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CN-122005496-A - X-ray controllable activated nanoparticle as well as preparation method and application thereof

CN122005496ACN 122005496 ACN122005496 ACN 122005496ACN-122005496-A

Abstract

The invention relates to X-ray controllable activated nano particles, a preparation method and application thereof, and relates to the technical field of biological medicine. Solves the technical problems that the whole body delivery of NO in the existing radiotherapy sensitization process lacks tumor selectivity, has high toxicity and can not be released specifically by radiotherapy. The nanoparticle comprises a polymer carrier, a nitric oxide donor and a targeting molecule, wherein the nitric oxide donor is coated in the polymer carrier, the targeting molecule is modified on the surface of the nanoparticle, the polymer PEG-PCL carrier is an amphiphilic block copolymer, the nitric oxide donor is BNN6, and the targeting molecule is GRP78 targeting peptide. The nanoparticle is a delivery system capable of simultaneously realizing GRP78 targeting and X-ray activated NO release, can actively target radiotherapy to resist tumors, and can trigger release of NO only under X-ray irradiation, so that safe and efficient radiotherapy sensitization is realized.

Inventors

  • XUE FUXIN
  • LIU ZHILIN
  • ZHANG WANZE
  • ZHAO ZHIPENG
  • WANG JINBAO
  • LIU LINLIN

Assignees

  • 吉林大学

Dates

Publication Date
20260512
Application Date
20260310

Claims (9)

  1. 1. The X-ray controllable activation nanoparticle is characterized by being a GRP78 targeted X-ray triggered nitric oxide release nanoparticle, and comprises a polymer carrier, a nitric oxide donor coated in the polymer carrier and a targeting molecule modified on the surface of the nanoparticle; the polymer carrier is a biodegradable polyethylene glycol-polycaprolactone (PEG-PCL) amphiphilic block copolymer; The nitric oxide donor is N, N '-di-sec-butyl-N, N' -dinitroso-1, 4-phenylenediamine (BNN 6) with radiation sensitive property; the targeting molecule is a targeting peptide with high affinity to GRP78 protein which is highly expressed in radiotherapy resistant tumors, and is called GRP78 targeting peptide.
  2. 2. The X-ray controllable activation nanoparticle according to claim 1, wherein the particle size of the nanoparticle is 117.4±9.2 nm and the zeta potential is-3.77±0.48 mV.
  3. 3. The X-ray controllable activation nanoparticle of claim 1, wherein the polyethylene glycol-polycaprolactone amphiphilic block copolymer is PEG 5000 -PCL 2000 .
  4. 4. A method for preparing the X-ray controllable activated nanoparticle according to any one of claims 1 to 3, comprising the steps of: (1) Preparation of drug-loaded nanoparticle PBN: Adopting a nano precipitation method, dissolving BNN6 and PEG-PCL amphiphilic block copolymer in DMF, dripping into water under stirring, volatilizing an organic solvent, centrifuging, washing, and re-suspending to obtain drug-loaded nanoparticle PBN; (2) Preparation of X-ray controllable activated nanoparticles PBTN: And (3) activating the drug-loaded nanoparticle PBN prepared in the step (1), then performing coupling reaction with GRP78 targeting peptide, and purifying to obtain the X-ray controllable activated nanoparticle PBTN.
  5. 5. The method for preparing the X-ray controllable activated nanoparticle according to claim 4, wherein in the step (1), the mass ratio of the BNN6 to the PEG-PCL amphiphilic block copolymer is 10:1.
  6. 6. The method for preparing X-ray controllable activated nanoparticles according to claim 4, wherein in the step (2), EDC and NHS are used to activate the drug-loaded nanoparticle PBN, so that the carboxyl on the surface of the drug-loaded nanoparticle PBN and the amino on the GRP78 targeting peptide undergo a coupling reaction.
  7. 7. Use of the X-ray controllable activation nanoparticle of any one of claims 1-3 for the preparation of a radiosensitizer or an anticancer drug.
  8. 8. The use according to claim 7, wherein the X-ray controllable activation nanoparticle is used in combination with an immune checkpoint inhibitor.
  9. 9. The use according to claim 8, wherein the immune checkpoint inhibitor is αpdl1.

Description

X-ray controllable activated nanoparticle as well as preparation method and application thereof Technical Field The invention relates to the technical field of biological medicine, in particular to GRP78 targeted and nitric oxide released X-ray controllable activated nano particles, and a preparation method and application thereof. Background Radiation therapy (Radiotherapy, RT) is one of the central means of treating localized solid tumors, with more than 50% of cancer patients receiving radiation therapy (hereinafter referred to as radiation therapy) during their treatment. However, tumor radiation resistance (Radioresistance) is the primary cause of treatment failure, and about 20-50% of patients experience recurrence or metastasis after radiation therapy. The tumor radiotherapy resistance generation mechanism is complex and mainly comprises (1) an anoxic region exists in the tumor, the sensitivity of anoxic cells to radiotherapy is obviously lower than that of the anoxic cells, (2) the radiotherapy can induce the tumor cells to overexpress pro-survival factors such as heat shock protein 70 (HSP 70), GRP78 and hypoxia inducible factor-1α (HIF-1α) so as to enhance the resistance capability of the tumor cells, and (3) the tumor cells have an efficient DNA damage repair system and can rapidly repair DNA breakage caused by radiation. Nitric Oxide (NO) is a gaseous signal molecule with vasodilating effect. In recent years, NO has been found to be effective in sensitizing radiation therapy by a mechanism in which NO reacts with radiation-generated Reactive Oxygen Species (ROS) to produce the highly oxidative peroxynitrite (ONOO -) which causes more severe DNA damage and inhibits the activity of key proteins for DNA repair. In addition, the vasodilation of NO is helpful for improving the blood flow perfusion of tumor, relieving hypoxia, and further improving the radiotherapy effect. However, the half-life of NO is extremely short and systemic delivery lacks tumor selectivity, which can lead to severe systemic toxicity such as hypotension, limiting its clinical use. Therefore, a delivery system capable of selectively delivering NO to a tumor site and responding to the local accurate release of X-rays is developed, and has important significance for overcoming the resistance of radiotherapy and improving the curative effect of the radiotherapy. Disclosure of Invention The invention provides an X-ray controllable activated nanoparticle and a preparation method and application thereof, and aims to solve the technical problems that NO systemic delivery in the existing radiotherapy sensitization process lacks tumor selectivity and has high toxicity and cannot be released specifically by radiotherapy. The nanoparticle is a delivery system capable of simultaneously realizing GRP78 targeting and X-ray activated NO release, can actively target radiotherapy to resist tumors, and can trigger release of NO only under X-ray irradiation, so that safe and efficient radiotherapy sensitization is realized. In order to solve the technical problems, the technical scheme of the invention is as follows: An X-ray controllable activation nanoparticle is a GRP78 targeted X-ray triggered nitric oxide release nanoparticle, and comprises a polymer carrier, a nitric oxide donor coated in the polymer carrier and a targeting molecule modified on the surface of the nanoparticle; the polymer carrier is a biodegradable polyethylene glycol-polycaprolactone (PEG-PCL) amphiphilic block copolymer; The nitric oxide donor is N, N '-di-sec-butyl-N, N' -dinitroso-1, 4-phenylenediamine (BNN 6) with radiation sensitive property; the targeting molecule is a targeting peptide with high affinity to GRP78 protein which is highly expressed in radiotherapy resistant tumors, and is called GRP78 targeting peptide. In the above technical solution, preferably, the particle diameter of the nanoparticle is 117.4±9.2 nm, and the zeta potential is-3.77±0.48 mV. In the above technical solution, preferably, the polyethylene glycol-polycaprolactone amphiphilic block copolymer is PEG 5000-PCL2000. The preparation method of the X-ray controllable activated nano particles comprises the following steps: (1) Preparation of drug-loaded nanoparticle PBN: Adopting a nano precipitation method, dissolving BNN6 and PEG-PCL amphiphilic block copolymer in DMF, dripping into water under stirring, volatilizing an organic solvent, centrifuging, washing, and re-suspending to obtain drug-loaded nanoparticle PBN; (2) Preparation of X-ray controllable activated nanoparticles PBTN: And (3) activating the drug-loaded nanoparticle PBN prepared in the step (1), then performing coupling reaction with GRP78 targeting peptide, and purifying to obtain the X-ray controllable activated nanoparticle PBTN. In the above technical solution, preferably, in the step (1), the mass ratio of the BNN6 to the PEG-PCL amphiphilic block copolymer is 10:1. In the above technical scheme, preferably, in the step (2)