CN107224592B - A kind of porphyrin liposome radiopharmaceutical 99mTc-Texaphyrin NPs and preparation method thereof - Google Patents
A kind of porphyrin liposome radiopharmaceutical 99mTc-Texaphyrin NPs and preparation method thereof Download PDFInfo
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- 150000004032 porphyrins Chemical class 0.000 title claims abstract description 39
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 229940121896 radiopharmaceutical Drugs 0.000 title claims description 15
- 230000002799 radiopharmaceutical effect Effects 0.000 title claims description 15
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- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
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- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 description 1
- JCABVIFDXFFRMT-DIPNUNPCSA-N [(2r)-1-[ethoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] octadec-9-enoate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC)OC(=O)CCCCCCCC=CCCCCCCCC JCABVIFDXFFRMT-DIPNUNPCSA-N 0.000 description 1
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- AARXZCZYLAFQQU-UHFFFAOYSA-N motexafin gadolinium Chemical compound [Gd].CC(O)=O.CC(O)=O.C1=C([N-]2)C(CC)=C(CC)C2=CC(C(=C2C)CCCO)=NC2=CN=C2C=C(OCCOCCOCCOC)C(OCCOCCOCCOC)=CC2=NC=C2C(C)=C(CCCO)C1=N2 AARXZCZYLAFQQU-UHFFFAOYSA-N 0.000 description 1
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- 238000007626 photothermal therapy Methods 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
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- 150000004033 porphyrin derivatives Chemical class 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229910052713 technetium Inorganic materials 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
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Classifications
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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
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/1217—Dispersions, suspensions, colloids, emulsions, e.g. perfluorinated emulsion, sols
- A61K51/1234—Liposomes
-
- 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
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0485—Porphyrins, texaphyrins wherein the nitrogen atoms forming the central ring system complex the radioactive metal
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Physics & Mathematics (AREA)
- Medicinal Chemistry (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dispersion Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of porphyrin liposome radiopharmaceutical99mTc Texaphyrin NPs and preparation method thereof, the porphyrin liposome radiopharmaceutical99mTc Texaphyrin NPs include nano material and radionuclide99mTc, the liposome nano liposomes that the nano material is made of Texaphyrin lipid, i.e. Texahyrin NPs, the radionuclide99mTc labels realize that self marker is formed in the case where not needing to connect the multi-functional chelating agent of any small molecule99mTc‑Texaphyrin NPs.The drug can gather so that the mode of passive target is dense in the tumor locus with EPR effects, using the SPECT imaging techniques of nuclear medicine, can carry out localization diagnosis and detection to tumour or other diseases with EPR effects.
Description
Technical field
The present invention relates to diagnosing tumor radiopharmaceutical, more particularly to a kind of porphyrin liposome radiopharmaceutical99mTc-
Texaphyrin NPs and preparation method thereof.
Background technology
Molecular probe is one of core research contents of molecular image technology.In recent years, it is contaminated with radionuclide, fluorescence
The research of the molecular probe for different imaging mode of the labels such as material, paramagnetic and super paramagnetic material increases into geometry magnitude.With
Traditional Small-molecule probe is compared, and there is nano molecular probe integration pluralistic function to be wrapped in delivery with design, drug, follow in vivo
The ring time is long and can pass through EPR (Enhanced Permeabilityand Retentioneffect) effect passive target
The features such as tumour, so as to increase the anticancer function of drug and reduce toxic side effect.Based on the multi-functional of nano molecular probe
Characteristic can be provided for clinical medicine one integrate early diagnosis, monitoring in real time, level diagnosis are examined with personalized intervention
Control system.The research of nano-probe has become one of important directions of modern medicine development, but past nano material is exhausted
Most of is inorganic, is not only difficult to degrade, but also have microtoxicity to human body.The master that lipid molecular is formed as organism
Want ingredient have unrivaled biocompatibility, the nanostructured being self-assembly of no matter from homogeneity, stability and
Repeated aspect, there is very big advantage.U.S. Food and Drug Administration (FDA) ratified to use and puts goods on the market
In the nano material of several species, liposome is current application nano-drug preparation form the most universal.
2011, the Zheng Gang of University of Toronto professor seminar construct it is a kind of it is completely new, nontoxic, can biology
Degradation, novel lipide-porphyrin nanovesicles that there is height sensitivity, be self-assembly of by porphyrin bilayer（It is named as
porphysome）.The internal layer and outer layer of Porphysome is made of phospholipid substance, has fabulous enzyme biodegradation
Property；And what is worked in intermediate course is natural porphyrin derivative, non-toxic degradable, it is harmless.Porphysome's is more
Functional character is embodied in：One side itself is a kind of photosensitizer, is treated available for PDT（Optical dynamic therapy）, when this organic
After Nano medication reaches tumor locus, with laser irradiation tumor locus, this drug can allow ground state present in tumor tissues
Oxygen switchs to the extremely strong excited oxygen of lethality, and killing is generated to tumour.On the other hand, this nano particle is by more than 80,000 a molecules
Composition, density is very high, itself with photo-thermal sexual function, can be used for photo-thermal therapy again.In addition, porphysome can be also used for cancer
The early diagnosis of disease.The Porphyrin Molecule of one of its constituent（It is four azo-cycle porphyrins herein）, on the one hand there is fluorescent characteristics, it can be into
Row fluorescence imaging.On the other hand it is also excellent metal-chelator, and four nitrogen-atoms at center can be with many divalent gold
Belong to ions binding and generate highly stable organic complex.Radionuclide is marked in porphysome by Zheng Gang seminars64Tc,
And tumor of prostate mouse model is successfully made PET imagings in situ（Positron Emission Computed
Tomography, Positron Emission Computed Tomography）.Porphysome has very good biological safety and physics and chemistry
Matter has great application prospect in terms of the polyfunctional molecule probe of exploitation diagnosis and treatment combination.But presently used porphyrin
（Four azo-cycle porphyrins）It cannot be with nuclear-magnetism reinforcing agent Gd and radionuclide177The trivalents metal ion such as Lu forms stable complex compound,
Limit its further exploitation in the fields such as NMR imaging and nuclear medicine image and treatment.
1988 Texas ,Usa university (Austin) J.L. professors Sessler leader research group synthesize
One kind is known as the extension porphyrin of Texaphyrin (original meaning is Texas porphyrin).Texaphyrin is a kind of tripyrrole pentaaza
The derivatives of porphyrin of ring（It can be also simply referred to as 5N porphyrins）, it can be with trivalent metal Gd3+Chelating obtains a kind of porphyrin for being chelated with Gd
Derivative gadolinium texaphyrin（Gd-Tex）.Gd-Tex can selectively assemble in tumor tissues, can be used for magnetic
Resonance image-forming（MRI, Magnetic Resonance Imaging）Carry out in-vivo tissue positioning.The 4N porphins mentioned before opposite
Quinoline, Texaphyrin have five-nitrogen heterocyclic, can be with forming stable 1 more than 28 metal ion species:1 compound, wherein not only
Including many divalent transition metals, also include the lanthanide metal ion of many particularly trivalents.Recently, a kind of novel manganese (II)-
5N porphyrins-phospholipid liposome is used for the imaging research of MRI, while be also proved can be with various metals ion for 5N porphyrins phosphatide
Form stable compound.At present, 5N porphyrins-phospholipid liposome is not had still to use the direct labeling method of single photon emission nucleic,
There is no 5N porphyrins-phospholipid liposome radioactively labelled substance in single photon tomography yet（Single-Photon Emission
Computed Tomography, SPECT）Vivo applications in field.
Invention content
The object of the present invention is to provide a kind of porphyrin liposome radiopharmaceutical99mTc-Texaphyrin NPs and its preparation
Method, the radiopharmaceutical is with Texas porphyrin-phosphatide cpd, cholesterol, soybean hydrogenated phospholipid and phosphatide-poly- second two
Alcohol 2000 is raw material, and does not need to be connected to required any difunctional chelating in conventional labels in the preparation process of the drug
Agent, such as DTPA（Diethyl pentetic acid）、HYNIC（6- tertiary butyloxycarbonyl hydrazinonicotinic acids）Deng radionuclide99mTc labels exist
It does not need to realize that self marker is formed in the case of connecting the multi-functional chelating agent of any small molecule99mTc-Texaphyrin NPs。
The drug can gather so that the mode of passive target is dense in the tumor locus with EPR effects, be imaged using the SPECT of nuclear medicine
Technology can carry out localization diagnosis and detection to tumour or other diseases with EPR effects.
The purpose of the present invention is what is be achieved through the following technical solutions：
A kind of porphyrin liposome radiopharmaceutical99mTc-Texaphyrin NPs, including nano material and radioactive nucleus
Element99mTc, the liposome nano liposomes that the nano material is made of Texaphyrin-lipid, i.e. Texahyrin
NPs, the radionuclide99mTc labels realize itself in the case where not needing to connect the multi-functional chelating agent of any small molecule
Label is formed99mTc-Texaphyrin NPs, the Texaphyrin NPs radiopharmaceutical are pale yellow transparent injection.
The porphyrin liposome radiopharmaceutical99mThe preparation method of Tc-Texaphyrin NPs, includes the following steps：
1）The preparation of Texaphyrin NPs nano materials
By Texas porphyrin-lysophosphatide（Texaphyrin-lipid）, cholesterol, hydrogenated soya phosphatide and distearyl
Acylphosphatidyl ethanolamine-polyethylene glycol 2000（DSPE-PEG2000）It is substantially soluble in chloroform, is steamed by depressurizing rotation
The slow solvent evaporated of hair instrument is simultaneously formed uniformly phospholipid membrane on eggplant type bottle inner wall, and being removed overnight in vacuum desiccator any has
Solvent adds in the ammonium acetate buffer solution that pH is 5.5 in bottle, and aquation carries out in 55 degrees Celsius of water bath sonicator, until
Adipose membrane dissolves, and prepares crude liposome solutions, and the crude liposome solutions are gathered by being equipped with double-deck 100 nm apertures
The Morgec LE-15 liposomes extruder of carbonic ester film carries out repeated processing, and extrusion temperature is 55 degrees Celsius, extrusion liquid pH
Ammonium acetate buffer solution for 5.5 is configured to the Texaphyrin NPs solution of a concentration of 0.4 mg/mL, is finally filtered by PVDF
Membrane filtration carries out aseptic subpackaged to get to the Texaphyrin NPs nano materials；
2）99mThe preparation of Tc-Texaphyrin NPs
By step 1）The Texaphyrin NPs nano materials being prepared are placed in the tubule of 1.5 mL, add in TPPTS
With Na [99mTcO4], place reaction liquid into 60 DEG C air bath or metal bath heater in react 15-20 minutes, reaction terminates
Room temperature cools down 10 minutes afterwards, adds in 1 mL phosphate buffers, and the porphyrin liposome radiopharmaceutical is made99mTc-
Texaphyrin NPs, are purified by hyperfiltration process, are reflected by radio thin layer's chromatography or radioactivity high performance liquid chromatography
Determine the radiochemical purity of marker.
Further, step 1）Described in Texas porphyrin-lysophosphatide（Texaphyrin-lipid）, cholesterol,
Hydrogenated soya phosphatide and distearoylphosphatidylethanolamine-polyethylene glycol 2000, the molar ratio of each component is respectively 30%：
30%：35%：5%.
Further, step 2）Described in radio thin layer chromatography method be：Paper is unfolded and selects long 10 cm, wide by 1.5
The Agilent ITLC-SG silica gel glass fibre rapid deployment paper of cm, sample spot are opened up at 1 cm with normal saline solution
It opens, is expanded at 9 cm and paper slip is taken out into naturally dry, the paper slip after expansion is detected with BioScan AR-2000, wherein,
Origin is99mThe marker of Tc, forward position are free99mTc ions.
Further, step 2）Described in radioactivity high-efficiency liquid chromatography method for detecting be：Use Agilent 1260
Infinity HPLC systems are equipped with Superose-12 exclusion columns, and mobile phase is the 0.01M of 1mL/min, and pH is 7.0 ammonium acetate
Buffer solution, elution time are 30 min,99mThe retention time of the Nanoparticle labeling object of Tc labels is 7 minutes, free99mThe guarantor of Tc
It is 15 minutes to stay the time.
Here the 5N porphyrins-phosphatide reported（Texaphyrin-lipid）The composition of structure and 5N porphyrin liposomes is（Figure
1A）, the 5N porphyrins that design in the present invention have a lipophilicity, and the hydroxyl on lysophosphatide covalently connects with the carboxyl on 5N porphyrins
It connects, forms the amphiphilic structure of a hydrophilic lipophilic.5N porphyrin phosphatide has the characteristics that similar general phosphatide, can form class
Different liposomes is formed like one of the self-assembled structures of liposome and raw material for can also be used as liposome.5N porphyrin lipids
The structure diagram and grain size and current potential of body be（Figure 1B）.5N porphyrins have the potentiality of various metals nucleic chelating and are being prepared into
It can be achieved after Texaphyrin NPs nano-probes99mThe intrinsic of Tc directly marks and for In vivo study.
The present invention having the beneficial effect that compared with prior art：
1st, porphyrin liposome radiopharmaceutical of the present invention, does not need to be connected in conventional labels in preparation process
Required any bifunctional chelating agent（Such as DOTA, HYNIC）, radionuclide99mTc label do not need to connect it is any small
Realize that self marker is formed in the case of the multi-functional chelating agent of molecule99mTc-Texaphyrin NPs；
2nd, porphyrin liposome radiopharmaceutical of the present invention is used for SPECT imagings in the disease with EPR effects, real
The purpose now " examined " in the novel nano-material diagnosis and treatment integration；
3rd, porphyrin liposome radiopharmaceutical of the present invention can medicine box, added in the porphyrin liposome of Texas
Three sulfonate sodiums of reducing agent triphenylphosphine（3,3′,3″-Phosphanetriyltris(benzenesulfonic acid)
Trisodium salt, TPPTS）And radionuclide99mHeating is carried out after Tc, intrinsic label can be realized；
4th, porphyrin liposome radiopharmaceutical of the present invention can with the mode of passive target it is dense gather imitated with EPR
In the tumor locus answered, using the SPECT imaging techniques of nuclear medicine, tumour or other diseases with EPR effects can be carried out
Localization diagnosis and detection.
The invention will be further described with reference to the accompanying drawings and embodiments.
Description of the drawings
Fig. 1 is constituent, chemical constitution and mole accounting of Texaphyrin NPs nano materials（A）And
The self assembly schematic diagram of Texaphyrin NPs nano-probes and the diameter characterization of the probe and current potential characterize（B）；
Fig. 2 is Texaphyrin NPs nano materials after purification with conventional liposome is reference substance radioactivity HPLC and
ITLC result figures（A）,99mTc-Texaphyrin NPs are compared with control experiment group echo situation（B）；
Fig. 3 is99mTc-Texaphyrin NPs 4 h after injection in C57B/L6 mouse lewis lung cancer subcutaneous models
With the bio distribution of 12 h；
Fig. 4 is99mTc-Texaphyrin NPs injected in C57B/L6 mouse lewis lung cancer subcutaneous models after 2,4,6
With the 3D-MIP imagings figure of the NanoSPECT/CT after 8 h (dotted line circle indicates knub position with arrow).
Specific embodiment
Embodiment 1
1 material：
Hydrogenated soya phosphatide（HSPC）And cholesterol（Cholesterol）Purchased from Shanghai Advanced viecle Technology Co., Ltd.
(AVT).Texas porphyrin phosphatide is provided by medical biotechnology physics system of University of Toronto.Distearyl acyl group phosphatidyl ethanol
Amine-polyethylene glycol 2000 is purchased from Avanti Polar Lipids companies of the U.S..Acetic acid and ammonium acetate are purchased from U.S. Sigma-
Aldrich.Tris (3-sulfonatophenyl) phosphine sodium salt (TPPTS) are purchased from Chinese J＆K larks
Prestige Science and Technology Ltd..Na99mTcO4Purchased from Chinese Atom High Tech Co., Ltd..
2 methods and result
2.1 radiochemical purity methods
ITLC methods：Agilent ITLC-SG silica gel all-glass papers are selected, are cut to a length of 10 centimetres, width 1.5
Centimetre rectangle paper slip.By sample spot at 1 cm, it is unfolded with normal saline solution, is expanded at 9 cm and takes paper slip
Go out naturally dry.Paper slip after expansion is detected with BioScan AR-2000.
HPLC detection methods：Superose-12 exclusion columns, stream are equipped with using 1260 Infinity HPLC systems of Agilent
Dynamic is mutually the 0.01M of 1mL/min, and pH is 7.0 ammonium acetate buffer.The elution time is 30min, 99mThe nanometer mark of Tc labels
The retention time for remembering object is 7 minutes, free99mPractical that of the reservation of Tc is 15 minutes.
The preparation of 2.2 Texaphyrin NPs nano materials
By 2 mg Texas porphyrins-lysophosphatide（Texaphyrin-lipid）, 0.86 mg cholesterol, 1.5 mg are big
Beans hydrolecithin（HSPC）With distearoylphosphatidylethanolamine-polyethylene glycol 2000（DSPE-PEG2000）It is fully molten
In 5 mL chloroforms, the molar ratio of each component is respectively 30%：30%：35%：5%.Fig. 1-A are Texaphyrin NPs lipids
Constituent, chemical constitution and the molar ratio of body nano material（A）.By depressurize the slow solvent evaporated of Rotary Evaporators and
Phospholipid membrane is formed uniformly on eggplant type bottle inner wall, removes any organic solvent overnight in vacuum desiccator.4 are added in bottle
ML pH are 5.5 ammonium acetate buffer solution（0.1 M, by 100 resin deionizations of Chelex）.Water of the aquation at 55 degrees Celsius
10 minutes in bath ultrasound, until adipose membrane dissolves, crude liposome solutions are prepared.By liposome solutions by being equipped with bilayer 100
The Morgec LE-15 liposomes extruder of nm apertures polycarbonate membrane carries out repeated processing, and extrusion temperature is 55 degrees Celsius.It squeezes
Go out the ammonium acetate buffer solution that liquid pH is 5.5（0.1 M）The Texaphyrin NPs for being configured to a concentration of 0.4 mg/mL are molten
Liquid carries out aseptic subpackaged to get to the Texaphyrin NPs nano materials by 0.22 μM of PVDF membrane filtrations.
Product carries out the characterization of grain size and current potential with 90 dynamic light scatterings of Nano ZS.Fig. 1-B are Texaphyrin NPs liposomes
The self assembly schematic diagram of nano material and the diameter characterization of the probe and current potential characterize, and grain size is 100 nm, point position for-
29 mV。
2.3 99mThe preparation of Tc-Texaphyrin NPs
The Texaphyrin NPs nano materials containing 100 μ g are placed in the tubule of 1.5 mL, add in 2.5 mg
TPPTS and 1.1Gbq Na [99mTcO4], it is placed in 60 degrees Celsius of air bath heater and heats 20 minutes.It prepares99mTc
- Texaphyrin NPs are purified using the method for ultrafiltration, the Millipore (MWCO=100 K) that ultrafiltration apparatus is 15mL
Super filter tube.Carried out after sample normal saline dilution to 2 mL ultrafiltration remove it is free99mTc, relative centrifugal force 3000g, time
For 15min.Ultrafiltration purification carries out 2 times altogether.Control sample is the conventional liposome for being prepared and being marked using same method（65% hydrogen
Change the soft phosphatide of soybean, 30% cholesterol and 5% DSPE-PEG2000）.Sample is analyzed by ITLC methods and with HPLC side
Method is verified.Fig. 2-A are99mThe conventional liposome Liposomes's of Tc-Texaphyrin NPs and negative control marker puts
Penetrating property HPLC result figures and radioactivity ITLC result figures.In radioactivity HPLC detections,99mThe reservation of Tc-Texaphyrin NPs
Time is 7 min, and the retention time of control negative marker object is 15 min.In radioactivity ITLC detections,99mTc-
The relative mobility of Texaphyrin NPs（RF）It is 0, the relative mobility of control negative marker object is 0.8.Fig. 2-B are feminine gender
The Liposomes of contrasting marking,99mTc-Texaphyrin NPs and two kinds of raw materials（Texaphyrin NPs, TPPTS）List
Solely label control.With reference to control experiment label the result shows that,99mTc-Texaphyrin NPs labeling effciencies are higher, and
Texaphyrin NPs are in TPPTS conducts99mDuring Tc reducing agents could significant notation, it is not by right to illustrate the label result
High technetium acid molecule99mTcO4 -Package caused by.
2.4 99mTc-Texaphyrin NPs are in mice with tumor bio distribution
If C57B/L6 lotus Lewis mice lung cancer subcutaneous model mouse are randomly divided into two groups, every group 2.Each group experiment is small
Mouse is respectively through 100 mL's of tail vein injection (740 KBq)99mTc-Texaphyrin NPs, 4 hours and 12 small after injection
The dead experiment mice in time-division other places, takes blood and main organs, weighs and measures radiocounting, every gram of group is calculated after decay correction
Knit percentage injection dose rate (%ID/g).In Mice Body, liver and spleen ID%/g highests meet the liver and spleen intake of nano material.
12 hours after injection, the % ID/g of blood still maintain higher level, meet the stealthy liposome after PEG2000 modification of surfaces
The blood long circulating of body.Within the observed time, tumor uptake is apparently higher than the normal structures such as muscle.
2.5 99mSPET/CT imagings of the Tc-Texaphyrin NPs in mice with tumor
It will be by C57B/L6 lotus Lewis mice lung cancer subcutaneous model mouse with through 100 mL of tail vein injection (~ 37 MBq)99mTc-Texaphyrin NPs image system in 2,4,8 and 12 hours after injection in injection in Mediso Nano SPECT/CT
SPECT/CT imagings are carried out in system.Fig. 4 is shown99mTc-Texaphyrin NPs are subcutaneous in C57B/L6 mouse lewis lung cancers
The 3D-MIP total body opacification figures of 2,4,8 and 12 hours after being injected in model.After injection in the imaging figure of 2 hours, we can be with
See the blood pool of mouse heart position and Cervical Vessels, illustrate the long circulating of drug in vivo.It is imaged in mouse systemic 3D
In, it can be seen that marker has apparent intake in tumour and liver, spleen tissue.In whole time of developing points, can it be clearly apparent
Marker has apparent dense poly- in tumor locus, can clearly differentiate knub position.
In conclusion the porphyrin liposome radiopharmaceutical based on novel porphyrin nanometer Texaphyrin NPs99mTc-
Texaphyrin NPs are useful for the application potential of whole body SPET/CT detection tumours.
Claims (4)
1. a kind of porphyrin liposome radiopharmaceutical99mTc-Texaphyrin NPs, which is characterized in that including nano material and put
Penetrating property nucleic99mTc, the liposome nano liposomes that the nano material is made of Texaphyrin-lipid, i.e.,
Texahyrin NPs, the radionuclide99mTc is marked in the situation for not needing to connect the multi-functional chelating agent of any small molecule
Lower realization self marker is formed99mTc-Texaphyrin NPs, the radiopharmaceutical99mTc-Texaphyrin NPs are yellowish
Color transparent shot injection；
The porphyrin liposome radiopharmaceutical99mThe preparation method of Tc-Texaphyrin NPs includes the following steps：
1）The preparation of Texaphyrin NPs nano materials
By Texas porphyrin-lysophosphatide（Texaphyrin-lipid）, cholesterol, hydrogenated soya phosphatide and distearyl acyl group
Phosphatidyl-ethanolamine-polyethylene glycol 2000（DSPE-PEG2000）It is substantially soluble in chloroform, by depressurizing Rotary Evaporators
Slow solvent evaporated is simultaneously formed uniformly phospholipid membrane on eggplant type bottle inner wall, is removed overnight in vacuum desiccator any organic molten
Agent adds in the ammonium acetate buffer solution that pH is 5.5 in bottle, and aquation carries out in 55 degrees Celsius of water bath sonicator, until adipose membrane
Dissolving, prepares crude liposome solutions, by the crude liposome solutions by being equipped with the double-deck 100 poly- carbonic acid in nm apertures
The Morgec LE-15 liposomes extruder of ester film carries out repeated processing, and extrusion temperature is 55 degrees Celsius, and extrusion liquid pH is 5.5
Ammonium acetate buffer solution be configured to the Texaphyrin NPs solution of a concentration of 0.4 mg/mL, finally by PVDF filter membrane mistakes
Filter carries out aseptic subpackaged to get to the Texaphyrin NPs nano materials；
2）99mThe preparation of Tc-Texaphyrin NPs
By step 1）The Texaphyrin NPs nano materials being prepared are placed in the tubule of 1.5 mL, add in TPPTS and Na
[99mTcO4], place reaction liquid into 60 DEG C air bath or metal bath heater in react 15-20 minutes, room after reaction
Temperature cooling 10 minutes, adds in 1 mL phosphate buffers, and the porphyrin liposome radiopharmaceutical is made99mTc-
Texaphyrin NPs, are purified by hyperfiltration process, are reflected by radio thin layer's chromatography or radioactivity high performance liquid chromatography
Determine the radiochemical purity of marker.
2. porphyrin liposome radiopharmaceutical according to claim 1, which is characterized in that step 1）Described in Texas
Porphyrin-lysophosphatide（Texaphyrin-lipid）, cholesterol, hydrogenated soya phosphatide and distearoylphosphatidylethanolamine-
Polyethylene glycol 2000, the molar ratio of each component is respectively 30%：30%：35%：5%.
3. porphyrin liposome radiopharmaceutical according to claim 199mTc-Texaphyrin NPs, it is characterised in that：
Step 2）Described in radio thin layer chromatography method be：The Agilent ITLC- that paper selects long 10 cm, wide 1.5 cm are unfolded
SG silica gel glass fibre rapid deployment paper, sample spot are unfolded at 1 cm with normal saline solution, and being expanded at 9 cm will
Paper slip takes out naturally dry, and the paper slip after expansion is detected with BioScan AR-2000, wherein, origin is99mThe label of Tc
Object, forward position are free99mTc ions.
4. porphyrin liposome radiopharmaceutical according to claim 199mTc-Texaphyrin NPs, it is characterised in that：
Step 2）Described in radioactivity high-efficiency liquid chromatography method for detecting be：It is equipped with using 1260 Infinity HPLC systems of Agilent
Superose-12 exclusion columns, mobile phase are the 0.01M of 1mL/min, and pH is 7.0 ammonium acetate buffer, and the elution time is 30
Min,99mThe retention time of the Nanoparticle labeling object of Tc labels is 7 minutes, free99mThe retention time of Tc is 15 minutes.
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