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CN-122005830-A - Temperature-sensitive hydrogel containing doxorubicin-loaded dendrimer as well as preparation method and application thereof

CN122005830ACN 122005830 ACN122005830 ACN 122005830ACN-122005830-A

Abstract

The invention discloses a drug delivery system containing loaded doxorubicin and a preparation method and application thereof. The drug delivery system comprises a poly beta amino ester which is coated with dextran sulfate on the surface and takes a fourth generation lysine dendritic molecule Lys-G4 as a core and is coupled with doxorubicin. The drug delivery system has pH-dependent drug release characteristics, has remarkable toxicity to C6 and U87MG glioma cells, induces apoptosis, inhibits migration and targets subcellular localization, and can effectively penetrate through a blood-brain barrier model and a 3D tumor sphere. The delivery system is compounded with PLA-PEG-PLA thermosensitive hydrogel to successfully construct thermosensitive hydrogel with a drug storage function. The tumor inhibition effect and biocompatibility are good in a nude mouse subcutaneous and in-situ glioma model. The invention not only provides a new strategy for overcoming the blood brain barrier, but also can effectively reduce the systemic toxicity, and opens up a new research idea and method for glioma treatment.

Inventors

  • ZHANG LUZHONG
  • ZHOU XINYI
  • WEI LE
  • LI SHUQI

Assignees

  • 南通大学

Dates

Publication Date
20260512
Application Date
20260320

Claims (10)

  1. 1. A drug delivery system comprising doxorubicin-loaded drug delivery system comprising a doxorubicin-conjugated poly- β -amino ester having dextran sulfate encapsulated on the surface and having the fourth generation lysine dendrimer Lys-G4 as the core.
  2. 2. The drug delivery system of claim 1, wherein doxorubicin is coupled via a hydrazone linkage to a pentahydrazide-coupled poly- β amino ester having Lys-G4 as a core.
  3. 3. The drug delivery system according to claim 2, wherein the tefraamino acid hydrazide-coupled poly- β -amino ester having Lys-G4 as a core is obtained by michael addition reaction of a tefraamino acid hydrazide-coupled poly- β -amino ester terminated with an acryl group and having a tefraamino acid hydrazide-coupled poly- β -amino ester having a fourth generation lysine dendrimer Lys-G4 having 32 amino groups.
  4. 4. The drug delivery system comprising doxorubicin-loaded according to claim 1, wherein the dextran sulfate is coated on the surface of the doxorubicin-coupled poly- β amino ester by electrostatic interaction to form a nanocomposite having a core-shell structure.
  5. 5. The doxorubicin-loaded drug delivery system according to claim 1 or 4, wherein the nanocomposite is of spherical structure having a hydrated particle diameter of 30-180nm and a zeta potential of-0.5-30 mV.
  6. 6. The drug delivery system comprising a load of doxorubicin according to claim 1, wherein the drug loading is 5-50% and the encapsulation efficiency is 10-70%.
  7. 7. A method of preparing a doxorubicin-loaded drug delivery system according to claim 1, comprising the steps of: (a) Synthesizing Boc-5-azido valeric acid hydrazide by condensation reaction of 5-azido valeric acid and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole in N, N-dimethylformamide; (b) The polyethylene glycol diacrylate and propargylamine are subjected to Michael addition reaction to synthesize the poly beta-amino ester which is end-capped by the acryloyl group and contains alkynyl; (c) Coupling the Boc-5-azido-pentanoyl hydrazine and the poly-beta-amino ester which is blocked by the acryloyl and contains alkynyl through copper-catalyzed azido-alkyne cycloaddition reaction to obtain the poly-beta-amino ester which is blocked by the acryloyl and is coupled with the pentanoyl hydrazine; (d) Synthesizing a fourth-generation lysine dendritic molecule Lys-G4 containing 32 amino groups by a 2-chlorotrityl chloride resin solid-phase polypeptide synthesis technology; (e) The poly beta-amino ester which is blocked by the acryloyl and is coupled with the tefrahydrazide and the fourth generation lysine dendritic molecule containing 32 amino groups are subjected to Michael addition reaction to obtain the poly beta-amino ester which takes the fourth generation lysine dendritic molecule as a core and is coupled with the tefrahydrazide; (f) Dissolving the poly beta-amino ester taking the fourth-generation lysine dendritic molecule as a core and being coupled with the pentanoyl hydrazide, doxorubicin hydrochloride and acetic acid in methanol, carrying out a light-shielding reaction, and separating and purifying to obtain the poly beta-amino ester taking the fourth-generation lysine dendritic molecule as the core and being coupled with the doxorubicin; (g) And dissolving the poly beta-amino ester taking the fourth-generation lysine dendritic molecule as a core and coupled with the doxorubicin and dextran sulfate in pure water, and stirring to obtain the poly beta-amino ester nano-composite taking the fourth-generation lysine dendritic molecule as the core and coupled with the doxorubicin, wherein the charge of the poly beta-amino ester nano-composite is reversible.
  8. 8. Use of a drug delivery system comprising a load of doxorubicin according to any one of claims 1-6 for the preparation of an antitumor drug.
  9. 9. The use according to claim 8, wherein the antitumor drug is used for the treatment of a disease requiring targeted delivery of the drug across the blood brain barrier, and wherein the antitumor drug is combined with a PLA-PEG-PLA temperature-sensitive hydrogel for the in situ injection treatment of glioma.
  10. 10. The use according to claim 9, wherein the drug delivery system incorporating the temperature sensitive hydrogel has an antitumor strength 0.5-3 times stronger than the drug delivery system not incorporating the temperature sensitive hydrogel, and wherein the brain glioma comprises astrocytoma, oligodendroglioma and ependymoma.

Description

Temperature-sensitive hydrogel containing doxorubicin-loaded dendrimer as well as preparation method and application thereof Technical Field The invention belongs to the technical field of biomedical materials, and particularly relates to a drug delivery system containing loaded doxorubicin and a preparation method thereof, and application of hydrogel in preparation of a biological material for resisting glioblastoma. Background Brain glioblastoma is a brain cancer with strong invasiveness, poor clinical prognosis, high death rate and high recurrence rate. Patients often have headache, vomiting symptoms, accompanied by mental changes, weakness in the limbs, disturbance of consciousness and speech impairment. The prognosis and treatment strategy for glioblastoma has not changed over the last 20 years by surgical excision of the primary tumor, and then adjuvant radiotherapy and systemic chemotherapy remain the only methods. Surgery and radiation therapy are local treatments that are only effective against tumors at the treatment site and are difficult to deliver effective treatments against potential metastatic lesions and cancers that have developed clinical metastasis. Despite the advances made in current surgery and chemotherapy, the median survival of patients diagnosed with glioblastoma is still only 12-15 months with 5% survival in 5 years. Due to the fine anatomy of the brain and the high invasiveness of glioma cells, complete glioblastoma surgical resection is rarely achieved, and residual glioblastoma infiltrates surrounding brain tissue and is protected by the blood brain barrier, so that the glioblastoma is unresponsive to conventional chemotherapeutic drugs. Thus, research on glioblastoma targeted drug delivery remains one of the most urgent challenges in cancer treatment. In order to solve the problems of the blood brain barrier blocking drug delivery, systemic toxicity of chemotherapeutic drugs and low targeting, development of novel therapeutic methods to promote tumor treatment is highly needed. Studies have shown that drug carriers smaller than 20nm in size are able to penetrate the blood brain barrier unimpeded and have a greater intratumoral permeability. The dendritic polymer has the advantages of uniform size, repeatable cell uptake, pharmacokinetics and the like as a drug carrier. However, the traditional dendritic macromolecule only has functional groups on the outer layer, but has no reactive groups in the available inner space, so that the surface-coupled pharmaceutically active molecules and the like are easy to be degraded by enzymes in the body, and the high drug loading and controllable release of the drug are difficult to realize. Meanwhile, the traditional dendrimer has the size capable of penetrating the blood brain barrier, but can be discharged out of the body through the glomerular filtration membrane, is easy to be quickly cleared by blood and is easy to be enriched in the liver. Polyethylene glycol is usually grafted to dendrimers, so that the dendrimers are not easily metabolized by kidneys to prolong the half-life of the drug. Therefore, the targeting group/the reactive group is introduced into the inner space of the dendrimer with larger size, so that the covalent grafting of the drug can not only avoid the degradation of enzyme, but also penetrate the blood brain barrier and not be discharged out of the body by the glomerular filtration membrane. For this reason, researchers have innovatively proposed charge reversible systems. The system dynamically regulates and controls the charge on the surface of a carrier by responding to tumor microenvironment specific stimuli such as a slightly acidic environment, high-concentration glutathione or specific enzymes, keeps neutral/negative electricity in blood circulation to reduce nonspecific adsorption and liver enrichment, and changes to positive electricity after reaching tumor tissues to enhance the uptake of tumor cells. The charge reversible system is combined with the novel dendritic macromolecule, so that an intelligent delivery platform with multiple functions of long circulation, high targeting, environment response drug release and the like can be constructed, and a brand new idea is provided for breaking through biological barriers in tumor treatment. Therefore, there is a need to develop a drug delivery system that combines structural stability, biocompatibility and functional drug release to enhance tumor treatment. Disclosure of Invention In order to solve the above-mentioned prior art problems or a part thereof, the present invention aims to provide a drug delivery system containing doxorubicin and a preparation method and application thereof, wherein the drug delivery system is used for local administration at a tumor site, realizes sustained release of a drug, completely avoids blood brain barrier, and promotes treatment of an antitumor drug. In order to achieve the above purpose, the present invention adopts t