Targeted drug delivery system against the blood-brain barrier

Abstract

This invention discloses a targeted drug delivery system against the blood-brain barrier. This application identifies a novel drug target, IGF1R, which is highly expressed in the blood-brain barrier but poorly expressed or almost nonexistent in the placental barrier. Based on this target, a drug delivery system was developed. Experimental verification shows that drugs delivered via this system can pass through the blood-brain barrier while significantly reducing drug passage through the placental barrier. This makes it a brain-targeted drug delivery target with safe application during pregnancy and childbirth, ensuring medication safety during pregnancy and showing broad clinical application prospects.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a targeted drug delivery system against the blood-brain barrier. Background Technology

[0002] Because the fetus's metabolic and excretory functions are not fully developed during pregnancy, most drugs can cross the placental barrier and accumulate in the fetus, inevitably causing some impact on the fetus. Studies show that 2% to 3% of birth defects are caused by drugs. Therefore, ensuring medication safety during pregnancy and avoiding adverse effects on the fetus has become an urgent issue.

[0003] The blood-brain barrier (BBB) ​​is a barrier system formed by the close connection between capillary endothelial cells in the brain and their interaction with surrounding pericytes and glial cells. The placental barrier (PB) is a barrier between the uterine sinusoids and placental villi tissue, consisting of the chorionic villi, decidua basalis, and intervillous spaces, protecting the fetus from damage by harmful external substances.

[0004] The placental barrier and blood-brain barrier are crucial for safe drug administration during pregnancy. Therefore, it is essential to find drug delivery targets that can utilize the placental barrier during pregnancy to achieve central nervous system drug delivery without affecting the fetus. Summary of the Invention

[0005] To overcome the shortcomings of existing technologies, this invention provides a targeted drug delivery system against the blood-brain barrier.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: A first aspect of the present invention provides an IGF1R-based targeted drug delivery system, the drug delivery system comprising at least one drug delivery carrier having a surface modified with a specific ligand of IGF1R.

[0007] Furthermore, the specific ligands of the IGF1R include natural ligands and artificial ligands.

[0008] Furthermore, the natural ligands include IGF1 and IGF2.

[0009] Furthermore, the artificial ligand includes a polypeptide that targets IGF1R.

[0010] Furthermore, the specific ligand of the IGF1R is selected from IGF1.

[0011] Furthermore, the drug delivery carrier includes liposome carriers, polymer carriers, and exosome carriers.

[0012] Furthermore, the drug delivery carrier is selected from polymer carriers.

[0013] Furthermore, the method of modifying the surface of the drug delivery carrier with IGF1R specific ligands is carried out through layer-by-layer self-assembly technology.

[0014] Furthermore, the drug delivery carrier is connected to a detectable marker.

[0015] Furthermore, the detectable marker is selected from fluorescent molecules.

[0016] Furthermore, the fluorescent molecule is selected from FITC.

[0017] A second aspect of the invention provides the use of the targeted drug delivery system described in the first aspect of the invention in brain-targeted drug delivery or in the preparation of pharmaceutical compositions for brain-targeted drug delivery.

[0018] Furthermore, brain-targeted delivery drugs include anesthetic drugs and / or drugs for treating neurological diseases.

[0019] A third aspect of the present invention provides the application of IGF1R as a drug delivery target in the preparation of brain-targeted drug delivery systems.

[0020] A fourth aspect of the invention provides the use of IGF1R ligands in the preparation of brain-targeted drug delivery systems that target IGF1R.

[0021] Advantages and beneficial effects of the present invention: This application identifies a novel drug target, IGF1R, which is highly expressed in the blood-brain barrier but poorly or almost absently expressed in the placental barrier. Based on this target, a drug delivery system was developed. Experimental results demonstrate that drugs delivered via this system can cross the blood-brain barrier while significantly reducing drug passage through the placental barrier. This makes it a brain-targeted drug delivery target with safe application during pregnancy and childbirth, ensuring medication safety during pregnancy and showing broad clinical application prospects. Attached Figure Description

[0022] Figure 1 This is a batch effect removal graph for the dataset; Figure 2 This is a graph showing differential gene expression analysis; Figure 3 It is a protein-protein interaction network diagram; Figure 4 It is a biomarker analysis diagram; Figure 5 This is a PPI subnetwork analysis diagram based on biomarkers; Figure 6 This is a graph showing the expression trend of IGF1R; Figure 7This is a graph showing the expression of IGF1R in cerebral vascular endothelium; Figure 8 This is a diagram showing the expression of IGF1R in syncytiotrophoblasts of the placenta; Figure 9 This is a diagram analyzing the brain-targeting capabilities of nanocarriers. Detailed Implementation

[0023] The following provides definitions for some of the terms used in this specification. Unless otherwise stated, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0024] The present invention provides an IGF1R-based targeted drug delivery system, the drug delivery system comprising at least one drug delivery carrier, the surface of which is modified with a specific ligand of IGF1R.

[0025] The specific ligands for IGF1R include natural ligands and artificial ligands.

[0026] In some embodiments, the natural ligands include IGF1 and IGF2; the artificial ligands include peptides targeting IGF1R, and the peptides targeting IGF1R include antibodies and small molecule inhibitors.

[0027] In a preferred embodiment, the specific ligand of the IGF1R is selected from natural ligands.

[0028] In a more preferred embodiment, the natural ligand is selected from IGF1.

[0029] The drug delivery carriers include liposome carriers, polymer carriers, exosome carriers, and other carrier materials commonly used in the art.

[0030] In some embodiments, the liposome carrier includes a base phospholipid material and a functionalized modification material; the base phospholipid material includes neutral phospholipids (such as phosphatidylcholine, synthetic phospholipids) and cationic phospholipids. Phosphatidylcholine (PC) includes lecithin and soybean phospholipids; synthetic phospholipids include dipalmitoylcholine (DPPC), distearatelcholine (DSPC), and myristoylphosphatidylcholine (DMPC). The functionalized modification material includes, but is not limited to, polyethylene glycol (PEG), such as DSPE-MPEG2000.

[0031] In some embodiments, the polymer carrier includes natural polymers (such as dextran, cellulose, chitosan) and synthetic polymers (such as polylactic acid-glycolic acid copolymer (PLGA), polyethylene glycol (PEG), polyvinylpyrrolidone (PVP)).

[0032] In some implementations, the exosome carriers include cell-derived exosomes, such as mesenchymal stem cells (MSCs), blood, milk, etc., which have low immunogenicity; or membrane proteins, such as natural targeting molecules (e.g., CD47).

[0033] In some embodiments, methods for modifying the surface of the drug delivery carrier with specific ligands of IGF1R include, but are not limited to, layer-by-layer self-assembly, chemical bonding, electrostatic adsorption, membrane encapsulation, and other techniques.

[0034] In some embodiments, the drug delivery carrier may encapsulate any known drug, especially drugs that cross the blood-brain barrier, such as anesthetic drugs and drugs for treating neurological disorders.

[0035] In some embodiments, the anesthetic drugs include, but are not limited to, propofol, etomidate, ketamine, thiopental sodium, sodium hydroxybutyrate, and fentanyl.

[0036] In some implementations, neurological disorders include, but are not limited to, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Angelman syndrome, attention deficit hyperactivity disorder, autism spectrum disorder, bipolar disorder, brain damage, brain injury, brain tumor, central pain syndrome, brain atrophy, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, complex regional pain syndrome, Creutzfeldt-Jakob disease, Alzheimer's disease, Down syndrome, Dravet syndrome, encephalitis, essential tremor, Friedreich's ataxia, and Fragile X syndrome. X-syndrome, fragile X-related tremor / ataxia syndrome (FXTAS), head injury, headache, herpes zoster, Huntington's disease, hypoxia, immune-mediated encephalomyelitis, infantile spasms, intracranial hypertension, Lafra disease, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, leukodystrophy, leukoencephalopathy with wasting white matter, Lewy body dementia, lissencephaly, Lyme disease - neurological sequelae, megalencephaly, meningitis, microcephaly, migraine, mini-stroke (transient ischemic attack), motor neuron disease - see amyotrophic lateral sclerosis, multiple infarct dementia, multiple sclerosis, infantile myoclonic encephalopathy, myoclonus, neurological manifestations of AIDS. AIDS, neurological sequelae of lupus, neuronal ceroid lipofuscin deposition disease, neuropathy, Niemann-Pick disease, Ōtahara syndrome, Parkinson's disease, paraneoplastic diseases, primary lateral sclerosis, prions, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, Rasmussen's encephalitis, restless legs syndrome, Rett syndrome, stiff-person syndrome, stroke, transient ischemic attack, traumatic brain injury, tremor, tuberous sclerosis, Unverricht-Lundborg disease, uncinate epilepsy, West syndrome, Wilson's disease.

[0037] The drug delivery carrier is connected to a detectable marker.

[0038] In some embodiments, a detectable marker refers to a composition capable of generating a detectable signal indicating the presence of a target polynucleotide in a sample. Suitable detectable markers include, but are not limited to, radioisotopes, nucleotide chromophores, enzymes, substrates, fluorescent molecules, chemiluminescent components, magnetic particles, and bioluminescent components. Therefore, a marker is any composition detectable by a device or method, including but not limited to spectroscopic, photochemical, biochemical, immunochemical, electrochemical, optical, chemical detection devices, or any other suitable device. In some embodiments, the marker can be detected visually without the aid of a device.

[0039] Among them, radioactive isotopes include but are not limited to 3 H, 14 C 35 S, 125 I, 131 I.

[0040] Enzymes include, but are not limited to, horseradish peroxidase, β-galactosidase, luciferase, alkaline phosphatase, and acetylcholinesterase.

[0041] Fluorescent molecules include, but are not limited to, FITC, rhodamine, and lanthanide phosphors.

[0042] In a preferred embodiment, the detectable label is selected from fluorescent molecules.

[0043] In a more preferred embodiment, the fluorescent molecule is selected from FITC.

[0044] The invention is further illustrated below with reference to specific embodiments. It should be understood that the specific embodiments described herein are by way of example and are not intended to limit the invention. The main features of the invention can be used in various embodiments without departing from the scope of the invention.

[0045] Example 1 Target Screening 1. Online dataset filtering 1.1 Public Dataset Placental barrier sequencing data: The main barrier through which substances are exchanged between the mother and fetus is the syncytiotrophoblast. Therefore, this project uses the GSE217210 dataset as placental barrier sequencing data, and the samples mainly include human primary syncytiotrophoblast cells.

[0046] Blood-brain barrier sequencing data: The blood-brain barrier is mainly composed of cerebral vascular endothelium, perithelial cells, and astrocytes. This project uses the GSE195519 dataset as the blood-brain barrier sequencing data. The samples mainly include induced pluripotent stem cells (iPSCs), iPSC-derived brain microvascular endothelial cell-like cells (iBMECs), iPSC-derived pericyte-like cells (iPCs), primary human dermal microvascular endothelial cells (HDMECs), and iPSC-derived endothelial cells (iECs).

[0047] 2. Data Processing 2.1 Data Filtering Primary syncytiotrophoblast cells from the GSE217210 dataset were used as placental barrier samples. All drug-treated groups were removed, and only control group primary syncytiotrophoblast cell samples without any drug treatment were selected. All blood-brain barrier-related cells from the GSE195519 dataset were used as blood-brain barrier samples. Two cytokine-treated cell samples were removed, and all other untreated cell samples were selected. Furthermore, to effectively remove batch effects, the FPKM-normalized data were converted to TPM data using a formula to maintain consistency with GSE217210.

[0048] 2.2 De-batch effect SVA was used to remove batch effects based on merged datasets. After the removal process, principal component analysis was performed again to confirm the effectiveness of the batch removal. Figure 1 ).

[0049] 3. Differential Expression Analysis This project used limma, based on its Voom algorithm to standardize TPM data, then constructed a linear model and corrected it using empirical Bayesian methods. Finally, differential gene expression analysis was performed, and graphs were generated using ggplot2 and ComplexHeatmap. The two datasets showed differential expression of 1311 genes, of which 715 were significantly upregulated and 596 were significantly downregulated. Figure 2 ).

[0050] 4. Biomarker screening Further, from over 1000 differentially expressed genes, more important biomarkers were identified. Based on these differentially expressed genes, this project explored the interactions between gene-expressed proteins using the STRING database, obtaining protein-protein interaction data and visualizing the protein-protein interaction network (PPI) using Cytoscape. Figure 3 ).

[0051] Subsequently, using Cytoscape-Cytohubba, based on the PPI network, the importance of all nodes in the network was evaluated using four network topology algorithms: Degree Centrality, EcCentricity, Closeness, Maximum Neighborhood Component (MNC), and Density of Maximum Neighborhood Component (DMNC). The top 30 results from all algorithms were combined to identify the nodes considered important by all algorithms, thus completing the identification of the biomarker. Finally, a subnetwork containing the biomarker and its neighboring nodes was constructed for visualization purposes. Figure 4 , Figure 5 ).

[0052] The final screening identified six key molecules (green nodes): PTPRC, H4C6, ESR1, POU5F1, PXDNL, and IGF1R. PTPRC and IGF1R are membrane proteins, PXDNL is located in the cytoplasm, and the other three are nuclear proteins. The remaining nodes are those that directly interact with the biomarkers.

[0053] 5. Analysis of expression trends of biomarkers Based on the biomarkers obtained through screening, IGF1R was highly expressed in brain microvascular endothelial cell-like cells (iBMEC) and iPSC-derived pericyte-like cells (iPC) in the blood-brain barrier, but almost not expressed in human primary syncytiotrophoblast cells in the placental barrier. Figure 6 ).

[0054] Therefore, IGF1R is highly expressed in the blood-brain barrier but almost not expressed in the placental barrier. Drugs targeting IGF1R can greatly reduce the passage of drugs across the placental barrier, making it a brain-targeted drug delivery target with safe application during pregnancy and childbirth.

[0055] 2. Clinical sample validation Clinical samples were collected to study IGF1R in blood-brain barrier and placental barrier samples, and it was found that IGF1R was highly expressed in cerebral vascular endothelium. Figure 7 IGF1R expression is low in syncytiotrophoblasts of the placenta. Figure 8 Differential expression analysis showed that IGF1R was significantly highly expressed in blood-brain barrier tissues and had high diagnostic efficacy.

[0056] Example 2: Designing a drug delivery system using target sites 1. Nanoparticle (NP) preparation and property detection 1.1 Preparation 1) The brain-targeting functional molecule insulin-like growth factor 1 (IGF1) was encapsulated onto a polymer carrier (polylactic acid polymer carrier) using the principle of layer-by-layer self-assembly. The amount of IGF1 encapsulated was determined using a BCA protein concentration assay kit.

[0057] 2) FITC-coupled nanoparticles Fluorescence spectroscopy was used to determine the excitation and emission wavelengths for subsequent quantitative fluorescence determination of the nanoparticle concentration.

[0058] Plot a standard curve for FITC with the concentration of the FITC standard on the x-axis and the OD value at 470 nm on the y-axis, and calculate the labeling rate of FITC.

[0059] 1.2 Nanoparticle Characterization Particle size and zeta potential were measured, morphology was examined by electron microscopy, and stability at different pH, temperature, storage, and serum was observed.

[0060] 1) Characterization of the size and potential of self-assembled nanoparticles: The hydrodynamic diameter, polydispersity index and zeta potential of the nanoparticles were determined by a particle size and zeta potential analyzer.

[0061] 2) Scanning electron microscopy-X-ray energy dispersive spectroscopy experiments were used for morphological observation and elemental distribution scanning and quantitative analysis of carbon (C), oxygen (O), cerium (Ce), and zirconium (Zr).

[0062] 3) Observe the microstructure, particle size and dispersion of nanoparticles using transmission electron microscopy.

[0063] 4) Characterization using infrared spectroscopy.

[0064] 5) Serum stability study: The stability of the formulation in serum was evaluated using the FRET test.

[0065] 6) In vitro drug release experiments calculate the cumulative drug release rate at preset time points.

[0066] 7) Drug loading and release: Encapsulation efficiency (EE) (%) = (mass of encapsulated drug) / (mass of drug feed) × 100% Drug loading rate LC (%) = (mass of drug loaded) / (total mass of drug-loaded liposomes) × 100%.

[0067] The in vitro release kinetics of nanomedicines were investigated using dialysis.

[0068] 2. In vitro biological evaluation of brain-targeted anesthetic drug nanoparticles 2.1 In vitro safety: including cytotoxicity and blood-brain barrier integrity. 2.1.1 Cell Culture The study used mouse neural cells PC12, mouse brain vascular endothelial cells bEnd.3, and human choriocarcinoma cells (BeWo) as research cells. The cells were obtained from the Cell Resource Center of the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, and the National Experimental Cell Resource Sharing Platform (Beijing Headquarters).

[0069] 2.1.2 In vitro safety evaluation of nanocarriers – cytotoxicity 1) CCK assay for the effect on cell proliferation in vitro 2) Flow cytometry detection of in vitro effects on apoptosis 2.2 Study on the mechanism of cellular nanoparticle uptake Fluorescent nanoparticles were constructed, and their cellular uptake and uptake mechanism were studied using fluorescence microscopy and flow cytometry.

[0070] 2.2.1 Qualitative detection of cellular uptake Cells were seeded in 24-well plates, incubated, and allowed to adhere before the culture medium was discarded. Free fluorescein isothiocyanate (FITC) and FITC-labeled nanoparticles were added, followed by incubation, fixation, and nuclear staining. Cell uptake was then observed under a fluorescence microscope.

[0071] 2.2.2 Study on factors influencing cellular uptake: concentration / temperature and time dependence 2.2.3 Study on cellular uptake mechanism – receptor binding experiment Qualitative study: To further verify the mechanism of nanoparticle uptake by cells, cells were pretreated with different inhibitors. FITC-NP was added, and changes in cell fluorescence within 120 min were detected using confocal microscopy live-cell imaging.

[0072] Quantitative study: Cells were seeded in 6-well plates, and inhibitors of different cell entry pathways were added for further culture. After washing with PBS, culture medium containing FITC-labeled nanocarriers was added and incubated for 2 h. Cells were collected and fluorescence intensity was detected by flow cytometry. The control group did not undergo inhibitor pretreatment.

[0073] 2.3 Blood-brain barrier and placental barrier transport rates 2.3.1 Constructing the blood-brain barrier An in vitro BBB cell model was constructed using bEnd.3 cells and PC12 cells to observe whether NPs could cross the blood-brain barrier.

[0074] 2.3.2 Constructing the placental barrier A trophoblast monolayer model was established using Bewo cells to observe whether NPs could enter the fetus through the maternal-fetal interface.

[0075] 2.3.3 Blood-brain barrier transport rate An in vitro BBB model was established using a Transwell chamber assay, and the fluorescence level of cells in the lower chamber was measured to evaluate the in vitro BBB permeation effect of nanoparticles. PC12 cells from the lower chamber were collected, and cell fluorescence levels were detected by flow cytometry.

[0076] 2.3.4 Placental barrier transport rate After cell monolayer formation, FITC-labeled nanocarriers of different concentrations were added. Based on the FITC concentration versus fluorescence intensity standard curve, carrier transport and cellular uptake were calculated, and transport and uptake efficiency were evaluated.

[0077] 3. In vivo experiments 3.1 Experimental Grouping Experimental mice were grouped as follows: ①FITC ②FITC-drug ③FITC + empty nanoparticles ④FITC + drug-loaded nanoparticles. Intervention began on day 19.5 of gestation.

[0078] 3.2 Pharmacokinetics (PK) and Tissue Distribution 3.2.1 Tissue distribution of drug-loaded NP in pregnant mice Fluorescent nanoparticles were constructed, and the in vivo distribution of the drug was studied by using fluorescence intensity images of live and ex vivo mouse organs captured by a small animal in vivo imaging system, in order to evaluate the brain targeting ability of the nanoparticles.

[0079] 3.2.2 Pharmacokinetics and Off-Target Risk Assessment of Drug-Loaded NP in Pregnant Rats Compare drug distribution in the brains of live and isolated female mice with other organs (heart, liver, spleen, lungs and kidneys, placenta), and in offspring mice (brain, heart, liver, spleen, lungs and kidneys).

[0080] 3.3 In vivo targeting validation—Evaluating active targeting based on a mouse brain IGF1R conditional knockout model 3.3.1 Construction and evaluation of a conditional knockout model of IGF1R in mouse brain A conditional knockout (CKO) model of IGF1R in the mouse brain was constructed using the Cre-loxp system. The CKO model was validated at the protein level using Western blot experiments.

[0081] 3.3.2 Evaluation of NP's in vivo brain targeting ability A mouse brain IR conditional knockout model was constructed based on the Cre-loxp system to further evaluate the brain targeting and mechanism of NP in vivo.

[0082] 3.4 Safety assessment: Acute, chronic, immunotoxic, and neurotoxic effects. 3.4.1 HE and Nissl staining to evaluate the neuroprotective effect of nanoparticles 3.4.2 Hematological and serum biochemical markers in mice Evaluation of blood routine and liver and kidney indicators in mice after tail vein injection.

[0083] 3.4.3 The biosafety of nanoparticles was assessed through changes in body weight and HE staining of major organs. To evaluate the biosafety of this formulation, mice were weighed after administration, and their general condition, including coat color, mental state, activity level, food intake, and water intake, as well as symptoms of poisoning and mortality, were recorded. Mice were sacrificed 24 hours after administration, and major organs (brain, heart, liver, spleen, lungs, and kidneys) from both mother and offspring, as well as placental tissue from the mother, were collected. After fixation, paraffin embedding, sectioning, and staining with hematoxylin and eosin, the tissues were observed under a light microscope to assess the lesions in each organ.

[0084] 3.4.4 Offspring Neurobehavioral Experiments Comparing the brain development processes of humans and mice reveals that the brain development of mice at 5-7 days after birth is comparable to that of full-term newborns; at 7-14 days, it is close to that of infants of a few months old; at 5-18 days, it is comparable to that of 1-year-old children; and at 28-30 days, it is comparable to that of 2-year-old children. Therefore, different time points were selected in different experiments to assess the neurobehavioral development of offspring: the righting test, negative ground attraction test, and cliff avoidance test were performed on the 5th and 7th days after birth, respectively, and the open field test was performed on the 9th, 13th, 15th, and 17th days after birth to assess the neurobehavioral development of mice.

[0085] 3.4.5 Hemolytic activity assessment Take a suspension of red blood cells. Add NP solution to the red blood cell suspension, gently shake to mix, incubate, centrifuge, and observe the color of the supernatant. After the red blood cells lyse, they will release heme. Measure the absorbance at 540 nm.

[0086] 4. Experimental Results This application successfully constructed nanoparticles encapsulating the brain-targeting functional molecule insulin-like growth factor 1 (IGF1). The nanoparticles have uniform particle size and high affinity for IGF1R. They exhibit good stability in vitro and in serum. In vitro and in vivo experiments showed that the nanoparticles actively target rat primary brain microvascular endothelial cells (BMECs) and mouse brains through IGF1R mediation, significantly increasing the blood-brain barrier transport rate and significantly reducing the transport rate at the placental barrier, thus achieving the goal of safe application during pregnancy and childbirth.

[0087] Thirty minutes after injection of the nanoparticles, the fluorescence signal in the brains of mice in the IGF1-NP group was the strongest, significantly higher than that in the NP group. Furthermore, no significant fluorescence was observed in the abdomen of the IGF1-NP group within 6 hours after injection, while fluorescence was observed in both the brain and abdomen of the NP group, with no significant fluorescence accumulation in the brain. Figure 9 ).

[0088] The above description of the embodiments is only for understanding the method and core ideas of the present invention. It should be noted that those skilled in the art can make various improvements and modifications to the present invention without departing from the principles of the invention, and these improvements and modifications will also fall within the protection scope of the claims of the present invention.

Claims

1. A targeted drug delivery system based on IGF1R, characterized in that, The drug delivery system includes at least one drug delivery carrier, the surface of which is modified with a specific ligand of IGF1R.

2. The targeted drug delivery system according to claim 1, characterized in that, The specific ligands for IGF1R include natural ligands and artificial ligands.

3. The targeted drug delivery system according to claim 2, characterized in that, The natural ligands include IGF1 and IGF2; Preferably, the artificial ligand comprises a polypeptide targeting IGF1R; Preferably, the specific ligand of the IGF1R is selected from IGF1.

4. The targeted drug delivery system according to claim 1, characterized in that, The drug delivery carriers include liposome carriers, polymer carriers, and exosome carriers.

5. The targeted drug delivery system according to claim 4, characterized in that, The drug delivery carrier is selected from polymer carriers.

6. The targeted drug delivery system according to claim 1, characterized in that, The method of modifying the surface of drug delivery carriers with IGF1R-specific ligands involves layer-by-layer self-assembly technology.

7. The targeted drug delivery system according to claim 1, characterized in that, The drug delivery carrier is connected to a detectable marker; Preferably, the detectable label is selected from fluorescent molecules; Preferably, the fluorescent molecule is selected from FITC.

8. The use of the targeted drug delivery system according to any one of claims 1-7 in brain-targeted drug delivery or in the preparation of a pharmaceutical composition for brain-targeted drug delivery; Preferably, the brain-targeted delivery of drugs includes anesthetic drugs and / or drugs for treating neurological diseases.

9. Application of IGF1R as a drug delivery target in the preparation of brain-targeted drug delivery systems.

10. Application of IGF1R ligands in the preparation of brain-targeted drug delivery systems that target IGF1R.

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