CN107899027A - Neuroendocrine tumor targeted nano-particle developer and preparation method and application - Google Patents
Neuroendocrine tumor targeted nano-particle developer and preparation method and application Download PDFInfo
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- CN107899027A CN107899027A CN201711086074.1A CN201711086074A CN107899027A CN 107899027 A CN107899027 A CN 107899027A CN 201711086074 A CN201711086074 A CN 201711086074A CN 107899027 A CN107899027 A CN 107899027A
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- octreotide
- ccpm
- nirf
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- particle
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
Abstract
The present invention provides a kind of nano-particle developer of neuroendocrine tumor targeting and preparation method and application.The present invention is used as carrier using the near-infrared core cross-linked polymeric micelles nano-particle (NIRF CCPM) with excellent biology performance, Octreotide with tumor-targeting and nano-particle are coupled, the nano molecular image probe NIRF CCPM Octreotide of new cancer target are obtained, and with radionuclide64Cu is marked, and obtains64Cu NIRF CCPM Octreotide can be with tumour growth inhibin receptor SSTR2Antigentic specificity combines, and SSTR is accurately positioned by infrared/nuclear medicine means respectively2The high tissue expressed, realizes the targeted molecular diagnostic imaging purpose of tumour, the research of different kinds of molecules image probe is carried out on same molecule, is early found, early diagnosed, the target of early treatment with reaching tumour.
Description
Technical field
The present invention relates to radiopharmaceutical chemistry and clinical nuclear medicine technical field, specifically, is related in a kind of nerve
Secreting tumor targeted nano-particle developer and preparation method and application.
Background technology
Neuroendocrine tumor (neuroendocrine tumours, NETs), is derived from neuroendocrine cell
One major class tumour, occurred in digestive system, but can be dispersed in and betide the other multiple organs of human body.Between Past 30 Years, NETs
Incidence improve about 5 times.Neuroendocrine tumor patient more than 60% is in late period when diagnosing.Image check often exists
It is very crucial in the initial diagnosis of NET and the state of illness monitoring in later stage.Initial purpose includes differentiating primary tumo(u)r, assesses disease
Scope and formulation treatment plan.The image check purpose in later stage be mainly perform the operation after or treatment after the stable disease phase monitoring, or
Curative effect evaluation.Sensitive, accurate, specific NET targeted probes are to carry out the key of imageological examination.
The content of the invention
The object of the present invention is to provide a kind of neuroendocrine tumor targeted nano-particle developer and preparation method thereof with
Using.
In order to realize the object of the invention, present invention firstly provides a kind of neuroendocrine tumor targeted nano-particle, it is
Coupling has the NIRF-CCPM nano-particles of Octreotide (Octreotide), i.e. NIRF-CCPM-Octreotide；Wherein NIRF-
CCPM nano-particles pass through covalent key connection with Octreotide.
Based on NIRF-CCPM nano-particles, in several ways, synthesis, which obtains, can be used for neuroendocrine tumor bimodulus
The multifunctional nano molecular probe of state imaging/treatment.
Present invention additionally comprises the NIRF-CCPM nano-particles i.e. NIRF-CCPM-Octreotide for being coupled and having Octreotide
Application in cancer target nano-particle developer is prepared；Especially show preparing neuroendocrine tumor targeted nano-particle
As the application in agent.
Wherein, NIRF-CCPM nano-particles, i.e. near-infrared core cross-linked polymeric micelles nano-particle, the reference of its construction method
Document ([1] Z Yang, SY Zheng, WJ Harrison, J Harder, XX Wen, JG Gelovani, A Qiao, C Li*
.Long-Circulating Near-Infrared Fluorescence Core-Cross-Linked Polymeric
Micelles:Synthesis,Characterization,and Dual Nuclear/Optical
Imaging.Biomacromolecules.2010,8,3422-3428).It is summarized as follows：
The tert-butyl group-aminoethyl ethanol is used as raw material, the 2- bromo acid t-Boc- amino ethyl esters of synthesis.Pass through trifluoro
After acetic acid takes off t-Boc- protections, the reacting precursor 2- bromo acid 2- amino ethyl ester trifluoroacetates of high-purity are obtained.It is poly-
The atom that is synthesized by of (PEG- acrylic acid)-b- poly- (triethoxysilicane alkyl acrylate) (PPEGMA-b-PESPMA) turns
Polymerization (ATRP) is moved, is prepared by the lead compound 2- different acrylate of amino-ethyl 2- bromos and catalyst CuBr reactions
's.Surface is to use both sexes block polymer PPEGMA-b-PESPMA and NIRF dyestuff 3- for the CCPM nano-particles of amino
(triethoxysilyl) propyl-Cy7 synthesizes to obtain.Add water to containing block polymer (10mg/mL) and hydrophobic
In the THF of NIRF fuel 3- (triethoxysilyl) propyl-Cy7, self-assembling formation polymeric micelle.When adding second into solution
After acid, polymeric micelle experienced a sol gel reaction process.Ethoxysilane precursor fast hydrolyzing first, PESPMA cores
Si-O keys are cross-linked to form with Cy7- derivatives.Crosslinking core provides a stable micelle nano structure, so as to avoid critical
The unstability that micellar copolymerization produces.The CCPM of preparation is purified using dialysis, and with 0.7 μm, 0.45 μm, 0.2 μm and 0.1 μm
Filter membrane carry out sequential filtering, ultrafiltration is then carried out using the film of 30000 dalton of molecular cut off, needed for centrifugal concentrating obtains
The near-infrared fluorescent of concentration-core cross-linked polymeric micelles nano-particle (NIRF-CCPM).
Hydrophobic fluorescent dye is embedded in nanometer core, is conducive to improve nanoparticle surface hydrophily, reduces macrophage
The phagocytosis of cell.NIRF-CCPM nano-particles provided by the invention have preferable tumor uptake and longer blood residence time,
And the netted epithelial tissue intake such as liver and spleen is low, tumor imaging is very clear.Carried further to carry out tumor cells targeting research
Good platform and nano-carrier system are supplied.
The present invention also provides the method for preparing the cancer target nano-particle, NIRF-CCPM is received with chelating agent NOTA
Rice corpuscles surface amino groups are modified, and obtain NOTA-NIRF-CCPM, are then carried out carboxylated modification to Octreotide, are contained
The Octreotide (Octreotide-COOH) of carboxyl structure, is then coupled to NOTA-NIRF-CCPM tables by Octreotide-COOH
Face, you can.
The present invention also provides a kind of neuroendocrine tumor targeted nano-particle developer, it is received with the cancer target
As labelled precursor, when use, carries out rice corpuscles64Cu isotope labelings.Its preparation method comprises the following steps：
1) NIRF-CCPM nanoparticle surface amino is modified with NCS-Bz-NOTA, obtains NOTA-NIRF-
CCPM, and with PD-10 post separations；
2) targeting modification of nano-particle：Carboxylated modification is carried out to Octreotide, obtains the Octreotide containing carboxyl structure,
Then Octreotide-COOH is coupled to above-mentioned isolated NOTA-NIRF-CCPM nanoparticle surfaces, forms tumour
Targeted nano-particle NOTA-NIRF-CCPM-Octreotide, by the use of being used as labelled precursor after PD-10 post separations；
3) mark：NOTA-NIRF-CCPM-Octreotide is carried out64Cu isotope labelings, obtain neuroendocrine tumor
Targeted nano-particle developer, i.e.,64Cu-NIRF-CCPM-Octreotide。
Further,64The radiochemical purity of Cu-NIRF-CCPM-Octreotide is more than 95%.
Wherein, step 1) is specially：According to number of amino groups on NIRF-CCPM surfaces and the molar ratio of NCS-Bz-DTPA 1:
1-50, preferred molar ratio 1:20 mixing, lucifuge reaction (General reactions 24h), uses PD-10 post separations after the completion of reaction.
Step 2) is specially：According to the molar ratio 1 of NOTA-NIRF-CCPM nano-particles and Octreotide-COOH:1-
50, preferred molar ratio 1:20 mixing, with PD-10 post separations after the completion of reaction.
Step 3) is specially：0.1M NaAc (pH=5.5), 185MBq are sequentially added into labelled precursor64CuCl2, 37
DEG C reaction 20-30min, to obtain the final product64Cu-NIRF-CCPM-Octreotide.Mark rate and radiochemical purity are measured, works as mark rate
Less than 90%, PD-10 post separations, gained need to be used64The radiochemical purity of Cu-NIRF-CCPM-Octreotide is more than 95%.
PD-10 columns are using preceding with through past metal ionization, 0.01M PBS buffer (pH7.4) elution.
In an embodiment of the invention, Octreotide is modified using ring succinic anhydride；Preferably, with
EDC, that is, 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides are as coupling activator.
It is provided by the invention64The PET image results of Cu-NIRF-CCPM-Octreotide show,64Cu-NIRF-CCPM-
SSTR can be accurately positioned in Octreotide2Positive tumor, and it is naked in the different plant of Non-small cell lung carcinoma A549 xenogenesis of 12h, 36h
It is high-visible in mouse tumour.64The infrared imaging of Cu-NIRF-CCPM-Octreotide shows,64Cu-NIRF-CCPM-
SSTR can be accurately positioned in Octreotide2Positive tumor, and in the different plant nude mice of 2~144h Non-small cell lung carcinoma A549 xenogenesis
It is high-visible in tumour.
The present invention is made with the near-infrared core cross-linked polymeric micelles nano-particle (NIRF-CCPM) with excellent biology performance
For carrier, the Octreotide with tumor-targeting and nano-particle are coupled, obtain the nano molecular shadow of new cancer target
As probe NIRF-CCPM-Octreotide, and with radionuclide64Cu is marked, and obtains64Cu-NIRF-CCPM-
Octreotide can be with tumour SSTR2Antigentic specificity combines, and SSTR is accurately positioned by infrared/nuclear medicine means respectively2It is high
The tissue of expression, realizes the targeted molecular diagnostic imaging purpose of tumour, and different kinds of molecules image probe is carried out on same molecule
Research, early found with reaching tumour, early diagnosis, the target of early treatment.
Brief description of the drawings
Fig. 1 is the novel nano particle of the present invention64The synthetic route of Cu-NIRF-CCPM-Octreotide.
Fig. 2 is in embodiment 264PETs of the Cu-NIRF-CCPM-Octreotide in the BALB/C nude mouses that A549 kinds are planted
Imaging figure.
Fig. 3 is in embodiment 364Cu-NIRF-CCPM-Octreotide is infrared in the BALB/C nude mices that A549 kinds are planted
Imaging figure.
Embodiment
Following embodiments are used to illustrate the present invention, but are not limited to the scope of the present invention.Unless otherwise specified, embodiment
In the conventional means that are well known to those skilled in the art of used technological means, raw materials used is commercial goods.
The construction method of the near-infrared core cross-linked polymeric micelles nano-particle (NIRF-CCPM) arrived involved in following embodiments
Bibliography ([1] Z Yang, SY Zheng, WJ Harrison, J Harder, XX Wen, JG Gelovani, A Qiao, C
Li*.Long-Circulating Near-Infrared Fluorescence Core-Cross-Linked Polymeric
Micelles:Synthesis,Characterization,and Dual Nuclear/Optical
Imaging.Biomacromolecules.2010,8,3422-3428)。
1 neuroendocrine tumor targeted nano-particle developer of embodiment and preparation method thereof
Neuroendocrine tumor targeted nano-particle developer (64Cu-NIRF-CCPM-Octreotide preparation) includes
Following steps：
(1) it is 1 according to amino on NIRF-CCPM surfaces and NCS-Bz-NOTA molar ratios:20 mixing, lucifuge reaction 24h,
NOTA-NIRF-CCPM is obtained, PD-10 post separations are used after the completion of reaction.PD-10 columns using preceding with through past metal ionization,
0.01M PBS buffer (pH7.4) elutes.
(2) it is 1 according to NOTA-NIRF-CCPM nano-particles and Octreotide-COOH molar ratios:20 mixing, have reacted
After with PD-10 post separations, up to tumor imaging labelled precursor.Nano-particle is dispensed, with N2Seal, dispense after protection
0.5mL/ bags, stand at 4 DEG C.
(3) 0.1M NaAc 65 μ L, 185MBq are sequentially added to labelled precursor64CuCl2, react at room temperature 20-30min.Survey
Determine mark rate and radiochemical purity, when mark rate be less than 90%, PD-10 column separating purifications need to be carried out, that is, obtained64Cu-NIRF-
CCPM-Octreotide。64The synthetic route of Cu-NIRF-CCPM-Octreotide is as shown in Figure 1.
The measure of mark rate uses instant thin-layer chromatography method.System：ITLC-SG (Flash silica thin-layer chromatography-silica gel paper)；
Solvent：4mM EDTA, 0.9%Nacl solution, pH7.4；Label is free in origin64CuCl2Ahead of the curve.The results show that
Mark rate and radiochemical purity are more than 95%.
The PET imagings of 2 neuroendocrine tumor targeted nano-particle developer of embodiment in animal body
The BALC/C nude mices of the A549 tumour cells plantation of the right preceding oxter plantations of 25g are taken, treat tumor tissues length to 0.8cm3
Afterwards, tail vein injection 18.5MBq/200 μ L64Cu-NIRF-CCPM-Octreotide (prepared by embodiment 1), respectively at injection
12h, 36h carry out Image Acquisition using Siemens's E.cam SPECT instrument afterwards, and energy peak is 246keV, and energy window is 20%, matrix
128 × 128, image magnification 3, carries out normotopia imaging.Observation64The intake change of Cu-NIRF-CCPM-Octreotide and complete
Body distribution situation, its image results are shown in Fig. 2.As seen from Figure 2, inject6412h after Cu-NIRF-CCPM-Octreotide,
36h can see the intake of tumor locus.In whole videograph process, in addition to liver, other non-specific intakes are less.For the medicine
Thing is used for SSTR2The imaging of positive tumor provides support.
The infrared imaging of 3 neuroendocrine tumor targeted nano-particle developer of embodiment in animal body
The BALC/C nude mices of the A549 tumour cells plantation of the right preceding oxter plantations of 25g are taken, treat tumor tissues length to 0.8cm3
Afterwards, tail vein injection 18.5MBq/200 μ L64Cu-NIRF-CCPM-Octreotide (prepared by embodiment 1), it is imaged in PET
Afterwards, infrared imaging, visual field 12.5cm, profit are carried out in 2~144h using the infrared displays of smart Nuo Zhen-IVIS Lumina II
With ICG sequences (exciting light 710nm), 1.3 × 1.3cm of CCD camera lenses, 1024 × 1024 pixels, time for exposure 1s.Concrete outcome is shown in figure
3.As seen from Figure 3, in 60h, tumor locus can be evident from more preferably bright with time lengthening, imaging results afterwards
It is aobvious.Should the result shows that, infrared imaging is in SSTR2Effective application in the imaging of positive tumor.
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements, belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1. a kind of neuroendocrine tumor targeted nano-particle, it is that the NIRF-CCPM for having Octreotide by covalent bond coupling receives
Rice corpuscles.
2. the neuroendocrine tumor targeted nano-particle described in claim 1 is preparing neuroendocrine tumor targeted nano granule
Application in sub- developer.
3. the method for neuroendocrine tumor targeted nano-particle described in claim 1, it is characterised in that including with chelating agent
NOTA modifies NIRF-CCPM nanoparticle surface amino, obtains NOTA-NIRF-CCPM, then carries out carboxylic to Octreotide
Baseization is modified, and is obtained the Octreotide Octreotide-COOH containing carboxyl structure, is then coupled to Octreotide-COOH
NOTA-NIRF-CCPM surfaces, you can.
4. a kind of neuroendocrine tumor targeted nano-particle developer, it is with cancer target nanoparticle described in claim 1
Cancer target nano-particle prepared by son or claim 3 the method is carried out as labelled precursor64Cu isotope labelings are made.
5. targeted nano-particle developer according to claim 4, it is characterised in that its radiochemical purity is more than
95%.
6. the preparation method of the targeted nano-particle developer of claim 4 or 5, it is characterised in that comprise the following steps：
1) NIRF-CCPM nanoparticle surface amino is modified with NCS-Bz-NOTA, obtains NOTA-NIRF-CCPM, and
With PD-10 post separations；
2) targeting modification of nano-particle：Carboxylated modification is carried out to Octreotide, obtains the Octreotide containing carboxyl structure
Octreotide-COOH, is then coupled to above-mentioned isolated NOTA-NIRF-CCPM nanoparticles by Octreotide-COOH
Sublist face, forms cancer target nano-particle NOTA-NIRF-CCPM-Octreotide, is marked by the use of being used as after PD-10 post separations
Precursor；
3) mark：NOTA-NIRF-CCPM-Octreotide is carried out64Cu isotope labelings, to obtain the final product.
7. preparation method according to claim 6, it is characterised in that step 1) is specially：According on NIRF-CCPM surfaces
Number of amino groups and the molar ratio of NCS-Bz-DTPA 1:1-50, preferred molar ratio 1:20 mixing, lucifuge reaction, are used after the completion of reaction
PD-10 post separations；And/or
Step 2) is specially：According to the molar ratio 1 of NOTA-NIRF-CCPM nano-particles and Octreotide-COOH:1-50, it is excellent
Select molar ratio 1:20 mixing, with PD-10 post separations after the completion of reaction；And/or
Step 3) is specially：0.1M NaAc (pH=5.5), 185MBq are sequentially added into labelled precursor64CuCl2, 37 DEG C anti-
Answer 20-30min, to obtain the final product.
8. the preparation method according to claim 6 or 7, it is characterised in that repaiied Octreotide using ring succinic anhydride
Decorations；Preferably, coupling activator is used as using EDC.
9. according to claim 6-8 any one of them preparation methods, it is characterised in that the PD-10 columns are passed through using preceding
The 0.01M PBS buffer (pH7.4) of metal ionization is gone to elute.
10. targeted nano-particle developer prepared by any one of claim 6-9 the method.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114617982A (en) * | 2022-03-23 | 2022-06-14 | 北京健康启航科技有限公司 | Preparation method of neuroendocrine tumor targeted nanoparticles |
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2017
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| US20100022449A1 (en) * | 2006-03-09 | 2010-01-28 | Mallinckrodt Inc. | Receptor-avid exogenous optical contrast and therapeutic agents |
| CN103480009A (en) * | 2013-09-17 | 2014-01-01 | 北京肿瘤医院 | Bi-modal tumor targeted nano particle photographic developer and method for preparing same |
| CN104491890A (en) * | 2014-11-21 | 2015-04-08 | 北京肿瘤医院 | Novel radionuclide labelled somatostatin analogue molecular probe and application thereof |
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| CN114617982A (en) * | 2022-03-23 | 2022-06-14 | 北京健康启航科技有限公司 | Preparation method of neuroendocrine tumor targeted nanoparticles |
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Application publication date: 20180413 |