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CN-122005845-A - Targeting nanoparticle for breast cancer treatment and preparation and application thereof

CN122005845ACN 122005845 ACN122005845 ACN 122005845ACN-122005845-A

Abstract

The invention discloses a targeting nanoparticle for breast cancer treatment, and preparation and application thereof, and belongs to the technical field of biological medicines. The three-mode synergistic anti-tumor strategy of chemotherapy-photothermal treatment-Fenton-like reaction mediated iron death is proposed for the first time. The targeting nanoparticle is efficiently enriched in 4T1 breast cancer cells by means of double targeting actions of ET peptide and EPR, and the combination of photothermal therapy remarkably enhances the chemotherapeutic effect of PTX and effectively inhibits proliferation, invasion and metastasis of tumor cells. Proteomic analysis found that the differential protein was mainly enriched in motor protein and iron death pathways after targeted nanoparticle intervention, revealing the core mechanism of synergistic treatment. Molecular docking proves that PTX has specific interaction with a key target protein receptor, and the multi-mode cooperation strategy provides an innovative technical platform for overcoming the limitation of traditional chemotherapy and developing a high-efficiency low-toxicity breast cancer treatment scheme.

Inventors

  • SONG HONGPING
  • CHENG YANNI
  • LIU JIAO
  • XIAO YAO

Assignees

  • 中国人民解放军空军军医大学

Dates

Publication Date
20260512
Application Date
20260202

Claims (10)

  1. 1. A targeted nanoparticle for breast cancer treatment, wherein the nanoparticle is of core-shell structure comprising: A metal-organic framework nanoparticle core loaded with a chemotherapeutic agent; The polydopamine layer is coated on the surface of the metal-organic framework nanoparticle; And a targeting polypeptide modified on the outer surface of the polydopamine layer by covalent linkage, the targeting polypeptide being capable of specifically binding LRG1 protein; the metal-organic framework material is a material with pH response degradation characteristic, and the polydopamine layer enables the targeting nanoparticle to have near infrared light absorption capacity.
  2. 2. The targeted nanoparticle for breast cancer treatment of claim 1, wherein the chemotherapeutic agent is paclitaxel, doxorubicin, or cisplatin.
  3. 3. The targeted nanoparticle for breast cancer treatment of claim 1, wherein the metal-organic framework material is ZIF-8.
  4. 4. The targeting nanoparticle for breast cancer treatment according to claim 1, wherein the targeting polypeptide is an ET polypeptide having the amino acid sequence shown in SEQ ID No.1 or a conservative variant thereof with LRG1 targeting function.
  5. 5. The targeting nanoparticle for breast cancer treatment according to claim 1, wherein the targeting nanoparticle has a particle size of 200-350 nm and a zeta potential of-30 mV to-50 mV.
  6. 6. A targeting nanoparticle for breast cancer treatment according to claim 1, wherein the targeting nanoparticle has a significantly higher drug release rate in a buffer solution at pH 5.0-6.5 than in a buffer solution at pH 7.4.
  7. 7. A method of preparing a targeted nanoparticle for breast cancer treatment according to any one of claims 1-6, comprising the steps of: step 1, stirring a chemotherapeutic drug and a metal-organic framework material in methanol in a dark place to obtain drug-carrying nanoparticles; Step 2, forming nanoparticles with polydopamine coating layers on the surfaces of the drug-loaded nanoparticles through oxidation polymerization reaction of dopamine; and 3, covalently grafting the targeting polypeptide to the surface of the polydopamine coating layer through a carbodiimide-mediated coupling reaction to obtain the targeting nanoparticle for treating breast cancer.
  8. 8. A pharmaceutical composition comprising a targeting nanoparticle according to any one of claims 1-6 for use in the treatment of breast cancer, and a pharmaceutically acceptable carrier.
  9. 9. Use of a targeting nanoparticle for breast cancer treatment according to any one of claims 1-6 for the preparation of a medicament for breast cancer treatment.
  10. 10. The use according to claim 9, wherein the medicament is a medicament for achieving a synergistic treatment in combination with photothermal therapy and/or wherein the medicament is a medicament for inhibiting proliferation of breast cancer cells by inducing pig iron death from the tumor cells.

Description

Targeting nanoparticle for breast cancer treatment and preparation and application thereof Technical Field The invention relates to the technical field of biological medicine, in particular to a targeting nanoparticle for breast cancer treatment, and preparation and application thereof. Background At present, clinical treatment means of breast cancer mainly comprise radiation treatment, operation treatment and chemical drug therapy, wherein the operation is a necessary means for local treatment of early breast cancer, but the operation is large in human body trauma, and tiny focus and metastasis are difficult to thoroughly remove, the radiation treatment can be used for local control, but the radiation treatment is large in damage to normal tissues and easy to cause dysfunction, and the chemotherapy is used as a standard therapy of non-operation breast cancer, particularly, the chemotherapy is mainly used for taxol medicaments and is widely applied in clinic. However, traditional chemotherapy presents serious challenges. The study reports that compared with the single drug treatment of the solvent type paclitaxel, the albumin combined paclitaxel nanoparticle has improved curative effect, but objective remission rate is still maintained at 33%, and single adverse events reported in the two groups are more than 20%. This indicates that the existing drug delivery system has the problems of poor biocompatibility, insufficient long-term safety, high manufacturing cost, limited targeting efficiency and the like. Therefore, the development of a novel nano-drug delivery system with high targeting, high biosafety and high therapeutic response is important for breaking through the breast cancer treatment bottleneck, improving the curative effect and reducing the toxic and side effects. Metal organic framework compounds (MOFs) are a class of porous hybrid materials formed by self-assembly of metal clusters/ions with organic ligands through coordination bonds, exhibiting great potential in the field of drug delivery. The zeolite imidazole ester framework material ZIF-8 is a nontoxic and biocompatible porous material constructed by zinc ions and 2-methylimidazole through coordination, has excellent biocompatibility and pH response degradation characteristics, has stable structure in a physiological environment (pH 7.4), and has skeleton dissociation caused by protonation of 2-methylimidazole in a tumor slightly acidic environment (pH 4.5-6.5), so that intelligent controlled release of the medicine is realized. This property makes it an ideal carrier for constructing tumor microenvironment-responsive drug delivery systems. However, release of drugs solely by means of the pH response of ZIF-8 still faces the problem of insufficient delivery efficiency caused by physiological barriers of tumor tissues. To overcome this obstacle, combination therapy strategies are of interest. Photothermal therapy (PTT) can locally raise the temperature of tumor by converting light energy into heat energy, so that tumor cells can be directly killed, vascular permeability can be enhanced, and drug permeation can be improved, thereby generating synergistic effect with chemotherapy. Polydopamine (PDA) is an excellent photothermal conversion agent as a biopolymer having strong absorption in the near infrared region. In addition, studies have shown that LRG1 (Leucine-RICH ALPHA-2-Glycoprotein 1) is highly expressed in a variety of malignancies, including breast cancer, and is closely related to tumor angiogenesis, epithelial-to-mesenchymal transition and progression, being a potential diagnostic marker and therapeutic target for tumors. The ET peptide obtained by phage display technology screening has high affinity to LRG1, shows good active targeting ability and biosafety, and provides a new molecular tool for constructing an accurate delivery system. The polypeptide-ET peptide with high affinity with the LRG1 is obtained by screening by utilizing a phage display technology, the high affinity with the LRG1 and the strong active targeting capability of tumors are detected on molecular, cellular and animal levels, and meanwhile, the ET peptide also has good biosafety. In summary, although smart carriers (pH response), photothermal therapeutic agents and active targeting molecules such as ZIF-8 have been studied, these technologies are mostly in isolated application or simple superposition states, only single drug controlled release, single hyperthermia or single targeted modification are realized, and no integrated design scheme has been available for integrated integration and synergistic regulation of active targeting, smart drug release, physical hyperthermia and inducible deep biochemical killing mechanisms (such as iron death). Disclosure of Invention Aiming at the technical bottlenecks of limited curative effect and obvious toxic and side effects caused by low targeting efficiency of chemotherapeutic drugs, insufficient biological safety of