realizes the synergistic anti-tumor effect of different action mechanisms of the two drugs. Specifically, the application is realized by the following scheme: a paclitaxel prodrug comprising a paclitaxel dimer prodrug and a supported 7-ethyl 10-hydroxy-camptothecin (SN 38). Further, as preferable: The paclitaxel dimer prodrug is PTX 2 -SS or PTX 2 -C8. The mass ratio of the taxol dimer prodrug to the 7-ethyl 10-hydroxy-camptothecin is 100-4:1. More preferably, the mass ratio of the paclitaxel dimer prodrug to the 7-ethyl 10-hydroxy-camptothecin is 100-10:1. The nano-drug provided by the scheme uses the taxol dimer prodrug as a self-assembled monomer to construct a PTX-SN38 cooperative treatment nano-system, has the advantages of water dispersibility, biocompatibility, tumor specific response, cooperative treatment and the like, and can effectively solve the limitation of taxol and SN38 in anti-tumor treatment. The preparation method of the taxol precursor nano-drug comprises the steps of co-assembling taxol dimer prodrug and bovine serum albumin, and directly doping 7-ethyl 10-hydroxy-camptothecin to obtain the 7-ethyl 10-hydroxy-camptothecin loaded nano-drug. Specifically, the preparation process comprises dissolving paclitaxel dimer prodrug in tetrahydrofuran, adding 7-ethyl 10-hydroxy-camptothecin solution, mixing, slowly dripping into bovine serum albumin aqueous solution, stirring, and dialyzing to obtain 7-ethyl 10-hydroxy-camptothecin-loaded nano-drug. Dissolving paclitaxel in dichloromethane, sequentially adding a connecting agent, EDC, HCl and DMAP, stirring for reaction, then adding EDC, HCl and DMAP again, continuing stirring for reaction until the reaction is complete, rotationally evaporating to remove dichloromethane, dissolving the obtained solid again, purifying by a column, rotationally evaporating, redissolving, and separating out in ice water to obtain the paclitaxel dimer prodrug. When the connecting agent is 3, 3-dithiodipropionic acid, the temperature of the stirring reaction is room temperature (20-30 ℃), and the obtained taxol dimer prodrug is marked as PTX 2 -SS. When the linker is suberic acid, the temperature of the stirring reaction is 30-40 ℃, and the obtained paclitaxel dimer prodrug is marked as PTX 2 -C8. The preparation process is based on the strategy of co-assembling the antitumor prodrug and the synergistic chemotherapeutic drug, and realizes the synergistic delivery and treatment of the chemotherapeutic drug Paclitaxel (PTX) and 7-ethyl 10-hydroxy-camptothecin (SN 38). First, a paclitaxel dimer prodrug (in particular PTX 2 -SS) is synthesized using a disulfide linker (e.g., 3-dithiodipropionic acid, etc.) that is dual responsive to high concentrations of Glutathione (GSH) and Reactive Oxygen Species (ROS) in the tumor microenvironment. The prodrugs can self-assemble in