CN104083771A - Fluorescence resonance energy transfer-based tumor imaging and therapeutic targeting system and construction method thereof - Google Patents

Fluorescence resonance energy transfer-based tumor imaging and therapeutic targeting system and construction method thereof Download PDF

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CN104083771A
CN104083771A CN201410288247.8A CN201410288247A CN104083771A CN 104083771 A CN104083771 A CN 104083771A CN 201410288247 A CN201410288247 A CN 201410288247A CN 104083771 A CN104083771 A CN 104083771A
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tumor
dox
resonance energy
fluorescence resonance
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郑耿锋
唐静
孔彪
王永成
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Fudan University
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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a fluorescence resonance energy transfer-based tumor imaging and therapeutic targeting system and a construction method thereof. According to the construction method, luminous carbon quantum dots (CDots) are synthesized by adopting an electrochemical stripping method, polyethylene glycol with amino at the terminal is grafted on the CDots by using an EDC/NHS (dichloroethane/ N-hydroxysuccinimide) chemical coupling method, and then a tumor targeted drug folic acid is grafted; adriamycin is grafted by means of the CDots and pi-pi stacking action on the surface of the anti-tumor drug adriamycin to obtain the fluorescence resonance energy jump-based two-photon imaging and targeting therapeutic tumor system. The system is a composite nano-material, can be used for judging drug release and property of energy resonance transfer according to illumination intensity and color and penetrating a deep animal tissue by using two-photon imaging, and can be developed to the field of tumor treatment. The fluorescence resonance energy transfer-based tumor imaging and therapeutic targeting system is stable in reaction and simple, easy to operate, low in cost, free of pollution and easily controlled in structure; the product is uniformly distributed, cannot easily agglomerate, and is high in purity, and easy to industrialize.

Description

Tumor imaging based on FRET (fluorescence resonance energy transfer) and treatment target system and construction method thereof
Technical field
The invention belongs to medical technical field, be specifically related to a kind of two-photon imaging and targeting therapy on tumor system and construction method thereof of fluorescence resonance energy transition.
Background technology
Carbon is the basis of all known life on the earth, and the research taking carbon as basic nanotechnology in recent years has become study hotspot.Carbon nano-structured material taking CNT as representative is considered to one of focus of current nanosecond science and technology research due to its unique structure and physics, chemical characteristic, and shows huge potential using value at aspects such as optics, electronics and informaticss.Conventional material with carbon element is a kind of typical low bandgap material, and therefore traditional view thinks that nano material has abundant photoluminescent property unlike other semi-conducting materials.Because it has various electron orbit characteristic (sp, sp2, sp3), form the material that many structures and character are peculiar, wherein fullerene and CNT be carbon nano-structured in the most popular object of study, in addition, the member of other carbon nanomaterial family, as carbon quantum dot also little by little receives increasing concern.
It is worth noting, recent research shows that CNT can send fluorescence under given conditions, and the surface of carbon quantum dot also can produce stronger fluorescence after macromolecule modified.The synthetic method of carbon quantum dot is mainly divided into two large class: top-down and bottom-up approach.Top-down approach refers to that carbon quantum dot forms or peels off out in larger carbon structure material, and it comprises arc cutting, laser ablation and electrochemical oxidation process.Bottom-up approach refers to the formation of carbon quantum dot.
Mainly from molecule predecessor, it mainly comprises calcining or heating, carrier synthetic method, microwave process for synthesizing and the ultrasonic method such as synthetic.Sun seminar prepares the fluorescent carbon nano-particle of maximum emission wavelength at 400-694 nm by laser ablation methods, modify and can give its good water dispersible by PEG, PEG is modified to carbon quantum dot surface and successfully realizes lymph circulation living imaging. [1]liu etc. by burning after wax candle ash carry out oxidizing acid processing, and with gel electrophoresis purify, prepare the multicolor fluorescence carbon nano-particle that particle diameter is less than 2 nm, maximum emission wavelength 415-615 nm. [2]pang seminar has good water dispersible and light stability by the carbon nano-particle of blue-light-emitting that graphite electroxidation is prepared [3]lee seminar in immediate development a kind of electrochemical method prepare the fluorescent carbon nano-particle of particle diameter at 1.2-3.8 nm, by electric current density regulation and control, can a step prepare glow color from blueness to orange-red carbon nano-particle.This carbon nano-particle also has good water dispersible, hyperfluorescence transmitting and up-conversion luminescence character. [4]because carbon nanomaterial has the advantages such as nontoxic, cheap, good stability, therefore fluorescent carbon nano material, particularly there is the fluorescent carbon nano-particle of clear and definite structure, there is important using value at the nano biological medical domain such as such as Biological imaging, lesion detection and diagnosis.Carbon quantum dot is a kind of new carbon of finding in recent years, with respect to traditional semiconductor-quantum-point and organic dyestuff, newcomer in Zhe Wei carbon family has not only kept the advantages such as biocompatible carbon material is good, toxicity is little, but also have that two-photon is easy to functionalization, absorption cross-section is large, light emitting region is adjustable, good light stability, without optical flare, inexpensive, the easy extensive advantage such as synthetic, not quencher of the light character of two-photon imaging for dynamically in real time accurately monitoring bio in vivo bioactivity material guarantee is provided; The optical excitation of two-photon imaging by low-yield long wavelength effectively avoided organism background autofluorescence having strengthened light penetration capacity and imaging depth simultaneously, thereby reduces photic biological damage.Therefore, will produce significant impact to the development of material science to the research of this emerging field of carbon quantum dot.
Two-photon also becomes the focus of research this year, two-photon absorption/excite as under exciting at high light, and molecule absorbs two photons simultaneously, the process of the excited state from ground state transition to twice photon energy.Two photons can be identical wavelength, can be also different wave lengths, but must be to absorb (interval that two photons arrive the molecule that is excited is less than 1 femtosecond) simultaneously.Can understand like this, first absorb energy jump to virtual intermediate state of a photon, and then the energy jump that absorbs a photon is to excited state.
Two-photon have a following advantage: darker penetration depth, photic damage is also less; photobleaching still less and phototoxicity; adjustable excitation wavelength-polychrome excites; imaging-the SHG of nonlinear effect; better signal to noise ratio; between excitation wavelength and emission wavelength, more easily separate; can excite UV and VIS by infrared (IR); Can realize details in a play not acted out on stage, but told through dialogues imaging, ambient interferences is very little.
(F rster resonance energy transfer (FRET) is to describe the one mechanism that between two chromophores, energy shifts to FRET (fluorescence resonance energy transfer).Require the emission spectra of donor and the absorption spectrum of receptor overlapping, when they are spatially close to each other when the certain distance (1-10 nm), excited donor and the fluorescent energy that produces are just in time absorbed by near receptor, make the fluorescence intensity decay of donor transmitting, the fluorescence intensity of acceptor fluorescence molecule strengthens.Distance between relative orientation, donor and the receptor of the efficiency of energy delivery and the emission spectra of donor and the transition dipole of overlapping degree, donor and the receptor of the absorption spectrum of receptor etc. is relevant.Fluorescent material must meet the following conditions: be 1. subject to, the exciting light of donor will enough separate; 2. the luminescent spectrum of donor and the excitation spectrum of receptor are overlapping.
Summary of the invention
The object of the present invention is to provide a kind of two-photon imaging and targeting therapy on tumor system and construction method thereof based on fluorescence resonance energy transition.
The present invention proposes carbon point drug delivery system f rster resonance energy transfer (the FRET)-based CDots drug delivery system (FRET-CDot-DDS) based on resonance energy transfer first, synthetic carbon point has good biocompatibility, between the fluorescence drug molecule of carbon point and load is as antitumor drug amycin, there is effective resonance energy transfer, this resonance energy transfer can promote drug conveying, cell imaging, realizes the real-time dynamic monitoring to tumour medicine effect.Further, the tracking that this carbon point drug conveying platform based on resonance energy transfer shows two-photon imaging and the medicine in very dark tissue, can be utilized in a large number in biological medicine carrying field.
First the present invention adopts electrochemical stripping method to synthesize luminous carbon quantum dot (being designated as CDots), process carbon point with concentrated nitric acid and make hydroxyl and carboxyl on its surface band, connect end with amino Polyethylene Glycol (PEG) (being designated as CDot-PEG) at CDots by EDC/NHS chemical coupling method, by EDC/NHS chemical coupling method, connect again tumor-targeting drug folic acid (being designated as CDot-PEG-FA), put with π-π stacking effect on antitumor drug amycin surface and connect amycin by carbon, obtain two-photon imaging and targeting therapy on tumor system based on fluorescence resonance energy transition, be designated as CDot-FA-DOX.This CDot-FA-DOX is a kind of composite nano materials.
Particularly, the synthesis step of composite nano materials CDot-FA-DOX is as follows:
(1) first, preparation 1.0-3.0 mg/ml CDots and 10-20 mg/ml, with six amino Polyethylene Glycol 5000, stir 5-15 min, then add 5-10 mM NHS, more ultrasonic 60-120 min; Add again the NHS of 20-30 mM EDC and 5-10 mM, stir together, reaction 24-72 h; By adding mercaptoethanol cessation reaction; Then using 2 × PBS high speed centrifugation 1-2 hour, obtain supernatant, is CDot-PEG, and it is stand-by that lyophilization is put in refrigerator;
(2) secondly, take 35-50 mg folic acid, add 15-30 mg EDC and 25-50 mg NHS simultaneously, add 1-2 ml pH7.4-9.0 PBS, under room temperature, stir 15-30 minute; Then add 20-40 mg CDot-PEG, under room temperature, stir 24-48h, clean centrifugal lyophilization stand-by;
(3) last, the DOX pH7.4-9.0 PBS stirred overnight at room temperature of the CDot-PEG-FA of 1-3 mg/ml and 2-5 mg/ml o, polymer is dialysed 48-72 hour in pure water by bag filter, changes water once every 4-8 hour; Product in bag filter, by lyophilization, obtains end product CDot-FA-DOX.
The present invention studies discovery, put the characteristic of the fluorescent energy resonance transfer between antitumor drug amycin by luminous carbon, in the time that both are an overall CDot-FA-DOX, with 405 nm laser excitations, emission wavelength is 495 nm, due to the effect of resonance energy transfer, mainly sends out the HONGGUANG of amycin, along with the continuous release of medicine, the effect of resonance energy transfer slowly disappears; At this moment use 405 nm laser excitations, emission wavelength is 498 nm, mainly sends out the green glow of amycin.Thereby can judge by sending out light intensity and color the character of release and the resonance energy transfer of medicine.CDot-FA-DOX, uses first two-photon imaging can penetrate very dark animal tissue, and then can look forward to therapeutic field of tumor simultaneously.
Cytotoxicity experiment shows: the average survival rate of cell is more than 80%, and cytotoxicity is 1 grade, can think that CDot-FA-DOX prepared by chemical coupling method has good cell compatibility.When CDot-FA and DOX can reduce the toxicity of simple DOX after compound.Experimental result can prove that CDot-PEG is that a toxicity is very little on the one hand, and the safety barrier of good biocompatibility, can prove that CDot-FA-DOX nano complex is a safe drugs transport system to normal cell on the other hand.The tumor control rate experimental result of cell shows along with DOX, CDot-FA-DOX and Cdot-PEG add the increase of concentration, three is significantly improved to the inhibition of Hela cell, the inhibition degree that simultaneously CDot-FA-DOX compound system and simple DOX compare tumor cell has had certain raising, is obviously greater than the activity of tumor cells suppression ratio of drug molecule DOX itself.Cell streaming apoptosis result shows that CDot-FA-DOX not only possesses the performance of good slow release than pure DOX simultaneously, and there is higher tumor control rate, thereby greatly improve the utilization ratio of drug of amycin, reduce certain normal cell toxicity simultaneously, thereby caused that the apoptosis of tumor cell improves the antitumor character of medicine.
The present invention has the following advantages:
One, this method has proposed the method for the two-photon imaging of a kind of novel fluorescence resonance energy transition and the structure of targeting therapy on tumor system first.Product amount is large, the little and distribution homogeneous of particle diameter, and monodispersity is good, and the present invention has filled up the two-photon imaging of fluorescence resonance energy transition and the construction method blank of targeting therapy on tumor system.
Two, the technology of the present invention operation is simple and easy, reaction system gentleness, stable, disturb less, product processing is easy to process, and is convenient to material synthetic on a large scale.
Three, the CDot-FA-DOX that prepared by the present invention has the advantages that drug loading is high, medicine carrying stable and can be absorbed by Bio-ontology degraded, is the effective pharmaceutical carrier of a class, can be applied to field of medicaments as a kind of active drug carrier.
Four, direct surface chemical coupling legal system for CDot-FA-DOX process not only reaction temperature and, also can avoid environment, and production cost is low, be a kind of desirable green material novel preparation method.
Five, the CDot-FA-DOX that prepared by the present invention, can realize the release of fluorescence energy transfer real-time dynamic monitoring antitumor drug, carries out first the imaging of two-photon living cells and imaging of tissue simultaneously, and penetrate tissue is dark.
Brief description of the drawings
The carbon quantum dot that Fig. 1 embodiment 1 is synthetic.Carbon quantum dot size is probably at 5 nm, and thickness is also 5 nm, and 002 crystal face of lattice and Graphene meets.
Fig. 2 is that CDot-FA-DOX is put comparison from the slow release of DOX in different pH.
Fig. 3 is CDot-FA-DOX and the suppression ratio of DOX to tumor cell.
Fig. 4 is CDot-FA-DOX and the apoptosis rate of DOX to tumor cell.
Fig. 5 is CDot-FA-DOX amycin passage situation of change in the time of 0.5 hour.
Detailed description of the invention
Embodiment 1:
The first step, prepare fluorescent carbon quantum dot and mainly contain following steps: electrolyte configuration: ethanol/water (V/V=99.5:0.5) slowly adds 0.2-0.4 g NaOH in above-mentioned solution, stirs with Glass rod. electrochemical electrolysis preparation process: two graphite rods (diameter 0.5 cm) are negative electrode and positive electrode respectively, and electric current density is controlled at 10-200mAcm -2, react 2 hours. luminescent quantum dot is purified: in above-mentioned thick product, add MgSO 4(5-7 wt%) stirs 20 min, and then spend the night silicagel column separating-purifying after desalination and water of sealed storage obtains the carbon quantum dot of size homogeneous.
Second step, preparation 1.0-3.0 mg/ml CDots and 20-40 mg/ml are with six amino Polyethylene Glycol 5000 (PEG-6NH 2), stir 5-10 min, then add 5 mM NHS, ultrasonic 60-120 min again, add together with the NHS of 20-30 mM EDC and 5-10 mM again and stir 24-72h, reaction, by adding mercaptoethanol to stop, is then used 2 × PBS high speed centrifugation (15000 turn), centrifugal 1-2 hour obtains supernatant is CDot-PEG, and it is stand-by that lyophilization is put in refrigerator.Take 35-50 mg folic acid and add 15-30 mg EDC and 25-50 mg NHS simultaneously, add 1-2 ml pH7.4-9.0 PBS stirring at room temperature 15-30 minute, then add 20-40 mg CDot-PEG, stirring at room temperature 24-48h, cleans centrifugal lyophilization stand-by.Last 1-3 mg/ml of CDot-PEG-FA and 2-5 mg/ml of DOX pH7.4-9.0 PBS stirred overnight at room temperature, polymer is dialysed 48-72 hour in pure water by bag filter (molecular cut off is 3500), changes water once every 4-8 hour.Product in bag filter obtains end product CDot-FA-DOX with lyophilization, is put in 4 ° of C refrigerators stand-by.(above-mentioned all reagent is analytical pure)
Embodiment 1 result: carbon quantum dot as synthetic in Fig. 1 disperses relatively homogeneous, and size is probably at 5 nm, and thickness is also 5 nm, and 002 crystal face of lattice and Graphene meets.
Embodiment 2:
Maximum absorption wavelength: take 0.003-0.005 g amycin (DOX), be placed in 10mL volumetric flask and use ddH 2o dissolves and carries out standardize solution.Within the scope of 200 ~ 800 nm, scan by ultraviolet-uisible spectrophotometer, the maximum absorption wavelength that 480 nm are amycin, so experimental selection concentration of amycin in test solution under this wavelength.
The ultraviolet of ultraviolet detection DOX/CDot-FA-DOX nano material of making to use the same method is composed entirely, observes its ultraviolet spectra absorbing state, judges whether this material exists interference at the responsive absorbing wavelength of DOX place.
The drafting of DOX working curve: prepare respectively 1,2,3,4,5,6,8,10 μ g/ml DOX standard solution, survey its absorbance at 480 nm places.Matching working curve.
The mensuration of DOX/CDot-FA-DOX composite nano materials drug loading: prepare sample, the DOX/CDot-FA-DOX dried powder of 0.003-0.005 g is placed in to 10 ml volumetric flasks, drip 6 M hydrochloric acid solution 100 μ L, the phosphate buffer of 0.02 M, pH 7.45 is settled to 10 ml, after ultrasonic 30 minutes, then be placed in 37 DEG C of water-baths and spend the night.Survey its ultraviolet absorptivity value at 480 nm places next day, and contrast is the DOX working curve of drafting before, can draw the concentration of Rhizoma Dysosmae Versipellis in sample.Employing following formula calculates:
Drug loading=(gross mass of the quality/composite of CDot-FA-DOX Chinese medicine) × 100% of CDot-FA-DOX
Embodiment 2 results: DOX/CDot-FA-DOX composite nano materials drug loading is 37.6 %.
Embodiment 3:
The first step: use normal cell strain HEK 293T to detect its cytotoxicity, the inhibition of tumor cell is selected to Hela tumor cell.
Second step: after preculture 24 h cell attachment growths, with the negative matched group of cell culture fluid, every group of 3 hole add respectively CDot-PEG, CDot-FA, DOX solution, CDot-FA-DOX suspension and the suspension of variable concentrations, and (concentration is respectively 0.5,1.0,2.5,5.0 μ g/ml).
The 3rd step: cultivate after 24 h, every hole adds MTT solution 20 μ l, hatches abandoning supernatant after 4 h, and every hole adds DMSO 150 μ l cessation reactions.
The 4th step: by culture plate level 30 min that vibrate, in 480 nm places mensuration traps, be calculated as follows cell survival rate with enzyme connection detector:
Cell survival rate %=A 480 (samples)/ A 480 (contrasts)× 100 %
A 570(sample): add sample sets absorbance; A 570(contrast): the absorbance of the blank culture medium cell of matched group.
Be inoculated in 24 orifice plates with 1.0 × 106, every hole cell, every pore volume is 500 μ l, culture plate is moved in CO2 incubator, under 37 oC, 5 % CO2 and saturated humidity condition, after cultivating 24 h, cell attachment is firm, add RPMI-1640 to be diluted to the CDot-FA-DOX of 10 μ g/ml, every plate is established every group of 1 blank cell matched group and is established 3 multiple holes, continues respectively to cultivate 48 hours.
Dyeing flow:
(1) PBS fully washes cell, and getting sum, to be about 5 ~ 2.5 × 104 cell to be measured;
(2) with 250 μ l binding buffer liquid Eddy diffusion cells and to make its concentration be 2 ~ 5 × 105/ml;
(3) cell suspension of getting 195 μ l adds 5 μ l Annexin V/ PI;
(4) hatch 10 minutes in room temperature lucifuge after mixing;
(5) wash cell once with the binding buffer liquid of 190 μ l;
(6) with the binding buffer liquid Eddy diffusion cell of 190 μ l;
(7) (final concentration is: 1 μ g/ml to add iodate the third ingot solution of 10 μ l 20 μ g/ml; Flow cytometer facs analysis.
Embodiment 3 results: CDot-FA-DOX not only possesses the performance of good slow release than pure DOX as shown in Figure 2, Figure 3 and Figure 4, and there is higher tumor control rate, thereby greatly improve the utilization ratio of drug of amycin, reduce certain normal cell toxicity simultaneously, thereby caused that the apoptosis of tumor cell improves the antitumor character of medicine.
Embodiment 4:
The first step: be inoculated in 6 orifice plates with 1.0 × 106, every hole cell, every pore volume is 1000 μ l, and culture plate is moved to CO 2in incubator, at 37 oC, 5 % CO 2and under saturated humidity condition, after cultivation 24 h, cell attachment is firm, adds CDot-PEG, the CDot-FA, DOX solution, the CDot-FA-DOX suspension that are diluted to 10 μ g/ml, every plate is established 1 blank cell matched group, continues respectively to cultivate 30 min.
Second step: added the cell of material with tri-cleanings of PBS, the culture medium that finally adds 0.5 mL serum-free directly goes up laser co-focusing observation of cell.
Embodiment 4 results: CDot-FA-DOX is in the time of 0.5 hour as shown in Figure 5, and while having FRET, amycin passage is very bright, at this moment be mainly that antitumor drug amycin is luminous, As time goes on, amycin passage slowly dies down, and at this moment slowly grow of carbon point passage has closed FRET.So the monitoring by the good Real-time and Dynamic of fluorescent energy resonance transfer the release of medicine.
list of references
[1]?L.?Cao,?M.?J.?Meziani,?S.?Sahu,?Y.-P.?Sun,?Accounts?of?chemical?research?2012,?46,?171-180.
[2]?S.?N.?Baker,?G.?A.?Baker,?Angewandte?Chemie?International?Edition?2010,?49,?6726-6744.
[3]?Q.-L.?Zhao,?Z.-L.?Zhang,?B.-H.?Huang,?J.?Peng,?M.?Zhang,?D.-W.?Pang,?Chemical?Communications?2008,?5116-5118.
[4]?H.?Li,?X.?He,?Z.?Kang,?H.?Huang,?Y.?Liu,?J.?Liu,?S.?Lian,?C.?H.?A.?Tsang,?X.?Yang,?S.?T.?Lee,?Angewandte?Chemie?International?Edition?2010,?49,?4430-4434.。

Claims (3)

1. a construction method for the tumor imaging based on FRET (fluorescence resonance energy transfer) and treatment target system, is characterized in that concrete steps are:
First adopt electrochemical stripping method to synthesize luminous carbon quantum dot, be designated as CDots, process carbon point with concentrated nitric acid and make hydroxyl and carboxyl on its surface band;
Connect end with amino Polyethylene Glycol (PEG) at CDots by EDC/NHS chemical coupling method, product is designated as CDot-PEG;
By EDC/NHS chemical coupling method, then connect tumor-targeting drug folic acid (FA), product is designated as CDot-PEG-FA);
Put with π-π stacking effect on antitumor drug amycin surface and connected amycin by carbon, obtain two-photon imaging and targeting therapy on tumor system based on fluorescence resonance energy transition, product is designated as CDot-FA-DOX; This CDot-FA-DOX is a kind of composite nano materials.
2. the construction method of the tumor imaging based on FRET (fluorescence resonance energy transfer) according to claim 1 and treatment target system, is characterized in that concrete operations flow process is as follows:
(1) first, preparation 1.0-3.0 mg/ml CDots and 10-20 mg/ml, with six amino Polyethylene Glycol 5000, stir 5-15 min, then add 5-10 mM NHS, more ultrasonic 60-120 min; Add again the NHS of 20-30 mM EDC and 5-10 mM, stir together, reaction 24-72 h; By adding mercaptoethanol cessation reaction; Then using 2 × PBS high speed centrifugation 1-2 hour, obtain supernatant, is CDot-PEG, and it is stand-by that lyophilization is put in refrigerator;
(2) secondly, take 35-50 mg folic acid, add 15-30 mg EDC and 25-50 mg NHS simultaneously, add 1-2 ml pH7.4-9.0 PBS, under room temperature, stir 15-30 minute; Then add 20-40 mg CDot-PEG, under room temperature, stir 24-48h, clean centrifugal lyophilization stand-by;
(3) last, the DOX pH7.4-9.0 PBS stirred overnight at room temperature of the CDot-PEG-FA of 1-3 mg/ml and 2-5 mg/ml o, polymer is dialysed 48-72 hour in pure water by bag filter, changes water once every 4-8 hour; Product in bag filter, by lyophilization, obtains end product CDot-FA-DOX.
3. construction method builds the tumor imaging based on FRET (fluorescence resonance energy transfer) and the treatment target system that obtain as claimed in claim 1 or 2.
CN201410288247.8A 2014-06-25 2014-06-25 Fluorescence resonance energy transfer-based tumor imaging and therapeutic targeting system and construction method thereof Pending CN104083771A (en)

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Title
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