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CN-122005500-A - Platinum folinate protein nanoparticle and preparation method and application thereof

CN122005500ACN 122005500 ACN122005500 ACN 122005500ACN-122005500-A

Abstract

The invention relates to a folinic acid platinum protein nanoparticle, a preparation method and application thereof, wherein the folinic acid platinum protein nanoparticle consists of a complex formed by platinum prodrug ions (cyclohexanediamine platinum dihydrate ions and/or diamineplatinum dihydrate ions) and folinic acid radical ions and proteins. The protein nanoparticle is prepared in an aqueous solution with the room temperature and the pH value of 7.5, the encapsulation rate of the folinic acid platinum is 70-99%, the drug loading rate is 3-30%, the platinum utilization rate is 5-30%, the protein nanoparticle has the pH response drug release characteristic, can release folinic acid and oxaliplatin or cisplatin with antitumor activity at the same time in a weak acid environment, and can remarkably improve the curative effect of the drug and the tolerance and safety of organisms. In addition, the protein nanoparticle can play a synergistic anti-tumor effect with 5-fluorouracil, and has a better therapeutic effect.

Inventors

  • CHEN HUABING
  • DENG YIBIN
  • CHEN XIAOLIAN
  • QIN MENGTING
  • LIU FAN
  • CHEN YITIAN
  • YAO LIJUAN

Assignees

  • 苏州大学

Dates

Publication Date
20260512
Application Date
20260123

Claims (9)

  1. 1. The folinic acid platinum protein nanoparticle is characterized by comprising a complex formed by platinum prodrug ions and folinic acid radical ions and proteins, wherein the platinum prodrug ions are cyclohexanediamine platinum dihydrate ions and/or diamine dihydrate platinum ions.
  2. 2. The platinum folinate protein nanoparticles according to claim 1, wherein the platinum folinate protein nanoparticles are prepared from platinum prodrug ions, protein and folinate ions in an aqueous solution with a pH of 7.5 under non-heating conditions; The folinic acid platinum protein nanoparticle has the encapsulation rate of 70% -99%, the drug loading rate of 3% -30% and the platinum utilization rate of 5% -30%.
  3. 3. The platinum folinate protein nanoparticle according to claim 1 or 2, wherein the platinum folinate protein nanoparticle has a core-shell structure, wherein the inner core is a complex formed by the platinum-based prodrug ions and the folinate ions, and the outer shell is albumin, hemoglobin, ferritin or transferrin.
  4. 4. The platinum folinate protein nanoparticle according to claim 1 or 2, wherein the hydrated particle size of the platinum folinate protein nanoparticle is 8-80 nm; The electron microscope particle size of the folinic acid platinum protein nanoparticle is 5-40 nm.
  5. 5. A method for preparing the platinum folinate protein nanoparticles according to any one of claims 1 to 4, comprising the steps of: Mixing a platinum prodrug ion solution and a protein solution to obtain a uniformly mixed solution, adding a sodium folinate solution to react, controlling the reaction temperature and time, and purifying to obtain the platinum folinate protein nanoparticle suspension, wherein the platinum prodrug ion solution is a cyclohexanediamine platinum ion dihydrate solution and/or a diamine platinum dihydrate ion dihydrate solution.
  6. 6. The method according to claim 5, wherein the solvent of the platinum-based prodrug ion solution and the solvent of the protein solution are both water; Adding sodium folinate solution to obtain a final reaction solution, wherein the concentration of platinum prodrug ions in the reaction solution is 1-60 mM, and the concentration of protein in the reaction solution is 1-50 mg/mL; the molar ratio of the platinum prodrug ions to the sodium folinate is (2:1) - (1:20).
  7. 7. The method according to claim 5, wherein the reaction temperature is 4-50 ℃ and the reaction time is 0.5-8 h; Adding sodium folinate solution to obtain final reaction solution, wherein the pH value of the reaction solution is 6-9.
  8. 8. The method of claim 7, wherein the reaction is performed under unheated conditions.
  9. 9. Use of the folinic acid platinum protein nanoparticle prepared by the preparation method of any one of claims 1 to 4 or any one of claims 5 to 8 in preparation of an antitumor drug, wherein the folinic acid platinum protein nanoparticle is decomposed into folinic acid and a platinum drug at a tumor site, and the platinum drug is oxaliplatin and/or cisplatin.

Description

Platinum folinate protein nanoparticle and preparation method and application thereof Technical Field The invention relates to the technical field of biological medicine, in particular to a platinum folinate protein nanoparticle and a preparation method and application thereof. Background Oxaliplatin (Oxaliplatin, OXA) is used as a third-generation platinum anticancer drug, and is a basic drug for chemotherapy of various solid tumors such as colorectal cancer, gastric cancer, pancreatic cancer and the like. Particularly in the FOLFOX combination therapy consisting of folinic acid (Folinic acid, fnA) and 5-fluorouracil (5-Fluorouracil, 5-Fu), the clinical curative effect is remarkably improved through the synergistic effect generated by acting various medicaments on different targets. However, this therapy still faces serious challenges during application. First, oxaliplatin itself presents serious dose-limiting toxicities, particularly peripheral neurotoxicity, greatly affecting patient treatment compliance and quality of life. Secondly, the three drugs in the FOLFOX regimen have different pharmacokinetic behaviors in vivo, and it is difficult to achieve effective therapeutic concentrations at the tumor site at the same time, so that the full play of the synergistic effect is limited, and systemic toxic and side effects may be caused. In order to improve the curative effect and safety of oxaliplatin, researchers developed novel delivery systems (ZL 201910780919.X; ZL 202210288446.3) such as oxaliplatin albumin nanoparticles. Albumin has good biocompatibility and potential targeting as a carrier. However, the conventional oxaliplatin albumin nanoparticle still has obvious technical bottlenecks that firstly, the drug utilization rate and encapsulation rate are generally low, so that raw materials are wasted and the production cost is high, secondly, the drug release behavior is poorly controlled, nonspecific toxic and side effects, especially neurotoxicity problems, are easily caused by the too fast release, particularly, the neurotoxicity problems cannot be effectively solved, thirdly, oxalate generated by hydrolysis of oxaliplatin participates in the occurrence and aggravation of neurotoxicity, wherein the oxalate possibly depletes calcium/magnesium ions in peripheral nerve components (deposited in the form of calcium oxalate/magnesium oxalate) so as to interfere with voltage-dependent sodium channels sensitive to the calcium ions, thereby causing cold sensitivity increase and pain response enhancement (Toxicol, applied, phacol 2018, 340, 77-84). In addition, with respect to the need for synergistic dosing of FOLFOX, researchers have attempted to construct drug-loaded liposomes co-entrapped with oxaliplatin prodrugs, such as dihydrate (1, 2-diaminocyclohexane) platinum (II), with folinic acid in an effort to achieve co-delivery of both drugs in a single nanosystem. Although the strategy is advanced in concept, the preparation itself has inherent defects that firstly, the size of the prepared liposome is large (the average diameter is about 120 nm), the liposome is difficult to effectively penetrate through tumors with dense fibrous matrix barriers (such as pancreatic cancer), the tumor penetration capacity and the treatment effect are limited, and secondly, an organic solvent is usually required to be used in the preparation process, potential safety risks caused by residual solvent exist, and the production process is unfavorable for large-scale production and clinical application. Therefore, there is an urgent need in the art to develop a novel drug delivery system and a preparation method thereof, which can overcome the above-mentioned drawbacks, and not only can realize high-efficiency entrapment and co-delivery of oxaliplatin and its synergistic drugs (such as folinic acid), but also has high entrapment rate and platinum utilization rate, wherein the platinum utilization rate refers to the ratio of the amount of platinum substances entrapped in nanoparticles to the total platinum substances added in the preparation process, and can intelligently respond to tumor microenvironment to control drug release at specific sites to reduce systemic toxicity, and meanwhile, the system should have a proper nano-size to promote tumor penetration, and a safe and green preparation process is adopted. Disclosure of Invention In order to solve the problems of low drug encapsulation rate, rapid release rate, high toxicity and the like of oxaliplatin albumin nanoparticles, the invention provides a folinic acid platinum protein nanoparticle, a preparation method and application thereof, wherein protein is used as a template, platinum precursor ions (cyclohexanediamine platinum dihydrate ions and/or diammineplatinum dihydrate ions) and proteins are interacted to induce the platinum precursor ions to enter into a protein internal cavity, and the coordination reaction of folinic acid ions and platinum is used to induce the f