Target tracing multi-mode diagnostic nano imaging medicine

A multi-mode, imaging technology, applied in pharmaceutical formulations, preparations for in vivo experiments, MRI/MRI contrast agents, etc., to achieve high resolution, rich physiological and pathological information, and good thermodynamic stability

Inactive Publication Date: 2013-05-29
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 transversal BBB polypeptide angiopep-2

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

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

[0060] 2. Continuously use TFA (trifluoroacetic acid) to deprotect twice, add the amount to the immersion resin, stir for 1 minute each time, and wash with DMF several times;

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

Embodiment 2

[0068] Example 2 Synthesis of Compound 1

[0069] 2.1mg(6.8×10 -6 mol, 1.3 times) SPDP (N-succinimidyl 3-(2-pyridyl dithio) propionate was dissolved in 300 μL of DMF, and was slowly added dropwise to 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 45 minutes of reaction at room temperature, a PEG derivative with maleimide at one end and 3-(2-pyridyldithio)propionate at the other end was formed.

Embodiment 3

[0070] Example 3 Synthesis of Compound 2

[0071] Add the above reaction solution directly to 1.0mL of 11.6mg (4×10 -7 mol) of the dendrimer PAMAM G5 in 1X PBS (pH 7.4 ~ 8.0) solution. After stirring for 1 hour at room temperature, compound 2 was formed, in which SPDP was connected to the surface of G5 dendrimer via PEG. The target product was obtained by centrifugal purification (4000 rpm, 30 minutes × 3 times) with a membrane ultrafiltration tube with a molecular weight of 10,000 Da. The molar ratio between G5 and PEG is determined by compound 2 1 Calculate by integrating the protons in the H NMR spectrum. The labeling level of SPDP in compound 2 was quantified by DTT (dithiothreitol) experiment. The simplified operation process is: adding excess DTT to the PBS solution of compound 2, stirring for 15 minutes, and measuring the absorbance of the above solution at 343 nm. The molar ratio between SPDP and G5 is determined by the formula R=ΔA 343 / 8080×C dendrimer To calculate,...

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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, and relates to a nano-imaging medicine, in particular to a multi-mode diagnostic nano-imaging medicine with targeted tracking. The invention includes the synthesis and characterization of fluorescent / magnetic multi-mode nano-medicine, in vitro cytotoxicity detection, cancer cell endocytosis efficiency, in vivo receptor-mediated evaluation of the function of crossing the blood-brain barrier, and the passive effect of nano-imaging medicine on in situ brain tumors And active receptor-mediated targeting efficiency, and its application in the process of multi-modal tracing of brain tumors. Background technique [0002] Brain glioma is the most common (69% of the total incidence) and the most fatal (average 5-year survival rate of 5%) of brain tumors. It has the characteristics of high malignancy and high recurrence. Surgical resection is currently the main method for the treatment of glioma. Howev...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K49/06A61K49/00A61K49/14A61K49/12
Inventor 李聪严蕙蕙高西辉魏勋斌
Owner FUDAN UNIV
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