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Cross-blood-brain-barrier targeting multimodal nano-medicine used in brain tumor diagnosis

A nano-drug, multi-modal technology, which is applied in the multi-modal nano-drug targeting across the blood-brain barrier, the synthesis of magnetic/fluorescent nano-diagnostic drugs and their intermediates, and the application in in vivo non-invasive brain tumor multi-modal imaging , In the field of diagnostic drugs, it can solve the problems that have not yet been reported on multimodal nanodiagnostic drugs with cross-BBB secondary targeting, and achieve the best tumor tracing effect and improve the effect of targeting efficiency.

Inactive Publication Date: 2013-05-08
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] So far, there are no reports of multimodal nanodiagnostic drugs with secondary targeting across the BBB

Method used

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  • Cross-blood-brain-barrier targeting multimodal nano-medicine used in brain tumor diagnosis
  • Cross-blood-brain-barrier targeting multimodal nano-medicine used in brain tumor diagnosis
  • Cross-blood-brain-barrier targeting multimodal nano-medicine used in brain tumor diagnosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Synthesis of Cysteine-modified Polypeptide Angiopep-2

[0056] In order to connect Angiopep-2 to G5 without affecting the specificity of receptor binding, we synthesized Angiopep-2 modified with a cysteine ​​residue at the C-terminus by Boc-protected solid-phase peptide synthesis method: TFFYGGSRGKRNNFKTEEYC( MW = 2402 Da). The resulting entire protected linear peptide chain is

[0057] H-Thr(Bzl)-Phe-Phe-Tyr(Br-Z)-Gly-Gly-Ser(Bzl)-Arg(Tos)-Gly-Lys(Cl-Z)-Arg(Tos)-Asn(Xan) -Asn(Xan)-Phe-Lys(Cl-Z)-Thr(Bzl)-Glu(OcHex)-Glu(OcHex)-Tyr(Br-Z)-Cys(PMeBzl)-OH. Deprotected with HF, purified by preparative HPLC, lyophilized. The purity of the product was confirmed by analytical HPLC. There is a single peak at 802.5 [M3+] in ESI-MS with a calculated molecular weight of 2404.6 [M+H+]. ESI-MS and analytical HPLC results are attached figure 1 , 2 . C-Angiopep-2 1 See attached for H NMR spectrum image 3 .

Embodiment 2

[0059] Synthesis of compound 1

[0060] 3.5mg (1.0×10 -5 mol)c[RGDyK] cyclic peptide was dissolved in 300 μL of DMF, and 6 μL of triethylamine was added to mix well. Quickly add 300 μL of 8.2 mg (4.1×10 -6 mol) maleimide-PEG 2k -N-hydroxysuccinimide ester (Malemide-PEG 2k -NHS) in DMF solution. After stirring and reacting at room temperature for 2 hours, a PEG derivative of c[RGDyK] cyclic peptide was formed.

Embodiment 3

[0062] Synthesis of compound 2

[0063] The above reaction solution was directly added to 1.0mL containing 11.6mg (4×10 -7 mol) of dendrimer G5 in 1X PBS (pH 7.4) solution. After stirring at room temperature for 1 h, compound 2 was formed, which was purified by ultrafiltration (4000 rpm, 30 min×3) using a centrifugal filter tube with a molecular weight of 10 kDa. The molar ratio between G5, PEG and RGD is determined by their concentration in compound 2 1 The integral in the H NMR spectrum is calculated. About 6 c[RGDyK] cyclic peptides were labeled on each G5 molecule. Compound 2 1 See attached for H NMR spectrum Figure 4 .

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Abstract

The invention belongs to the field of imaging medicines, and relates to a cross-blood-brain-barrier (cross-BBB) targeting multimodal nano-medicine used in brain tumor diagnosis. The invention especially relates to the synthesis of magnetic / fluorescent nano-diagnostic medicines with cross-BBB receptor active targeting effect and intermediate thereof. The invention also relates to an application of the medicine and the intermediate in living noninvasive brain tumor multimodal imaging. The multimodal nano-diagnostic medicine provided by the invention is respectively marked with tumor new vessel targeting group, cross-BBB transporting group, and magnetic and optical imaging group. The medicine is first targeted to tumor peripheral new vessels, then is delivered into brain with a receptor-mediated cross-BBB transportation effect, and is secondarily targeted to tumor cells. With magnetic resonance imaging / optical multimodal imaging techniques, and with the medicine, noninvasive high SNR tracing of brain tumor and especially BBB-undamaged brain tumor can be realized. The medicine provided by the invention can provide a novel reference approach for brain tumor preoperative localization and brain tumor resection under real-time image guidance.

Description

technical field [0001] The invention belongs to the field of imaging medicine and relates to diagnostic medicine, in particular to a cross-blood-brain-barrier targeted multimodal nanomedicine for the diagnosis of brain tumors, especially a magnetic / fluorescent nano-diagnosis with active targeting across BBB receptors Synthesis of drugs and their intermediates, and their application in non-invasive multimodal imaging of brain tumors in vivo. Background technique [0002] Brain tumors are tumors that occur in the neuroectoderm, which have the characteristics of high incidence, recurrence rate, high mortality rate and low cure rate. Glioma is the most common primary brain tumor (accounting for 69% of all intracranial tumors), and it is also the deadliest type of brain tumor (average 5-year survival rate is 5%). At present, the treatment of glioma is a recognized problem in the world. Surgical resection is the main method in the treatment of glioma. However, due to the diffus...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K49/12A61K49/18A61K49/00A61K49/14
Inventor 李聪高西辉严蕙蕙
Owner FUDAN UNIV
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