Target tracing multi-mode diagnostic nano imaging medicine

A multi-modal, imaging technology, applied in pharmaceutical formulations, preparations for in vivo experiments, MRI/MRI contrast agents, etc., to achieve high resolution, enrich physiological and pathological information, and overcome the limitations of sensitivity or resolution Effect

Inactive Publication Date: 2012-04-11
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] There are no reports about nanoprobes labeled with optical and paramagnetic bifunctional imaging moieties using angiopep-2 as the BBB spanning moiety

Method used

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  • Target tracing multi-mode diagnostic nano imaging medicine
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  • Target tracing multi-mode diagnostic nano imaging medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1 Synthesis of cysteine-modified cross-BBB polypeptide angiopep-2

[0058] In order to modify angiopep-2 with BBB crossing ability to G5 dendrimer without affecting its binding specificity to low-density lipoprotein-associated receptors, a C-terminal modification was synthesized by Boc-protected solid-phase peptide synthesis Angiopep-2 with one cysteine ​​residue: TFFYGGSRGKRNNFKTEEYC (MW = 2402 Da).

[0059] 1. Weigh 0.156g Boc-L-Cys(pMeBzl)-PAM resin (degree of substitution 0.8mmol / g, about 0.125mmol), swell with DMF (N,N-dimethylformamide) for 20 minutes, and wash several Second-rate;

[0060] 2. Deprotect with TFA (trifluoroacetic acid) twice continuously, add the amount until the resin is submerged, stir for 1 minute each time, and wash with DMF several times;

[0061] 3. Weigh 1.1mmol of the required amino acid, and use 2ml of HBTU (benzotriazole-N, N, N', N'-tetramethyluronium hexafluorophosphate) and 0.5ml of DIEA (N, N- Diisopropylethylamine) was dis...

Embodiment 2

[0068] The synthesis of embodiment 2 compound 1

[0069] 2.1mg (6.8×10 -6 mol, 1.3 times) of SPDP (N-succinimidyl 3-(2-pyridyl dithio)propionate was dissolved in 300 μL of DMF, and slowly added dropwise to 1.0 mL of 1.0 mL of 10.4 mg (5.2 ×10 -6 mol, the molecular weight is considered to be 2KDa) NH 2 -PEG 2k -Malemide (amino-polyethylene glycol 2k -maleimide) in 1X PBS (pH 7.4) solution. After reacting at room temperature for 45 minutes, a PEG derivative with maleimide at one end and 3-(2-pyridyldithio)propionate at the other end was formed.

Embodiment 3

[0070] The synthesis of embodiment 3 compound 2

[0071] The above reaction solution was directly added to 1.0 mL of 11.6 mg (4×10 -7 mol) of dendrimer PAMAM G5 in 1X PBS (pH 7.4-8.0) solution. After stirring at room temperature for 1 hour, compound 2 was formed, in which SPDP was linked to the surface of G5 dendrimer through PEG. The target product was obtained by centrifugation and purification (4000 rpm, 30 minutes x 3 times) with a filter membrane ultrafiltration tube with a molecular weight of 10,000 Da. The molar ratio between G5 and PEG was determined by the 1 The proton integrals in the H NMR spectrum were calculated. The labeling level of SPDP in compound 2 was quantified by DTT (dithiothreitol) assay. The simplified operation process is as follows: excess DTT is added to the PBS solution of compound 2, stirred for 15 minutes, and the absorbance of the above solution at 343 nm is measured. The molar ratio between SPDP and G5 is given by the formula R=ΔA 343 / 808...

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Abstract

The invention belongs to the technical field of medical diagnostic medicine and relates to a target tracing multi-mode diagnostic nano imaging medicine. The invention uses G5 as probe carrier to optimize blood circulation time and passive targeting of the target imaging medicine, marks near-infrared fluorescent group and Gd-DOTA paramagnetic group on G5 dendritic macromolecule, and links angiopep-2 polypeptide and G5 dendritic macromolecule by dual-functional polyethylene glycol PEG to make the nano imaging medicine with blood brain barrier overcoming ability and marked with optical and magnetic dual-functional imaging groups. PEG chain in the invention not only improves water solubility of nano probe and its blood circulation time, but also reduces the influence of steric hindrance of the dendritic macromolecule to the blood brain barrier overcoming ability of the angiopep-2 peptide chain. The medicine of the invention can be used to noninvasive dynamic tracing of in-situ cerebral gliomas and can have excellent target tracing function to neuroglioma when the blood brain barrier is not destroyed.

Description

technical field [0001] The invention belongs to the field of medical diagnostic drugs, relates to nano-imaging drugs, in particular to a multi-mode diagnostic nano-imaging drug for target tracing. The invention includes the synthesis and characterization of fluorescent / magnetic multimodal nano-medicines, in vitro cytotoxicity detection, cancer cell endocytosis efficiency, in vivo receptor-mediated cross-blood-brain barrier function evaluation, and the passive effect of nano-imaging drugs on orthotopic brain tumors. and active receptor-mediated targeting efficiency, as well as its application in multimodal tracking of brain tumors. Background technique [0002] Brain glioma is the most common (69% of the total incidence) and deadliest (average 5-year survival rate is 5%) type of brain tumor, which is characterized by high malignancy and high recurrence. Surgical resection is currently the most important method for the treatment of glioma. However, due to the diffuse and inf...

Claims

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Application Information

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IPC IPC(8): A61K49/06A61K49/00A61K49/14A61K49/12
Inventor 李聪魏勋斌严蕙蕙
Owner FUDAN UNIV
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