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CN-122005559-A - Application of thalidomide and drug-loaded nanogel thereof in preparation of drugs for treating ischemic cerebral apoplexy

CN122005559ACN 122005559 ACN122005559 ACN 122005559ACN-122005559-A

Abstract

The invention discloses application of thalidomide in preparation of a medicament for treating ischemic stroke, and a thalidomide medicament-carrying nano gel, a preparation method and application thereof. The drug-loaded nanogel comprises a polyacrylic acid skeleton, thalidomide loaded on the polyacrylic acid skeleton, and three functional polypeptides, namely transferrin coupled with the skeleton, microglial cell targeting peptide and pH low insertion peptide. According to the invention, through the synergistic effect of the three polypeptides, the nanogel penetrates through the blood brain barrier, precisely targets microglial cells in an ischemic region, and responsively releases thalidomide in an acidic microenvironment. In-vitro experiments show that the nano gel can effectively inhibit the expression of microglial inflammatory factors, and in-vivo experiments show that the nano gel can obviously reduce cerebral infarction volume, protect blood brain barrier, improve the nerve function and cognitive behavior of model animals and improve survival rate. The invention provides an accurate and efficient drug delivery platform for treating ischemic stroke.

Inventors

  • LI RAN
  • HUANG YIMIN
  • XIA YUZE

Assignees

  • 华中科技大学同济医学院附属同济医院

Dates

Publication Date
20260512
Application Date
20260302

Claims (10)

  1. 1. Use of thalidomide in the preparation of a medicament for the treatment of ischemic stroke.
  2. 2. The use of claim 1, wherein the medicament exerts a therapeutic effect by targeted inhibition of inflammatory factor expression or activity of microglial cells in the ischemic region of the brain.
  3. 3. A drug loaded nanogel of thalidomide, characterized in that the drug loaded nanogel comprises: (a) A polyacrylic acid backbone; (b) Thalidomide supported on the polyacrylic acid skeleton, and (C) Three functional polypeptides coupled to the polyacrylic acid backbone, including transferrin, microglial targeting peptides, and pH low insertion peptides.
  4. 4. The drug-loaded nanogel of claim 3, wherein the transferrin, microglial targeting peptide and pH low insertion peptide are present in a molar ratio of (1-5): 1-5.
  5. 5. The drug-loaded nanogel of claim 3, wherein the polyacrylic acid backbone is covalently coupled to the amino groups of the three functional polypeptides through the carboxyl groups thereof to form amide bonds under EDC and NHS catalysis.
  6. 6. The drug-loaded nanogel of claim 3, wherein the particle size of the drug-loaded nanogel is 10-50 nm and/or the Zeta potential of the drug-loaded nanogel is-30 to-10 mV.
  7. 7. A method for preparing the drug-loaded nanogel according to any one of claims 3 to 6, comprising the steps of: (1) Polyacrylic acid is dissolved in water, transferrin, microglial targeting peptide and pH low insertion peptide are sequentially added, and coupling reaction is carried out under the catalysis of EDC and NHS; (2) Dialyzing and freeze-drying the reaction product to obtain polypeptide modified blank nanogel; (3) Mixing the blank nanogel obtained in the step (2) with thalidomide and CaCl 2 , stirring, adding Na 2 CO 3 , continuously stirring, and loading thalidomide through mineralization.
  8. 8. The method of claim 7, wherein the polyacrylic acid has a molecular weight of 1000-3000, and the coupling reaction is carried out under stirring at room temperature for 20-30 hours.
  9. 9. A pharmaceutical composition comprising the drug-loaded nanogel of any one of claims 3-6 and a pharmaceutically acceptable carrier or adjuvant.
  10. 10. Use of a drug-loaded nanogel according to any one of claims 3 to 6 or a pharmaceutical composition according to claim 9 in the manufacture of a medicament for the treatment of ischemic stroke.

Description

Application of thalidomide and drug-loaded nanogel thereof in preparation of drugs for treating ischemic cerebral apoplexy Technical Field The invention belongs to the field of biological medicine, relates to a new pharmaceutical application of thalidomide, in particular to a new application of thalidomide in preparation of a medicine for treating ischemic cerebral apoplexy, and also relates to a medicine-carrying nano gel of thalidomide, a preparation method and an application thereof. Background Ischemic stroke (Ischemic Stroke, IS) IS one of the leading diseases worldwide leading to disability and death, with its incidence rising year by year. Current treatments for acute IS, including intravenous thrombolysis and intravascular treatment, are limited by a narrow treatment window (typically within 4.5 hours) and various contraindications, resulting in poor prognosis for many patients. Recent studies have found that neuroinflammation plays a critical role in the development and progression of ischemic stroke. After ischemia, resident immune cells of the central nervous system, microglia, are rapidly activated. Moderate activation helps to clear damaged debris and repair tissue, but excessive or sustained activation results in polarization of microglia to the pro-inflammatory phenotype (M1 type), releasing large amounts of pro-inflammatory factors such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and Inducible Nitric Oxide Synthase (iNOS). These pro-inflammatory factors not only exacerbate neuronal damage directly, but also disrupt the integrity of the Blood-Brain Barrier (BBB), causing infiltration of peripheral immune cells, forming a vicious circle, ultimately exacerbating acute and long-term Brain damage. Single cell RNA sequencing (scRNA-seq) studies also demonstrated the presence of significant expansion of specific Tnf expressing microglial cell subsets (e.g., subset 2) following ischemia, these cells being major contributors to early neuroinflammation. Therefore, inhibition of early microglial activation in ischemic regions, particularly targeting these pro-inflammatory subgroups, is expected to be an effective strategy for treating ischemic stroke. Thalidomide (Thalidomide) is a glutamic acid derivative that was initially withdrawn due to severe teratogenicity and later re-used for treatment of leprosy nodular erythema and multiple myeloma where the benefits far outweigh the risk of adverse events due to its immunomodulatory and anti-inflammatory properties. One of its mechanisms of action is to bind TNF- α mRNA, inhibiting its transcription and expression. Despite the clear anti-inflammatory potential of thalidomide, its use in the treatment of ischemic stroke, in particular in regulating microglial activation, is still less studied. The direct application of the drug to the central nervous system diseases faces two major challenges, namely that the existence of a blood brain barrier limits the drug to enter brain parenchyma, and that systemic administration can cause off-target effects and cause side effects. In recent years, the development of nano-drug delivery systems has provided new ideas to overcome the above-mentioned challenges. Polyacrylic acid (Poly (acrylic acid), PAA) is an ideal material for preparing responsive nanogels due to its good biocompatibility and pH sensitivity. By functional modification, the nanogel can be endowed with active targeting capability. For example, transferrin (TF) binds to its receptor (TfR) that is highly expressed on blood brain barrier endothelial cells, mediating receptor-mediated transcytosis, thereby achieving drug delivery [1-2] across the blood brain barrier. In addition, polypeptides targeting specific cell types, such as polypeptide MG1, which can specifically bind inflammation-associated microglia, can achieve accurate delivery [3-5] at the cellular level. Hypoxia and acidic microenvironment created by the ischemic region also provide conditions [6-7] for focal site-specific release using pH-sensitive delivery systems (e.g., pH low-intercalating peptides, pHLIP). However, there is currently no multifunctional nano-platform for ischemic stroke that can simultaneously achieve blood brain barrier penetration, microglial cell specific targeting and focal microenvironment responsive release. Reference is made to: 1.S.J. Barker, M.B. Thayer, C. Kim, et al. Targeting the transferrin receptor to transport antisense oligonucleotides across the mammalian blood-brain barrier. Sci Transl Med.16(760) (2024). 2.D. Xu, T. Qiao, Y.M. Zhou, X.Y. Wu, Y.L. Cui, A brain-targeted and ROS-responsive natural polysaccharide nanogel for enhancing antidepressant therapy, Chem Eng J 507 (2025). 3.T. Terashima, N. Ogawa, Y. Nakae, T. Sato, et al. Gene Therapy for Neuropathic Pain through siRNA-IRF5 Gene Delivery with Homing Peptides to Microglia, Mol Ther-Nucl Acids 11 (2018) 203-215. 4.Y. Lu, S. Liu, P. Wang, X. Guo, Z. Qin, H. Hou, T. Tao, A novel micr