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CN-121987826-A - Targeted medicine for inducing copper death by sensitized Li Simo-copper complex and application

CN121987826ACN 121987826 ACN121987826 ACN 121987826ACN-121987826-A

Abstract

Disclosed are a targeting drug for sensitization of Li Simo-copper complex-induced copper death and application thereof, which can sensitize tumor cells to Cu (II) -Elesclomol-induced copper death and realize high-efficiency and low-toxicity renal cell carcinoma treatment by combining with a c-Met targeting technology. The targeting drug for inducing copper death by the sensitized illite Li Simo-copper complex takes mesoporous silicon dioxide as a nano carrier, specific polypeptide for targeting the c-Met receptor of renal cancer cells is modified on the surface of the carrier, and taurine and Cu (II) -Elesclomol complex are loaded in the inner pore canal of the carrier.

Inventors

  • ZHANG MINGXIAO
  • MA CHANGYU
  • CHEN ZIYIN
  • TAN HAOTIAN
  • WANG JIANFENG

Assignees

  • 中日友好医院(中日友好临床医学研究所)

Dates

Publication Date
20260508
Application Date
20260320

Claims (9)

  1. 1. The targeting drug for inducing copper death by the sensitized illite Li Simo-copper complex is characterized in that mesoporous silica is used as a nano carrier, specific polypeptides for targeting the c-Met receptor of renal cancer cells are modified on the surface of the carrier, and taurine and Cu (II) -Elesclomol complex are loaded in the inner pore canal of the carrier.
  2. 2. The targeted drug for inducing copper death by sensitized illitemo-copper complex according to claim 1, wherein the sequence of the specific polypeptide targeting the c-Met receptor of renal cancer cells is NH2-AGSCYCSGPPRFECWCYETEGTGGGK-COOH.
  3. 3. The targeted drug for copper death by sensitized illitemo-copper complex according to claim 1 or 2, characterized in that said carrier is aminated by (3-aminopropyl) triethoxysilane and coupled to said polypeptide by an amide reaction.
  4. 4. The use of a targeted drug for the induction of copper death by a sensitized illitemo-copper complex as claimed in claim 1, characterized in that it is used for the preparation of a drug for the treatment of renal cell carcinoma.
  5. 5. The use of a targeting drug for inducing copper death by a sensitized illitemo-copper complex according to claim 4, wherein the targeting drug is actively targeted by a specific polypeptide targeting a c-Met receptor of renal cancer cells to increase accumulation of the drug at a cancer site of the renal cells, taurine induces a transition of tumor cells from glycolysis to oxidative phosphorylation, and Cu (II) -Elesclomol complex transports copper ions to mitochondria to induce copper death.
  6. 6. The use of a targeted drug for the induction of copper death by a sensitized illitemo-copper complex as claimed in claim 4, wherein said taurine and Cu (II) -Elesclomol complex are synergistically enhanced.
  7. 7. The use of the targeted drug for inducing copper death by a sensitized illitemo-copper complex as claimed in claim 4, wherein the preparation method of the targeted drug for inducing copper death by a sensitized illitemo-copper complex comprises the following steps: (1) Preparing mesoporous silica nanoparticles; (2) Preparing aminated mesoporous silica; (3) Preparing c-Met targeting peptide modified mesoporous silica; (4) And preparing the targeting nano-drug carrying taurine and CuES together.
  8. 8. Use of a targeted drug for sensitization of illitemo-copper complexes to induce copper death according to claim 7, characterized in that: In the step (1), 1.0 g hexadecyl trimethyl ammonium p-benzenesulfonate is dissolved in 70 mL deionized water, 0.3 g sodium hydroxide is added, the mixture is vigorously stirred for 1 hour at 80 ℃, then 5mL tetraethoxysilane is added dropwise, the mixture is continuously stirred for 2 hours at 80 ℃, after the reaction is finished, the precipitate is centrifugally collected and alternately washed with ethanol and water for three times, the product is dispersed in ethanol solution containing hydrochloric acid, the mixture is refluxed for 24 hours to remove hexadecyl trimethyl ammonium p-benzenesulfonate, and the mixture is centrifugally dried to obtain white powdery MSN; In the step (2), 200 mg of the prepared MSN is dispersed in 50mL absolute ethyl alcohol, and uniformly dispersed by ultrasonic, 200 mu L (3-aminopropyl) triethoxysilane is added for reflux reaction for 12 hours at 80 ℃, after the reaction is finished, centrifugal separation is carried out, ethanol is used for washing for three times to remove unreacted silane coupling agent, and MSN-NH 2 is obtained by vacuum drying; In the step (3), 10 mg c-Met targeting polypeptide is weighed and dissolved in PBS buffer solution, EDC of an activator 10 mg and NHS of 5 mg are added for activation for 30 minutes, then MSN-NH 2 of 50 mg dispersed in PBS is added for reaction for 24 hours at room temperature under light-proof stirring, centrifugation and washing with water are carried out, and a nano carrier MSN-cMet of the c-Met polypeptide is obtained; In the step (4), preparing taurine aqueous solution and Cu (II) -Elesclomol dimethyl sulfoxide solution, adding 100 mg MSN-cMet carrier into the mixed liquor, stirring for 24 hours in a dark place to enable the medicine to fully enter a mesoporous pore canal, centrifugally separating, using supernatant to calculate medicine carrying capacity, using a small amount of water to wash sediment to remove surface adsorption medicine, and freeze-drying to obtain a final product Tau/CuES@MSN-cMet.
  9. 9. The use of a targeted drug for sensitization of illitemo-copper complexes to induce copper death as claimed in claim 8, wherein said method further comprises step (5) of characterizing a nanomedicine comprising: appearance characterization, namely, observing by adopting a Transmission Electron Microscope (TEM), wherein the prepared nano-drug has a uniform spherical structure and a clear mesoporous channel; the particle size and the potential are measured by a dynamic light scattering particle size analyzer DLS, wherein the average particle size of MSN is 55.57+/-2.61 nm, the hydration particle size of the final product Tau/CuES@MSN-cMet is increased to 72.49+/-4.83 nm after polypeptide and drug delivery, PDI is 0.15, the particle size distribution is uniform, and the Zeta potential measurement shows that the Tau/CuES@MSN-cMet potential is +19.1 mV; measuring the drug loading, namely measuring by an ultraviolet-visible spectrophotometry to calculate that the drug loading of taurine is 5.8 percent, the encapsulation efficiency is 72.4 percent, the drug loading of CuES is 6.9 percent, and the encapsulation efficiency is 95.9 percent; In-vitro release, the drug release condition is detected by adopting a dialysis bag method under the simulated tumor microenvironment with the pH of 5.5 and the physiological environment with the pH of 7.4, and the drug release rate is faster than the physiological environment under the tumor microenvironment condition, so that the drug release rate has the pH response release characteristic.

Description

Targeted medicine for inducing copper death by sensitized Li Simo-copper complex and application Technical Field The invention relates to the technical field of biomedicine, in particular to a targeting drug for inducing copper death by a sensitized Evaporation-Li Simo-copper complex and application of the targeting drug for inducing copper death by the sensitized Evaporation-Li Simo-copper complex in treating renal cell carcinoma. Background Renal Cell Carcinoma (RCC) is a common malignancy of the urinary system, with clear cell renal cell carcinoma (ccRCC) being the most common subtype. Advanced renal cell carcinoma is insensitive to radiotherapy and chemotherapy, and the current targeted therapeutic drugs (such as sorafenib and sunitinib) have the common drug resistance problem although prolonging the survival time of patients to a certain extent. Therefore, development of new therapeutic mechanisms and delivery systems is urgent. Copper death (Cuproptosis) is a recently discovered novel mode of cell death that is distinguished from apoptosis, necrosis and iron death. The mechanism is that copper ions cause aggregation of the lipid acylated protein and loss of iron sulfur cluster proteins by direct binding to the lipid acylated components of the tricarboxylic acid (TCA) cycle, thereby triggering protein toxic stress and cell death. Elesclomol is a highly efficient copper ionophore capable of transporting copper ions to mitochondria, inducing copper death. However, studies have shown that the susceptibility to copper death is closely related to the metabolic state of the cell. Tumor cells that rely primarily on glycolysis for energy are somewhat resistant to copper death, whereas cells that rely on mitochondrial oxidative phosphorylation (OXPHOS) are highly susceptible to copper death. Renal cell carcinoma cells often exhibit a pronounced Warburg effect (i.e., primarily dependent on glycolysis), which limits the efficacy of Elesclomol classes of drugs. Disclosure of Invention In order to overcome the defects of the prior art, the technical problem to be solved by the invention is to provide a targeting drug for sensitization of the copper death induced by the Li Simo-copper complex, which can sensitize tumor cells to the copper death induced by Cu (II) -Elesclomol and realize high-efficiency and low-toxicity renal cell carcinoma treatment by combining with a c-Met targeting technology. The technical scheme is that the targeting drug for inducing copper death by the sensitized illite Li Simo-copper complex takes mesoporous silica as a nano carrier, specific polypeptide of a targeting renal cancer cell c-Met receptor is modified on the surface of the carrier, and taurine and Cu (II) -Elesclomol complex are loaded in the inner pore canal of the carrier. Also provided is the use of a targeting drug that sensitizes the Li Simo-copper complex to induce copper death, for the manufacture of a medicament for the treatment of renal cell carcinoma. Compared with the prior art, the invention has the following remarkable beneficial effects: 1. The dual targeting and synergy mechanism is to realize active targeting by using c-Met polypeptide to increase the accumulation of the medicine at the kidney cancer part, and to induce the transformation of tumor cells from glycolysis to oxidative phosphorylation by using taurine to relieve the metabolic resistance of the kidney cancer cells to copper death and obviously enhance the killing effect of CuES. 2. The mesoporous silica has the characteristics of large specific surface area and large pore volume, can effectively co-load two medicines, and has good biocompatibility. 3. In vitro experiments prove that the killing effect of the nano-drug on kidney cancer cells is obviously better than that of a single drug, and the synergism of the strategy of metabolic remodeling and copper death induction is proved. Drawings Fig. 1 is a Transmission Electron Microscope (TEM) image of a nano-drug prepared according to an embodiment of the present invention. Figure 2 is a graph showing particle size distribution of the nano-drug of the present invention at various stages of the preparation process. FIG. 3 is an in vitro drug release profile of the nanomaterials of the present invention. FIG. 4 is a graph showing the results of the detection of the targeting ability of different nanoparticles to kidney cancer 786-O cells. FIG. 5 is a graph showing the results of in vitro cytotoxicity (CCK-8 method) of 786-O cells against renal cancer in different drug-treated groups. FIG. 6A shows the results of intracellular ATP levels in different drug-treated groups, and FIG. 6B shows the results of intracellular lactate levels in different drug-treated groups, demonstrating metabolic remodeling and copper death mechanisms. Detailed Description The targeting drug for inducing copper death by the sensitized illite Li Simo-copper complex takes mesoporous silicon dioxide as a nano carrier, specific polype