CN105300939A - Nanometer particle microenvironment temperature control fluorescence-based molecular probe and system and method thereof - Google Patents
Nanometer particle microenvironment temperature control fluorescence-based molecular probe and system and method thereof Download PDFInfo
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Abstract
The invention discloses a nanometer particle microenvironment temperature control fluorescence-based molecular probe, a system and a method. A molecular probe instant controlling method which does not change excitation light is realized by indirectly controlling fluorescent molecules bound with nanometer particles to emit light by a nanometer particle microenvironment temperature control method. The method is simple and feasible in operation; due to the fact that nanometer particles with different absorption peaks are adopted to control, and different target points are correspondingly labeled respectively, the fluorescence intensity of each position can be controlled by external control light corresponding to the different absorption peaks under the same fluorescent molecule and the same fluorescent light path, and fluorescence labeling at multiple positions is observed and imaged; the molecular probe can be precisely labeled and positioned easily by image comparison after the fluorescence intensity is changed, and the specificity is good; due to the fact that background fluorescence is not controlled by an external heating source, interference of background fluorescence is reduced, signal to noise ratio is increased, the spatial resolution is improved, and the molecular probe has an enormous application prospect.
Description
Technical field
The present invention relates to biomedical optical fluorescent technique, be specifically related to a kind of molecular probe based on nano particle microenvironment temperature control fluorescence and system and method thereof.
Background technology
Molecular medicine image is the probe adopting high specific, and non-invasively target site specific with cells in vivo is combined, with the physiology of imaging modality reflection molecular level and pathological information.Because molecular image studies disease at cell and molecular level, so molecular medicine image has high sensitivity and high specific.A kind of compound that the material (as part or antibody etc.) that energy and target site specificity combine combines with ad hoc approach with the material (as isotope, fluorescence molecule or paramagnetic atom) that can produce iconography signal and formed, is molecular probe.As the gordian technique in molecular medicine image, the preparation level of molecular probe will affect the image quality of whole system.According to the needs of clinical diagnosis or fundamental research, the probe different molecular biology carrier design can being selected to meet molecular imaging require, to complete the task of specific diagnosis or research.In biomedical Imaging-PAM, normal fluorescence molecule or the fluorescin of adopting, as signaling molecule, carrys out position probe by detecting the fluorescence signal excited.
In the middle of traditional many fluorescence labeling dyeing, first need to find the mutual nonoverlapping multiple fluorescence molecule of suitable emission spectrum, can realize observing the separation of different-waveband fluorescence by optical filter; Secondly, all fluorescence molecules chosen also need to have with other molecule to bind performance preferably, in conjunction with common ingredient probe, can inherently have certain difficulty for many fluorescence labelings in the selection of fluorescence molecule.In addition detecting each fluorescence molecule needs corresponding complete from excitation source, optical filter to the required element of a set of light paths such as dichroic mirror, and hardware cost is higher.Due to the incomplete separation between fluorescence molecule emission spectrum and there is the reasons such as background fluorescence interference widely in practical operation, cause when certain wavelength fluorescent is observed and be mixed into other fluorescence signal, reduce observation signal to noise ratio (S/N ratio), affect observed result.
Summary of the invention
In order to overcome above problems of the prior art, the present invention proposes a kind of molecular probe based on nano particle microenvironment temperature control fluorescence and detection system thereof and detection method.
One object of the present invention is to provide a kind of molecular probe based on nano particle microenvironment temperature control fluorescence.
Molecular probe based on nano particle microenvironment temperature control fluorescence of the present invention comprises: nano particle, fluorescence molecule and targeting molecule; Wherein, fluorescence molecule is thermally sensitive small molecule fluorescent molecule; Directly be connected between the nano particle that fluorescence molecule and known absorbing are composed or indirectly connect; Nano particle is directly or indirectly connected with targeting molecule again; Targeting molecule is attached to target site by specific binding effect.
Another object of the present invention is to provide a kind of molecular probe system based on nano particle microenvironment temperature control fluorescence.
Molecular probe system based on nano particle microenvironment temperature control fluorescence of the present invention comprises: nano particle, fluorescence molecule, targeting molecule, exciting light, heating source and fluorescent probe; Wherein, fluorescence molecule is thermally sensitive small molecule fluorescent molecule; Directly be connected between the nano particle that fluorescence molecule and known absorbing are composed or indirectly connect; Nano particle is directly or indirectly connected with targeting molecule again; Fluorescence molecule, nano particle and targeting molecule form molecular probe; When molecular probe is distributed in imaging region, targeting molecule is attached to target site by specific binding effect; Exciting light incides imaging region, and fluorescence excitation molecule sends fluorescence; Fluorescent probe detects fluorescence; Heating source is incident to imaging region, to nano particle heating, changes the temperature of nano particle, change nano particle surrounding microenvironment temperature simultaneously, thus affecting the characteristics of luminescence of the fluorescence molecule be connected with nano particle, fluorescence intensity or spectrum change, and realize light regulation and control.
Another object of the present invention is the detection method providing a kind of molecular probe based on nano particle microenvironment temperature control fluorescence.
The detection method of the molecular probe based on nano particle microenvironment temperature control fluorescence of the present invention, comprises the following steps:
1) be directly connected by covalent bond between the nano particle selected thermally sensitive small molecule fluorescent molecule and known absorbing composes or pass through to connect and intermolecularly to connect in succession, nano particle connects targeting molecule again, and fluorescence molecule, nano particle and targeting molecule form molecular probe;
2) when molecular probe is distributed in imaging region, targeting molecule is attached to target site by specific binding effect;
3) exciting light incides imaging region, and fluorescence excitation molecule sends fluorescence;
4) heating source is incident to imaging region, to nano particle heating, change the temperature of nano particle, change nano particle surrounding microenvironment temperature simultaneously, thus affecting the characteristics of luminescence of the fluorescence molecule be connected with nano particle, fluorescence intensity or spectrum change;
5) remove heating source, on micro-nano-scale, heat diffusion speed is fast, and the temperature of nano particle reduces rapidly, thus realizes instant light regulation and control.
Wherein, in step 1) in, for target site to be detected, select can with its combination and only with the targeting molecule of its combination.Connection between fluorescence molecule and nano particle, adopt nanoparticle surface itself with group and the activated group of fluorescence molecule form covalent bond, thus fluorescence molecule is connected directly between the surface of nano particle; The group of nano particle is the one in hydroxyl, carboxyl and sulfydryl, and the covalent bond of formation is the one in amido link, ester bond, disulfide bond and ehter bond.If under fluorescence molecule and nano particle are easy to energy transferring and interactional situation, then by the organic molecule of linear or cladodification, high molecular polymer or biomolecule as connection molecule, the one end connecting molecule is connected with nano particle, the other end is connected with the molecule of fluorescence molecule, thus the molecule of fluorescence molecule to be fixed on around nano particle but direct contact does not occur, formed and indirectly connect.Or, be indirectly connected by clad between fluorescence molecule with nano particle.Similarly, targeting molecule is connected to the surface of nano particle by covalent bond; Or by the oligomer of linear or cladodification to superpolymer as connecting molecule, be indirectly connected to the surface of nano particle; Or targeting molecule is connected with nano particle indirectly by clad.
In step 2) in, molecular probe is distributed in imaging region and is divided into three kinds of modes: a) the target site tissue being combined with molecular probe is made into microsection, at fluorescence microscopy Microscopic observation; If b) for live body image, then need by be administered systemically or topical method by molecular probe injection or be injected in body; If c) for checking in art, then need in art, molecular probe to be injected, smeared or be coated in imaging region.
In step 4) in, heating source adopt regulation and control light, microwave or ultrasonic in one.It is made to heat up as heating source to nano particle heating according to regulation and control light, then the absorption peak of nano particle should avoid the wavelength of the exciting light as fluorescence molecule, avoid producing cross influence, to ensure, when exciting light is incident, only having fluorescence molecule to be excited to send fluorescence.
The fluorescence signal comprised further by extracting regulation and control removes background fluorescence, and specifically comprise the following steps: a) open exciting light light path, fluorescence molecule is excited, fluorescent probe carries out imaging to imaging region, is regulated front image; B) open heating source, heat imaging region, fluorescence intensity changes, and fluorescent probe carries out imaging to imaging region again, is regulated rear image; C) image before and after regulation and control is carried out subtracting each other or filtering process, thus remove most of background fluorescence, realize the object removing noise and background signal.
For multiple different target site, select targeting molecule corresponding thereto respectively, and different targeting molecule is connected to different nano particles correspondingly respectively, different nano particles has different absorption peaks; When heating source is for regulation and control light, for the regulation and control light of different wave length, the nano particle corresponding with it heats up, the intensity of the fluorescence molecule regulating and controlling to be connected with nano particle or spectrum, thus for same fluorescence molecule, same exciting light, adopt different nano particle regulation and control, the target site that correspondence markings is different respectively, namely under can realizing same fluorescence molecule, same fluorescence light path, the additional regulation and control light utilizing different absorption peak corresponding regulates and controls the fluorescence intensity of each target site, realizes the fluorescently-labeled observation of multidigit point and imaging.In existing Imaging-PAM, as needs carry out multiple fluorescence labeling, need to find multiple material overlapping less between suitable spectrum, and each fluorescence needs to excite light, optical filter, dichroic mirror etc. to match to use with corresponding.
On the other hand, molecular probe is formed for each fluorescence molecule, nano particle and targeting molecule, contrast process is subtracted each other by the picture before and after changing fluorescence intensity, can easily realize locating the precise marking of this molecular probe, specificity is good, and does not regulate and control by external heat source due to background fluorescence, background fluorescence interference will be greatly reduced, improve signal to noise ratio (S/N ratio), room for promotion resolution, has considerable application prospect.
Advantage of the present invention:
The present invention is luminous by the fluorescence molecule bound the temperature controlled method indirect adjustments and controls of nano particle microenvironment and nano particle, and achieve a kind of instant regulate and control method of molecular probe not changing exciting light, operation is simple; The present invention adopts the different nano particle of absorption peak to regulate and control to same fluorescence molecule, the target site that correspondence markings is different respectively, can realize under same fluorescence molecule, same fluorescence light path, the additional regulation and control light utilizing different absorption peak corresponding regulates and controls the fluorescence intensity of respective position, realizes the fluorescently-labeled observation of multidigit point and imaging; Molecular probe is formed for each fluorescence molecule, nano particle and targeting molecule, contrasted by the picture before and after changing fluorescence intensity, can easily realize locating the precise marking of this molecular probe, specificity is good, and because background fluorescence does not regulate and control by extra heating sources, background fluorescence interference will be greatly reduced, improve signal to noise ratio (S/N ratio), room for promotion resolution, has considerable application prospect.
The present invention also can be applied to living body fluorescent imaging.By be administered systemically or topical method by molecular probe injection or be injected in body, observe the probe mark situation under shallow layer skin in imaging systems, and by additional regulation and control light, fluorescence molecule not of the same race is regulated and controled, concrete grammar and principle are as above-mentioned, Treatment Analysis is carried out to result picture, comparatively accurate living body fluorescent imaging results can be obtained.
Accompanying drawing explanation
Fig. 1 is the schematic diagram of an embodiment of the molecular probe system based on nano particle microenvironment temperature control fluorescence of the present invention;
Fig. 2 is the schematic diagram of an embodiment of the molecular probe based on nano particle microenvironment temperature control fluorescence of the present invention;
Fig. 3 (a) ~ (f) is respectively the schematic diagram of the different connected modes of the molecular probe based on nano particle microenvironment temperature control fluorescence of the present invention.
Embodiment
Below in conjunction with accompanying drawing, by embodiment, the present invention will be further described.
As shown in Figure 1, the molecular probe system based on nano particle microenvironment temperature control fluorescence of the present invention comprises: nano particle 11, fluorescence molecule 12, targeting molecule 13, exciting light 2, heating source 3 and fluorescent probe 4; Wherein, fluorescence molecule, nano particle and targeting molecule form molecular probe; Molecular probe is injected into imaging region 5; Exciting light 2 incides imaging region, and fluorescence excitation molecule sends fluorescence; Fluorescent probe 4 detects fluorescence; Heating source 3 is incident to imaging region 5, and change nano particle surrounding microenvironment temperature, thus affect the characteristics of luminescence of the fluorescence molecule be connected with nano particle, fluorescence intensity or spectrum change, and realizes light regulation and control.Thermally sensitive fluorescence molecule refers to that the fluorescent characteristic of fluorescence molecule changes when the surrounding microenvironment temperature of fluorescence molecule changes, and fluorescence intensity or spectrum change.
As shown in Figure 2, nano particle 11, fluorescence molecule 12 and targeting molecule 13 form molecular probe; Wherein, the molecule of fluorescence molecule is connected to the surface of nano particle 11 indirectly by connecting molecule 14.
As shown in Figure 3, fluorescence molecule and targeting molecule both can be connected directly between nano-material surface, also indirectly can be connected to the surface of nano material by connection molecule or clad; Wherein, (a) is connected with nano particle 11 respectively by being connected molecule 14 with targeting molecule 13 indirectly for fluorescence molecule 12; B () is directly connected with nano particle 11 for targeting molecule 13, fluorescence molecule 12 connects by being connected molecule 14 indirectly with nano particle 11; C () connects indirectly for targeting molecule 13 passes through to be connected molecule 14 with nano particle 11, fluorescence molecule 12 is directly connected with nano particle 11; D () is directly connected with nano particle 11 with targeting molecule 13 respectively for fluorescence molecule 12; E () directly connects for targeting molecule 13 passes through to be connected molecule 14 with nano particle 11, fluorescence molecule 12 is connected by clad 15 indirectly with nano particle 11; F () is directly connected with nano particle 11 for targeting molecule 13, fluorescence molecule 12 is connected by clad 15 indirectly with nano particle 11, the shell structurre of the organic or inorganic that nano particle itself has also as clad, as hyaluronic acid shell, can gather dopamine shell, porous silica shell, zinc sulphide shell etc.
Embodiment one
In the present embodiment, select maximum absorption band at the gold nanorods of 512nm and 780nm as nano particle, fluorescence molecule adopts rhdamine B; Rhdamine B molecule is connected with nanometer rods as connection molecule by the peg molecule with sulfydryl utilizing molecular weight to be 3.4kDa, and to add excessive in sulfydryl and amino peg molecule simultaneously.Finally, targeting molecule is connected to the surface of gold nanorods by amide bond chemistry, and is separated with centrifugal method, obtain molecular probe.
Above-mentioned molecular probe and histotomy are hatched jointly, and washes away unnecessary molecular probe with PBS buffer solution.Fluorescent microscope is utilized to carry out imaging to section.Then utilize wavelength for 785nm, output power is that the regulation and control light of 110mW irradiates 20s to imaging region, ensures that the irradiation that in imaging region, every bit is subject to is basically identical.Close regulation and control light, rapidly re-imaging is carried out to the same area.Difference or filtering are asked to the distribution of the fluorescence intensity of twice imaging, obtains the amplitude that fluorescence intensity weakens and namely reflect the dense poly-degree of molecular probe.
Embodiment two
Three kinds of different molecular probes are adopted, all identical with embodiment 1 of its structure and preparation method in the present embodiment.Unique difference is, three kinds of molecular probes in the present embodiment, and the longitudinal resonance peak of its gold nanorods used is respectively 780nm, 1064nm and 1240nm, and three kinds of a kind of targeting molecule different from each other of each correspondence of gold nanorods.
Use these three kinds of molecular probes to mark histotomy simultaneously, and carry out imaging with fluorescent microscope.Then, the difference of the target site studied as required, the laser instrument selecting wavelength to be respectively 785nm, 1064nm and 1240nm separately or jointly irradiate imaging region.Each irradiation is rapid afterwards carries out re-imaging to the same area, and carries out asking difference or filtering with the fluorescence distribution of pre-irradiation.The degree that after respective wavelength irradiation, fluorescence intensity weakens reflects the dense poly-situation of the molecular probe corresponding to respective absorption wavelength gold nanorods.By the switch of three tunnels regulation and control light, can fluorescence signal on a certain target site of oriented detection, reach the effect to the fluorescently-labeled Real-Time Monitoring imaging of multidigit point, the synchronous imaging of multiple biological target can be realized.Image procossing for imaging results also can improve the precision of fluoroscopic examination.
Embodiment three
The present embodiment is applied to living body fluorescent imaging.Using hypodermic tumour as probe target site, adopt the molecular probe that two kinds different, all identical with embodiment 1 of its structure and preparation method, different places is the antibody that uses of the two kinds of probes corresponding mark in conjunction with blood vessel hyperplasia and cancer cell respectively, and the longitudinal resonance peak of two kinds of gold nanorods is respectively 780nm and 1064nm.These two kinds of probes are passed through the method for tail vein injection or direct local injection, inject in Mice Body.And fluorescence is observed in whole body optical imaging system, the red/infrared light of 785nm and 1064nm is used to modulate respectively, and difference or filtering process are asked to result, method and principle same as above, can obtain the comparatively accurate fluorescence imaging result for blood vessel hyperplasia mark and cancer cell mark, auxiliary detection is observed.
It is finally noted that, the object publicizing and implementing mode is to help to understand the present invention further, but it will be appreciated by those skilled in the art that: without departing from the spirit and scope of the invention and the appended claims, various substitutions and modifications are all possible.Therefore, the present invention should not be limited to the content disclosed in embodiment, and the scope that the scope of protection of present invention defines with claims is as the criterion.
Claims (10)
1. based on a molecular probe for nano particle microenvironment temperature control fluorescence, it is characterized in that, described molecular probe comprises: nano particle, fluorescence molecule and targeting molecule; Wherein, described fluorescence molecule is thermally sensitive small molecule fluorescent molecule; Directly be connected between the nano particle that described fluorescence molecule and known absorbing are composed or indirectly connect; Described nano particle is directly or indirectly connected with targeting molecule again; Described targeting molecule is attached to target site by specific binding effect.
2. molecular probe as claimed in claim 1, it is characterized in that, described fluorescence molecule is connected with the direct of nano particle, employing nanoparticle surface itself with group and the activated group of fluorescence molecule form covalent bond; Described fluorescence molecule and nano particle intermolecularly to connect in succession by being connected, and the organic molecule of linear or cladodification, high molecular polymer or biomolecule are as connection molecule, and one end of connection molecule is connected with nano particle, and the other end is connected with the molecule of fluorescence molecule; Or indirectly connected by clad.
3. molecular probe as claimed in claim 1, it is characterized in that, described targeting molecule is connected to the surface of nano particle by covalent bond; Or by the organic molecule of linear or cladodification, high molecular polymer or biomolecule as connection molecule, be indirectly connected to the surface of nano particle; Or targeting molecule is connected with nano particle indirectly by clad.
4. based on a molecular probe system for nano particle microenvironment temperature control fluorescence, it is characterized in that, described molecular probe system comprises: nano particle, fluorescence molecule, targeting molecule, exciting light, heating source and fluorescent probe; Wherein, described fluorescence molecule is thermally sensitive small molecule fluorescent molecule; Directly be connected between the nano particle that described fluorescence molecule and known absorbing are composed or indirectly connect; Described nano particle is directly or indirectly connected with targeting molecule again; Described fluorescence molecule, nano particle and targeting molecule form molecular probe; When molecular probe is distributed in imaging region, targeting molecule is attached to target site by specific binding effect; Exciting light incides imaging region, and fluorescence excitation molecule sends fluorescence; Described fluorescent probe detects fluorescence; Described heating source is incident to imaging region, to nano particle heating, changes the temperature of nano particle, change nano particle surrounding microenvironment temperature simultaneously, thus affecting the characteristics of luminescence of the fluorescence molecule be connected with nano particle, fluorescence intensity or spectrum change, and realize light regulation and control.
5. molecular probe system as claimed in claim 1, is characterized in that, described heating source adopt regulation and control light, microwave or ultrasonic in one.
6. molecular probe system as claimed in claim 5, is characterized in that, for regulation and control light as heating source, the absorption peak of nano particle avoids the wavelength of the exciting light as fluorescence molecule.
7., based on a detection method for the molecular probe of nano particle microenvironment temperature control fluorescence, it is characterized in that, comprise the following steps:
1) be directly connected by covalent bond between the nano particle selected small molecule fluorescent molecule and known absorbing composed or intermolecularly connect in succession by connecting, nano particle connects targeting molecule again, and fluorescence molecule, nano particle and targeting molecule form molecular probe;
2) when molecular probe is distributed in imaging region, targeting molecule is attached to target site by specific binding effect;
3) exciting light incides imaging region, and fluorescence excitation molecule sends fluorescence;
4) heating source is incident to imaging region, to nano particle heating, change the temperature of nano particle, change nano particle surrounding microenvironment temperature simultaneously, thus affecting the characteristics of luminescence of the fluorescence molecule be connected with nano particle, fluorescence intensity or spectrum change;
5) remove heating source, on micro-nano-scale, heat diffusion speed is fast, and the temperature of nano particle reduces rapidly, thus realizes instant light regulation and control.
8. detection method as claimed in claim 7, is characterized in that, in step 2) in, molecular probe is distributed in imaging region and is divided into three kinds of modes: a) the target site tissue being combined with molecular probe is made into microsection, at fluorescence microscopy Microscopic observation; B) by be administered systemically or topical method by molecular probe injection or be injected in imaging region; C) molecular probe is injected, smeared or be coated in imaging region.
9. detection method as claimed in claim 7, it is characterized in that, for multiple different target site, select targeting molecule corresponding thereto respectively, and different targeting molecule is connected to different nano particles correspondingly respectively, different nano particles has different absorption peaks; When heating source is for regulation and control light, for the regulation and control light of different wave length, the nano particle corresponding with it heats up, the intensity of the fluorescence molecule regulating and controlling to be connected with nano particle or spectrum, thus for same fluorescence molecule, same exciting light, adopt different nano particle regulation and control, the target site that correspondence markings is different respectively, namely under can realizing same fluorescence molecule, same fluorescence light path, the additional regulation and control light utilizing different absorption peak corresponding regulates and controls the fluorescence intensity of each target site, realizes the fluorescently-labeled observation of multidigit point and imaging.
10. detection method as claimed in claim 7, it is characterized in that, the fluorescence signal comprised further by extracting regulation and control removes background fluorescence, comprise the following steps: a) open exciting light light path, fluorescence molecule is excited, fluorescent probe carries out imaging to imaging region, is regulated front image; B) open heating source, heat imaging region, fluorescence intensity changes, and fluorescent probe carries out imaging to imaging region again, is regulated rear image; C) image before and after regulation and control is carried out subtracting each other or filtering process, thus remove most of background fluorescence.
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