CN101229382A - Novel type radiographic contrast suitable for multi-imaging pattern - Google Patents
Novel type radiographic contrast suitable for multi-imaging pattern Download PDFInfo
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- CN101229382A CN101229382A CNA2008100693565A CN200810069356A CN101229382A CN 101229382 A CN101229382 A CN 101229382A CN A2008100693565 A CNA2008100693565 A CN A2008100693565A CN 200810069356 A CN200810069356 A CN 200810069356A CN 101229382 A CN101229382 A CN 101229382A
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Abstract
The invention pertains to a biomedical engineering field and particularly relates to a novel contrast agent applicable to a plurality of imaging models; the novel contrast agent is prepared from porphyrin and derivative(s) thereof and/or phthalocyanin and derivative(s) thereof combining with acoustic contrast agent. When in use, the novel contrast agent is systemically or partly acted on target tissue, thus intensifying X ray, ultrasonic, computer X ray tomoscan (CT), magnetic resonance imaging and optical imaging for the target tissue.
Description
Technical field
The invention belongs to biomedical engineering field, more particularly, the present invention relates to a kind of novel type radiographic contrast that is applicable to multiple imaging pattern.
Background technology
Medical Imaging is gone through a century, and imaging technique emerges in an endless stream.Certainly, no matter be traditional imaging technique such as X ray, ultrasonic, computer tomography (CT), still modern molecular imaging technology such as nuclear magnetic resonance (MRI), optical imagery are preclinical medicine and distinctions won on the battlefield have been made in clinical medical development.Because existing imaging technique respectively has pluses and minuses in many-sides such as time and spatial resolution, penetration depth and energy extensibility, the use in conjunction of the imaging technique of various modes will provide more more fully information, and this has proposed new requirement for the development of following contrast agent.Yet, imaging technique commonly used at present all uses different contrast agent separately, in medical experiment in order to obtain more comprehensive information, often need to use simultaneously multiple contrast agent, this not only strengthens the risk of contrast agent practical application, but also the financial burden that increases the weight of can't be satisfied following multi-modal imaging technical tie-up application and development needs.Therefore, step up to research and develop a kind of novel type radiographic contrast of multiple imaging pattern that is applicable to simultaneously and become contemporary iconography pressing issues anxious to be solved.
In recent years, acoustic contrast has been brought into play enormous function in the ultrasonoscopy of organ, tissue.Perfect along with ultrasonic technique such as second harmonic, the development that triggers video picture etc. and contrast agent technology of preparing, acoustic contrast can improve the diagnosis to various lesion tissues greatly.In recent years along with people to the deepening continuously of acoustic contrast research, can obviously strengthen ultrasonic, the CT image of target area by changing the liquid fluorocarbon emulsion-type acoustic contrast that its filmogen and core material obtain; After adding Gd-DTPA, the MRI image of target area is strengthened, be expected to develop into a kind of novel shared formula contrast agent that is applicable to multi-modal imaging, but because the toxic and side effects of Gd-DTPA itself seriously limit its actual application prospect.Porphyrin and derivant thereof and/or phthalocyanine and derivant thereof, especially metalloporphyrin and derivant thereof and metal phthalocyanine and derivant thereof are not only the important probe of optical imagery, and can significantly strengthen the image of magnetic resonance/nuclear magnetic resonance, NMR, add to it and have tumor tissues targeting selectivity and the little advantage of toxic and side effects.Therefore,, be expected to research and develop a kind of, will the development of modern and future medicine iconography be exerted far reaching influence safely and efficiently applicable to the shared formula contrast agent of multi-modal imaging in conjunction with the advantage separately of acoustic contrast and porphyrin and phthalocyanines material.
Summary of the invention
The purpose of this invention is to provide a kind of novel type radiographic contrast that is applicable to multiple imaging pattern, by system and act locally on target tissue, can strengthen X ray to target tissue, ultrasonic, computer tomography (CT), nuclear magnetic resonance (MRI) and optical imagery effect, expand the application of acoustic contrast.
For achieving the above object, the technical solution used in the present invention is such, promptly a kind of novel type radiographic contrast that is applicable to multiple imaging pattern, and this contrast agent is
(1), the bonded coalition of porphyrin, derivatives of porphyrin and/or phthalocyanine, phthalocyanine derivates and acoustic contrast;
Or (2), in porphyrin, derivatives of porphyrin and/or phthalocyanine, phthalocyanine derivates and acoustic contrast coalition, adding has the material of pathoklisis to constitute to target tissue or lesions position;
Or (3), in porphyrin, derivatives of porphyrin and/or phthalocyanine, phthalocyanine derivates and acoustic contrast coalition, add penetrating peptide/wear the film peptide to constitute;
Or (4), in porphyrin, derivatives of porphyrin and/or phthalocyanine, phthalocyanine derivates and acoustic contrast coalition, add Polyethylene Glycol and derivant thereof and constitute.
Described porphyrin, derivatives of porphyrin and/or phthalocyanine, phthalocyanine derivates first-selection have metalloporphyrin and derivant and/or the metal phthalocyanine and the derivant thereof of biocompatibility and biological safety.Its combination is: physical bond as by absorption (as: static, weak force etc.), mixing, phase embedding, insert, coating, embedding, phase embedding, adhesion etc.; Chemical bond such as coordination, bonding etc. and biological combination such as antigen and antibody, part and receptor, complementary base or complementary nucleotide.As porphyrin and derivant thereof and/or phthalocyanine and derivant thereof being adhered to the surface of acoustic contrast: selected porphyrin and derivant thereof and/or phthalocyanine and derivant thereof are fully mixed with acoustic contrast the amount of blended proportioning Mesoporphyrin and derivant and/or phthalocyanine and derivant thereof (as described in be the safe and effective dosage that living organism can be accepted), can porphyrin and derivant thereof and/or phthalocyanine and derivant thereof be adhered to the acoustic contrast surface by electrostatic adsorption.
Acoustic contrast can be existing acoustic contrast in (but being not limited only to) market such as Sonovue, Optison, Albunex, the German products of producing such as Levovist produced in USA, also can be homemade acoustic contrast,
Described acoustic contrast comprises the continuous phase that the discontinuous phase that is made of filmogen parcel core body and aqueous medium constitute, and wherein said discontinuous phase is evenly dispersed in the described continuous phase, and the particle diameter of described discontinuous phase is 5nm～7 μ m.
Described filmogen is the filmogen with biological safety, biocompatibility and biodegradability; The material of described core body adopts gas, liquid or nano grade biological compatibility solid.
Its membrane material can be lipid, polymer, albumin, chitosan or surfactant-based.The gas that described core material adopted is selected from air, nitrogen, carbon dioxide, fluorine carbon appropriate hydrocarbon gas or alkanes gas; The liquid that described core material adopted is selected from C
5-C
6Alkane, C
5-C
12Fluorine carbon hydrocarbon, satisfied fatty acid, unsaturated fatty acid.After also the porphyrin of the safe and effective dosage that low temperature can be able to be accepted for liquid fluorocarbon liquid and living organism down and derivant thereof and/or phthalocyanine and derivant thereof were mixed, the acoustic contrast of fluorocarbon liquid and porphyrin and derivant and/or phthalocyanine and derivant thereof was wrapped up in formation by materials such as lipid, albumin, polymer, chitosan, surfactants in sonic oscillation or mechanical oscillation process.Wash porphyrin and derivant and/or phthalocyanine and the derivant thereof that does not entrain into phosphate buffer, the resulting contrast agent that is parcel porphyrin and derivant and/or phthalocyanine and derivant thereof.Also can in sonic oscillation or mechanical oscillation process, add core material and obtain to wrap up the contrast agent of porphyrin and derivant and/or phthalocyanine and derivant thereof.The gas that core material adopted is selected from air, nitrogen, carbon dioxide, fluorine carbon appropriate hydrocarbon gas or alkanes gas.Certainly, the size of acoustic contrast also can be micron order or nano level.
Lipid in the above-mentioned membrane material is selected from the 3-sn-phosphatidylcholine, 1 in the phospholipid; 2-two palmityls-sn-glyceryl-3-phosphatidyl glycerol base-sodium salt, 1; 2-distearyl acyl group-sn-glyceryl-3-phosphatidylcholine, 1; 2-two palmityls-sn-glyceryl-3-phosphatidyl acid-sodium salt, 1,2-two palmityls-sn-glyceryl-3-phosphatidylcholine, Phosphatidylserine or hydrogenated phospholipid acyl serine.Surfactant is selected from Tween surfactant and Span surfactant such as monolaurate (Tween20, Tween21, Span20), monopalmitate (Tween40, Span40), monostearate (Tw-een60, Tween61, Span60), tristearate (Tween65, Span65), monoleate (Tw-een80, Tween81, Span80) and trioleate (Tween85, Span85).Polymer can be (but being not limited only to) PLA (polylactic acid, PLA), glutin (gelatin), Polyethylene Glycol (polyethylene glycol, PEG), polysiloxanes (polysiloxane), polyethylene glycol oxide (polyethy-l ene oxide, PEO), polyacrylamide (polyacrylamid), polyacrylic acid (ester) (polyacry-late), polyurethane (polyurethane, PU), poly phosphate (polyphosphate ester), polyglycolic acid (ester) (polyglycolide, PGA), poly butyric (ester) (polyhydroxylbutyrate, PHBT), poly-(acid) acid anhydride (polyanhydrides, PAN), polycaprolactam (polycaprolactone, PCL), polyamino acid (polyamine acid), poly-hydroxyethyl methacrylic acid (ester) (polyhydroxy-ethylmethacrylate) and polylactic acid-glycolic guanidine-acetic acid { [poly (D, L-lactic-co-glycolic) acid], the copolymer (co-polymer) between PLGA} and above-mentioned polymer.
The measure that the targeting aggregation of contrast agent enhanced described in the present invention is taked is: target tissue or lesions position are had the material of pathoklisis on contrast agent surface connects, can improve the targeting of contrast agent greatly.Be mixed in the liquid in sonic oscillation or mechanical oscillation process by the proportioning of mass volume ratio 4-10% material various pathoklisises, can form contrast agent with targeting, wherein the material of pathoklisis can be an antibodies/receptors, as protein, peptide, aminoacid, adaptive son, oligonucleotide, vitamin B, folic acid, glycyrrhizic acid etc.
Be to increase the contrast agent body-internal-circulation time among the present invention, the proportioning of press mass volume ratio 1-10% add Polyethylene Glycol (polyethylene glycol, PEG) and derivant obtain to grow the circulation contrast agent.
For the function that initiatively penetrates that increases contrast agent among the present invention can be by adding penetrating peptide/wear film peptide (Cell Permeable Peptides, CPPs) obtain, as add tat peptide, PEP-1 peptide, MPG peptide etc., wherein the addition of penetrating peptide/wear film peptide is the safe and effective dosage that living organism can be accepted.
Also can utilize paramagnet, superparamagnetism material, isotope and fluorescein for the radiography effect that increases contrast agent among the present invention further modifies it.
Porphyrin that the present invention relates to and derivant thereof and/or phthalocyanine and derivant thereof are selected from all porphyrins with biocompatibility and biological safety and derivant thereof and/or phthalocyanine and derivant thereof; Be preferable over metalloporphyrin and derivatives of porphyrin thereof and/or metal phthalocyanine and derivant thereof.
The present invention is owing to being applicable to that the good effect that multiple imaging pattern produces is: during use with contrast agent of the present invention by system and act locally on target tissue, can strengthen X ray to target tissue, ultrasonic, CT, MRI and optical imagery effect, being expected to develop becomes a kind of novel common type contrast agent that is applicable to multiple imaging pattern, reduce contrast agent application risk and financial burden, have wide actual application prospect.
Description of drawings
Finding is carried the Manganese Porphyrin microbubble contrast agent under accompanying drawing 1 optical microscope;
Finding is carried the Manganese Porphyrin microbubble contrast agent under accompanying drawing 2 ultramicroscope;
Finding is carried the Manganese Porphyrin microbubble contrast agent under accompanying drawing 3 fluorescence microscopies;
The healthy experiment of accompanying drawing 4A Hepar Leporis seu Oryctolagi ultra sonic imaging figure;
Accompanying drawing 4B radiography carries the enhancement effect of Manganese Porphyrin microbubble contrast agent to ultra sonic imaging in the time of 3 seconds;
Accompanying drawing 4C radiography carries the enhancement effect of Manganese Porphyrin microbubble contrast agent to ultra sonic imaging in the time of 5 minutes;
Accompanying drawing 4D radiography carries the enhancement effect of Manganese Porphyrin microbubble contrast agent to ultra sonic imaging in the time of 30 minutes.
The specific embodiment
Example 1: the preparation of carrying the Manganese Porphyrin microbubble contrast agent
With phosphatidylcholine (DPPC), PHOSPHATIDYL ETHANOLAMINE (DPPE), DPPA fat acid (DPPA) is pressed mass ratio 5: 2: 1 and is mixed with Manganese Porphyrin (1mg), and other adds poloxamer 50 μ l, glycerol 0.5mg; With 37 ℃ of water-bath 30min behind the rubber stopper seal plastic tube, the air in the reuse perfluoropropane gas displacement plastic tube is after obtain carrying the Manganese Porphyrin microbubble contrast agent behind the mechanical oscillation 60s.(as Fig. 1, Fig. 2, Fig. 3).
Example 2: the preparation of carrying the phthalocyanine microbubble contrast agent
With phosphatidylcholine (DPPC), PHOSPHATIDYL ETHANOLAMINE (DPPE), DPPA fat acid (DPPA) is pressed mass ratio 5: 2: 1 and is mixed with phthalocyanine (1mg), and other adds poloxamer 50 μ l, glycerol 0.5mg; With 37 ℃ of water-bath 30min behind the rubber stopper seal plastic tube, the air in the reuse perfluoropropane gas displacement plastic tube is after obtain carrying the phthalocyanine microbubble contrast agent behind the mechanical oscillation 60s.
Example 3: carry the enhancement effect of Manganese Porphyrin microbubble contrast agent to ultra sonic imaging
Use GE Vivid7 colorful ultrasonic diagnostic apparatus, 12L linear array probe, second harmonic tranmitting frequency 5.2MHz, receive frequency 10.5MHz.The instrument all conditions is set to same standard: mechanical index during second harmonic (MI) is set at 0.24, gains to be-14dB, and the video picture degree of depth is fixed as 4cm, and parameters such as TGC, focusing range all transfer to optimum state.With Ultrasound Instrument internal work station storage sound attitude radiography data.
With new zealand white rabbit (deriving from Medical University Of Chongqing's Experimental Animal Center) is experimental subject, after using 4% pentobarbital sodium (1ml/kg) intramuscular injection anesthesia new zealand white rabbit, dorsal position is fixed, adopt self cross-reference method, conventional first-harmonic ultrasonic scan obtains Hepar Leporis seu Oryctolagi tangent plane ultrasonogram before the radiography, change imaging modality into second harmonic, 0.05ml carries the Manganese Porphyrin microbubble contrast agent with the dilution of 0.45ml normal saline, inject in the rabbit body time of developing and imaging results behind the observation liver radiography through auricular vein group.And measure image changes of echo intensity before and after the radiography with " DFY type ultrasonic image quantitatively analyzing diagnostic apparatus ".Found that visual observations under the harmonic wave state, injection of contrast medium the contrast agent filling occurred after 3 seconds in the liver blood vessel, and liver parenchyma echo obviously strengthens after 5 minutes, still as seen more obviously strengthened after 30 minutes.(as Fig. 4 A, Fig. 4 B, Fig. 4 C, Fig. 4 D).
Example 4: carry the Manganese Porphyrin contrast agent or carry the enhancement effect of phthalocyanine contrast agent to CT, MRI imaging
Method (Invest Radiol, 1991 with reference to Mattrey RF etc.; 26 (9): 792-798) in the process of preparation liquid fluorocarbon liplid emulsions, add Manganese Porphyrin or phthalocyanine (1mg/5ml Emulsion) and obtain to carry Manganese Porphyrin or carry the phthalocyanine contrast agent.Choosing 24 new zealand white rabbits (deriving from Medical University Of Chongqing's Experimental Animal Center) is experimental subject, 6 every group, carries out CT, MRI imaging experiment respectively.Found that, carry Manganese Porphyrin or carry obviously enhanced CT imaging effect of phthalocyanine contrast agent, and can obvious Contrast-enhanced MRI imaging effect.
Claims (9)
1. novel type radiographic contrast that is applicable to multiple imaging pattern, it is characterized in that: this contrast agent is:
(1), the bonded coalition of porphyrin, derivatives of porphyrin and/or phthalocyanine, phthalocyanine derivates and acoustic contrast;
Or (2), in porphyrin, derivatives of porphyrin and/or phthalocyanine, phthalocyanine derivates and acoustic contrast coalition, adding has the material of pathoklisis to constitute to target tissue or lesions position;
Or (3), in porphyrin, derivatives of porphyrin and/or phthalocyanine, phthalocyanine derivates and acoustic contrast coalition, add penetrating peptide/wear the film peptide to constitute;
Or (4), in porphyrin, derivatives of porphyrin and/or phthalocyanine, phthalocyanine derivates and acoustic contrast coalition, add Polyethylene Glycol and derivant thereof and constitute.
2. a kind of novel type radiographic contrast that is applicable to multiple imaging pattern according to claim 1 is characterized in that: described porphyrin, derivatives of porphyrin and/or phthalocyanine, phthalocyanine derivates first-selection have metalloporphyrin and derivant and/or the metal phthalocyanine and the derivant thereof of biocompatibility and biological safety.Described combination comprises: physical bond, chemical bond and biological combination.
3. a kind of novel type radiographic contrast that is applicable to multiple imaging pattern according to claim 1, it is characterized in that: described acoustic contrast comprises the continuous phase that the discontinuous phase that is made of filmogen parcel core body and aqueous medium constitute, wherein said discontinuous phase is evenly dispersed in the described continuous phase, and the particle diameter of described discontinuous phase is 5nm～7 μ m.
4. a kind of novel type radiographic contrast that is applicable to multiple imaging pattern according to claim 3 is characterized in that: described filmogen is the filmogen with biological safety, biocompatibility and biodegradability; The material of described core body adopts gas, liquid or nano grade biological compatibility solid.
5. a kind of novel type radiographic contrast that is applicable to multiple imaging pattern according to claim 4 is characterized in that described filmogen is selected from lipid, albumin, chitosan and derivant thereof, surfactant and polymer.
6. a kind of novel type radiographic contrast that is applicable to multiple imaging pattern according to claim 5; it is characterized in that: described lipid is selected from the 3-sn-phosphatidylcholine, 1 in the phospholipid; 2-two palmityls-sn-glyceryl-3-phosphatidyl glycerol base-sodium salt, 1; 2-distearyl acyl group-sn-glyceryl-3-phosphatidylcholine, 1; 2-two palmityls-sn-glyceryl-3-phosphatidyl acid-sodium salt, 1,2-two palmityls-sn-glyceryl-3-phosphatidylcholine, Phosphatidylserine or hydrogenated phospholipid acyl serine.
7. a kind of novel type radiographic contrast that is applicable to multiple imaging pattern according to claim 5, it is characterized in that: described surfactant is selected from monolaurate (Tween20, Tween21, Span20), monopalmitate (Tween40, Span40), monostearate (Tween60, Tween61, Span60), tristearate (Tween65, Span65), monoleate (Tween80, Tween81, Span80) and trioleate (Tween85, Span85).
8. a kind of novel type radiographic contrast that is applicable to multiple imaging pattern according to claim 5, it is characterized in that: described polymer is selected from PLA (polylactic acid, PLA), glutin (gelatin), Polyethylene Glycol (polyethylene glycol, PEG), polysiloxanes (polysiloxane), polyethylene glycol oxide (polyethylene oxide, PEO), polyacrylamide (polyacrylamid), polyacrylic acid (ester) (polyacrylate), polyurethane (polyurethane, PU), poly phosphate (polyphosphate ester), polyglycolic acid (ester) (polyglycolide, PGA), poly butyric (ester) (polyhydroxylbutyrate, PHBT), poly-(acid) acid anhydride (polyanhydrides, PAN), polycaprolactam (polycaprolactone, PCL), polyamino acid (polyamine acid), poly-hydroxyethyl methacrylic acid (ester) (polyhydroxyethyl methacrylate) and polylactic acid-glycolic guanidine-acetic acid { [poly (D, L-lactic-co-glycolic) acid], the copolymer (co-polymer) between PLGA} and above-mentioned polymer.
9. a kind of novel type radiographic contrast that is applicable to multiple imaging pattern according to claim 4 is characterized in that the gas that described core material adopts is selected from air, nitrogen, carbon dioxide, fluorine carbon appropriate hydrocarbon gas or alkanes gas; The liquid that described core material adopted is selected from C
5-C
6Alkane, C
5-C
12Fluorine carbon hydrocarbon, satisfied fatty acid, unsaturated fatty acid.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102398026A (en) * | 2010-09-10 | 2012-04-04 | 聚和国际股份有限公司 | Chitosan-modified gold nanoparticles and preparation method thereof |
| CN107206111A (en) * | 2014-12-31 | 2017-09-26 | 蓝瑟斯医学影像公司 | The gas micro composition and correlation technique of lipid envelope |
| CN108853520A (en) * | 2018-08-24 | 2018-11-23 | 重庆医科大学 | A kind of quick type lipid nano particle of sound, using and preparation method thereof |
| US10583208B2 (en) | 2016-07-06 | 2020-03-10 | Lantheus Medical Imaging, Inc. | Methods for making ultrasound contrast agents |
| US10588988B2 (en) | 2016-05-04 | 2020-03-17 | Lantheus Medical Imaging, Inc. | Methods and devices for preparation of ultrasound contrast agents |
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2008
- 2008-02-04 CN CNA2008100693565A patent/CN101229382A/en active Pending
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| CN102398026B (en) * | 2010-09-10 | 2013-10-23 | 聚和国际股份有限公司 | Chitosan-modified gold nanoparticles and preparation method thereof |
| CN102398026A (en) * | 2010-09-10 | 2012-04-04 | 聚和国际股份有限公司 | Chitosan-modified gold nanoparticles and preparation method thereof |
| CN107206111B (en) * | 2014-12-31 | 2021-04-27 | 蓝瑟斯医学影像公司 | Lipid-encapsulated gas microsphere compositions and related methods |
| CN107206111A (en) * | 2014-12-31 | 2017-09-26 | 蓝瑟斯医学影像公司 | The gas micro composition and correlation technique of lipid envelope |
| US11395856B2 (en) | 2014-12-31 | 2022-07-26 | Lantheus Medical Imaging, Inc. | Lipid-encapsulated gas microsphere compositions and related methods |
| US10583207B2 (en) | 2014-12-31 | 2020-03-10 | Lantheus Medical Imaging, Inc. | Lipid-encapsulated gas microsphere compositions and related methods |
| US10588988B2 (en) | 2016-05-04 | 2020-03-17 | Lantheus Medical Imaging, Inc. | Methods and devices for preparation of ultrasound contrast agents |
| US11266749B2 (en) | 2016-07-06 | 2022-03-08 | Lantheus Medical Imaging, Inc. | Methods for making ultrasound contrast agents |
| US11266750B2 (en) | 2016-07-06 | 2022-03-08 | Lantheus Medical Imaging, Inc. | Methods for making ultrasound contrast agents |
| US10583208B2 (en) | 2016-07-06 | 2020-03-10 | Lantheus Medical Imaging, Inc. | Methods for making ultrasound contrast agents |
| US11344636B2 (en) | 2016-07-06 | 2022-05-31 | Lantheus Medical Imaging, Inc. | Methods for making ultrasound contrast agents |
| US11529431B2 (en) | 2016-07-06 | 2022-12-20 | Lantheus Medical Imaging, Inc. | Methods for making ultrasound contrast agents |
| US11857646B2 (en) | 2016-07-06 | 2024-01-02 | Lantheus Medical Imaging, Inc. | Methods for making ultrasound contrast agents |
| US11925695B2 (en) | 2016-07-06 | 2024-03-12 | Lantheus Medical Imaging, Inc. | Methods for making ultrasound contrast agents |
| CN108853520A (en) * | 2018-08-24 | 2018-11-23 | 重庆医科大学 | A kind of quick type lipid nano particle of sound, using and preparation method thereof |
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