CN109053809A - A kind of photosensitizer and its preparation method and application of the energy optical dynamic therapy of film targeting type - Google Patents
A kind of photosensitizer and its preparation method and application of the energy optical dynamic therapy of film targeting type Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
- C07F15/0053—Ruthenium compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- General Health & Medical Sciences (AREA)
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Abstract
Present invention discloses a kind of photosensitizers and its preparation method and application of the energy optical dynamic therapy of film targeting type, belong to organic photoelectrical material technical field, preparation method is the bipyridyl dichloro bridge that nine carbon are prepared by the reaction of bipyridyl, ruthenium trichloride and lithium chloride, then reacts to obtain ruthenium complex with bipyridyl assistant ligand b by bipyridyl dichloro bridge.The photosensitizer is capable of the cell membrane of selectively targeted cancer cell, and active oxygen is generated under the irradiation of particular excitation light, destroys cell membrane surface, eventually leads to Apoptosis, and have good optical dynamic therapy effect, adds a kind of new approaches for optical dynamic therapy.The photosensitizer of the energy optical dynamic therapy of this film targeting type has very big potentiality in future biological medical application.
Description
Technical field
The present invention relates to a kind of photosensitizers and its preparation method and application of the energy optical dynamic therapy of film targeting type, and belonging to has
Machine optoelectronic materials technology.
Background technique
Tumor environment is acid and anoxia state, therefore can detect weary oxygen ring with a series of can have of targeted design
Border or be able to detect acidic environment targeting photosensitizer, tumor region and normal cell region can be distinguished, and
It is not that differentiation purpose is reached in the specific enrichment of tumour endogenous markers by photosensitizer (PS).Further, PS is determined
Positioned at organelle structures such as mitochondria, cytoplasm, lysosome, golgiosome and nucleus, so that PS is in specific cell knot
Content in structure increases, and can be accurately positioned the position of ROS, to induce cell apoptosis, improves optical dynamic therapy (PDT) effect
Fruit.In these organelles, cell membrane is considered as one of most important eucaryotic cell structure, it can not only guarantee the complete of cell
Whole property and the basic function that can guarantee cell.Apoptosis, necrosis and the autophagy that will lead to cell to the destruction of cell membrane, because
This cell membrane becomes a kind of new target site in PDT.
PS is positioned at cell membrane, under the action of illumination, cell membrane generates reactive oxygen species (ROS) in situ, induces film phosphorus
Lipid peroxidation, further result in cell permeability of the membrane increase, or even destroy cell membrane structure, excitation photo-irradiation intensity with
There is direct relationship in time to the lesion size of cell membrane, under the irradiation of short time exciting light, this cell membrane damage effect quilt
Applied to removing to improve cell to the intake power and photochemical internalisation (PCI) of bioactive substance, shone in slightly prolonged exciting light
It penetrates down, the ROS of generation can achieve the effect of PDT.It can also be by adjusting the PS concentration on laser power and cell membrane come real
Existing cell death.But problems faced is at present, none effective method can target cell membrane and by PS thin
Retain for a long time on after birth.
Summary of the invention
The object of the invention is to propose a kind of energy of film targeting type to solve the above-mentioned problems in the prior art
Photosensitizer of optical dynamic therapy and its preparation method and application.
A kind of the purpose of the invention will be achieved through the following technical solutions: light of the energy optical dynamic therapy of film targeting type
Quick dose, have following structure formula:
Preferably, wherein N^N ligand is any type in following ligand:
Present invention further teaches a kind of preparation methods of the photosensitizer of the energy optical dynamic therapy of film targeting type, including walk as follows
It is rapid:
S1: being added raw material bipyridyl, ruthenium trichloride and lithium chloride at 155 DEG C, and DMF reflux 8h, reaction terminate under nitrogen
After be cooled to room temperature, be added acetone, frost overnight, suction filtration obtain black solid, washed with water and ether and be drying to obtain product
A --- bipyridyl ruthenium dichloro bridge；
S2: water and ethyl alcohol are added in two mouth flask, nitrogen protection weighs 50mg a and 43mg b raw material respectively --- class
Bipyridine ligand, flow back 20h at a certain temperature, and solution becomes kermesinus from red, glows, and saturation KPF is then added6
Aqueous solution has a large amount of precipitatings to generate at this time, filters, be washed with water and wash, remove excessive KPF6 and KCl, be drying to obtain product
The ruthenium complex photosensitizer of the energy optical dynamic therapy of c --- film targeting type；
General structure are as follows:
Preferably, the molar ratio of the bipyridyl, ruthenium trichloride and lithium chloride is 2: 1: 10, the yield 53% of product c.
Preferably, in S1 step, acetone 50mL.
Preferably, in S2 step, water 10mL, ethyl alcohol 15mL, the certain temperature are 80 DEG C.
Preferably, the photosensitizer product c that S2 step obtains is dissolved in DMSO and is tested, test photosensitizer product c
Absorption and transmitting, in DMSO solution, ruthenium complex absorption maximum is at 458nm, and most hyperfluorescence emission peak exists
620nm。
Present invention further teaches a kind of applications of the photosensitizer of the energy optical dynamic therapy of film targeting type, and Hela cell is killed
Overstrain is smaller, can be used for the cell experiment in later period.
A kind of application of the photosensitizer of the energy optical dynamic therapy of film targeting type has specific target membrane effect, can be fine
Be used for cell membrane imaging.
A kind of application of the photosensitizer of the energy optical dynamic therapy of film targeting type, can generate a large amount of activity in the cell under illumination
Oxygen；The a large amount of active oxygens generated after illumination can destroy cell membrane, and light power effect is preferable.
A kind of application of the photosensitizer of the energy optical dynamic therapy of film targeting type, the application are that the light power of vivo tumor is controlled
It treats, there is good optical dynamic therapy effect, add a kind of new approaches for optical dynamic therapy.
The advantages of technical solution of the present invention, is mainly reflected in:
The photosensitizer of the energy optical dynamic therapy of film targeting type of the invention has shining for long wavelength, is conducive to eliminate cell
Background imaging interference.The photosensitizer of the energy optical dynamic therapy of film targeting type of the invention to the lethality of HeLa cell very
It is small, on this basis, Ru complex can be used for subsequent biological test.The energy optical dynamic therapy of film targeting type of the invention
Photosensitizer can accurate target cancer cell cell membrane, singlet oxygen can be generated under illumination, cell membrane can be destroyed, there is good light
Power effect.
The present invention has synthesized a kind of photosensitizer of the energy optical dynamic therapy of film targeting type, is merely present in the cell of cancer cell
Film, for normal cell cell membrane there is no targeting, cancer cell and normal cell can be distinguished well.In addition,
Under certain photostimulation, the POS generated on cell membrane is capable of the kill cancer cell of short time, and the efficiency of PDT mentions significantly
It is high.Therefore, this kind of photosensitizer is expected to be applied to the optical dynamic therapy of vivo tumor from now on.
Detailed description of the invention
Fig. 1 is the uv-visible absorption spectra (a) and fluorescence emission spectrum (b) of ruthenium complex of the present invention.
Fig. 2 is that flow cytometry of the present invention tests the toxicity test figure of ruthenium complex in the cell.
Fig. 3 is the co-focusing imaging of the ruthenium complex of HeLa and 3T3 cell incubation various concentration in the present invention.
Fig. 4 is in the present invention added with the co-focusing imaging figure of the ruthenium complex of nucleus indicator.
Fig. 5 is the total dye experiment of ruthenium complex in the present invention.
Fig. 6 is cell membrane of the present invention and nucleus indicator stacking chart.
Fig. 7 is micro- for the laser scanning co-focusing that ruthenium complex under illumination in the present invention generates singlet oxygen experiment into the cell
Mirror image.
Fig. 8 is the stacking chart of intracellular ruthenium complex imaging and the active oxygen imaging generated in the present invention.
Fig. 9 is that the laser scanning co-focusing that monitoring ruthenium complex induces cell apoptosis experiment into the cell under illumination of the present invention is shown
Micro mirror image.
Figure 10 is the HeLa cell imaging figure of calcein and PI coloring in the present invention.
The apoptosis light field image of Figure 11 present invention ruthenium complex in instances.
Specific embodiment
The purpose of the present invention, advantage and feature, by by the non-limitative illustration of preferred embodiment below carry out diagram and
It explains.These embodiments are only the prominent examples using technical solution of the present invention, it is all take equivalent replacement or equivalent transformation and
The technical solution of formation, all falls within the scope of protection of present invention.
Present invention discloses a kind of photosensitizers and its preparation method and application of the energy optical dynamic therapy of film targeting type.Cell
Film can not only guarantee the integrality of cell and can guarantee the basic function of cell as one of most important organelle.
It will lead to apoptosis, necrosis and the autophagy of cell to the destruction of cell membrane, therefore, cell membrane becomes a kind of new targeting in PDT
Site still enables to photosensitizer target cell membrane currently without an effective method and will protect for a long time on cell membrane
It stays.Our target is the photosensitizer for synthesizing a kind of energy optical dynamic therapy of film targeting type, it is made to exist only in the thin of cancer cell
On after birth, and there is no targeting to the cell membrane of normal cell.It therefore, can be well by cancer cell and normal cell area
Point.Most of all, the ROS generated on cell membrane is capable of the kill cancer cell of short time under certain photostimulation,
So that the efficiency of PDT greatly improves.
A kind of photosensitizer of the energy optical dynamic therapy of film targeting type, has following structure formula:
Wherein, N^N ligand is any type in following ligand:
Present invention further teaches a kind of preparation methods of the photosensitizer of the energy optical dynamic therapy of film targeting type, including walk as follows
It is rapid:
S1: being added raw material bipyridyl, ruthenium trichloride and lithium chloride at 155 DEG C, and DMF reflux 8h, reaction terminate under nitrogen
After be cooled to room temperature, be added acetone, frost overnight, suction filtration obtain black solid, washed with water and ether and be drying to obtain product
A --- bipyridyl ruthenium dichloro bridge；
S2: water and ethyl alcohol are added in two mouth flask, nitrogen protection weighs 50mga and 43mgb raw material respectively --- class connection
Pyridine ligand, flow back 20h at a certain temperature, and solution becomes kermesinus from red, glows, and saturation KPF is then added6Water
Solution has a large amount of precipitatings to generate at this time, filters, be washed with water and wash, remove excessive KPF6 and KCl, be drying to obtain product
The ruthenium complex photosensitizer of the energy optical dynamic therapy of c --- film targeting type；
General structure are as follows:
The molar ratio of the bipyridyl, ruthenium trichloride and lithium chloride is 2: 1: 10, the yield 53% of product c.In S1 step
In, acetone 50mL.In S2 step, water 10mL, ethyl alcohol 15mL, the certain temperature are 80 DEG C.S2 step is obtained
Photosensitizer product c be dissolved in DMSO and tested, test the absorption and transmitting of photosensitizer product c, in DMSO solution,
Ruthenium complex absorption maximum is at 458nm, and most hyperfluorescence emission peak is in 620nm.
Present invention further teaches a kind of applications of the photosensitizer of the energy optical dynamic therapy of film targeting type, and Hela cell is killed
Overstrain is smaller, can be used for the cell experiment in later period.
A kind of application of the photosensitizer of the energy optical dynamic therapy of film targeting type has specific target membrane effect, can be fine
Be used for cell membrane imaging.
A kind of application of the photosensitizer of the energy optical dynamic therapy of film targeting type, can generate a large amount of activity in the cell under illumination
Oxygen；The a large amount of active oxygens generated after illumination can destroy cell membrane, and light power effect is preferable.
A kind of application of the photosensitizer of the energy optical dynamic therapy of film targeting type, the application are that the light power of vivo tumor is controlled
It treats, there is good optical dynamic therapy effect, add a kind of new approaches for optical dynamic therapy.
Embodiment 1: the preparation method of the photosensitizer of the energy optical dynamic therapy of film targeting type, the preparation method are by joining pyrrole
The bipyridyl dichloro bridge of nine carbon is prepared in pyridine, ruthenium trichloride and lithium chloride reaction, then passes through bipyridyl dichloro bridge and connection pyrrole
Pyridine assistant ligand b reacts to obtain ruthenium complex.The photosensitizer is capable of the cell membrane of selectively targeted cancer cell, in particular excitation
Light irradiation is lower to be generated active oxygen, destroys cell membrane surface, eventually leads to Apoptosis, and have good optical dynamic therapy effect
Fruit adds a kind of new approaches for optical dynamic therapy.The photosensitizer of the energy optical dynamic therapy of this film targeting type is in future biological
There are very big potentiality in medical application.
The photosensitizer of the energy optical dynamic therapy of film targeting type, synthesis step are as follows:
It is 2: 1: 10 that raw material bipyridyl, ruthenium trichloride and lithium chloride, molar ratio are added at 155 DEG C, and DMF flows back under nitrogen
8h.It is cooled to room temperature after reaction, 50mL acetone is added, frost is overnight.Suction filtration obtains black solid, is washed with water and ether
It washs and is drying to obtain product a.Second step is that 10mL water and 15mL ethyl alcohol are added in two mouth flask, nitrogen protection.It weighs respectively
50mg a and 43mg b raw material, 80 DEG C of reflux 20h, solution become kermesinus from red, glow.Then KPF is added6Saturated water
Solution has a large amount of precipitatings to generate at this time, filters, be washed with water and wash, remove excessive KPF6And KCl, it is drying to obtain product c, is produced
Rate 53%.
1H NMR (400MHz, CDCl3) δ 8.46-8.38 (m, 4H), 8.16 (s, 2H), 8.02-7.91 (m, 4H), 7.75-
7.64 (m, 4H), 7.53 (d, J=5.6Hz；2H), 7.47-7.37 (m, 4H), 7.29-7.26 (m, 2H), 2.80 (t, J=
7.6Hz；4H), 1.73-1.63 (m, 4H), 1.40-1.17 (m, 24H), 0.85 (t, J=7.2Hz；6H).
Embodiment 2: the absorption of ruthenium complex and emission spectrum
As shown in Figure 1, Ru complex absorption maximum is at 458nm and most hyperfluorescence emission peak exists in DMSO solution
620nm.The interference of the luminous background imaging for being conducive to eliminate cell of Ru complex long wavelength.
Embodiment 3: the cytotoxicity test of the photosensitizer of the energy optical dynamic therapy of film targeting type
Cytotoxicity experiment refers to that detecting simple complex introduces lethality after cell to cell, surveys with traditional toxicity
Examination MTT is similar, we have detected under dark condition mainly by flow cytometer, lethality of the Ru complex to cell.
First by HeLa cell incubation in 6 orifice plates, in 20%O2, 75%N2, 5%CO2In the normal oxygen incubator that temperature is 37 DEG C
24 hours, be that 0,1,3,5,7 and 9 μM of ruthenium complex is separately added into 6 orifice plates by concentration, in 20%O2, 75%N2, 5%CO2Temperature
It is incubated in the normal oxygen incubator that degree is 37 DEG C.After 48h, 6 are taken to indicate 1,2,3,4,5 and 6 centrifuge tubes, it respectively will be different dense
Spend ascending supernatant be separately added into indicate 1,2,3,4,5 and 6 volumes be 10mL centrifuge tube in, later will be in 6 orifice plates
Be separately added into the pancreatin of 500 μ L, after waiting digestion completely in 3-5 minutes, by be separately added into orifice plate equivalent without containing serum
DMEM culture medium terminates cell dissociation.The liquid in orifice plate is removed after this in corresponding centrifuge tube, is turned in 760r/min
Speed is lower to be centrifuged 3 min, and apoptosis indicator (5 μ L of FITC, 10 PI μ L are added in centrifuge tube after removing the supernatant in centrifuge tube
With in conjunction with 180 μ L of liquid), finally the cell in 10mL centrifuge tube is transferred in the centrifuge tube that volume is 150 μ L and is used for cell toxicant
The detection of property.
If Fig. 2 is fluidic cell figure of the ruthenium complex under 0,1,3,5,7 and 9 μM of concentration, pass through the fluorescence of FITC and PI
Power, cell mass is divided into four kinds of states by us.The weak FITC light of strong PI light, the cell in this region do not pass through in a-quadrant
It crosses cell early to wither the stage, cell membrane is directly damaged to be dyed by PI, and such cell is defined as non-viable non-apoptotic cell；It is weak in B area
PI and FITC light, this region cell is not both early to wither, and also not by breakage, such cell is defined as normally living thin cell membrane
Born of the same parents；Strong PI and FITC light in the region C, this region cell experienced it is early wither-evening withers process, such cell is defined as late
Wither cell；Strong FITC and weak PI light in the region D, this region cell experienced early process of withering, and still cell membrane does not meet with
It is not dyed to destruction, nucleus by PI, such cell is defined as the early cell that withers.
In toxotest, our main detections are to remain in the cell number in the area B to account for the percentage of total cell number, from figure
In can be seen that 87% or more of the cells on total cells number remained in the area B under various concentration, sufficiently prove Ru complex pair
The lethality very little of HeLa cell, on this basis, Ru complex can be used for subsequent biological test by we.
Embodiment 4: the cell membrane imaging of the photosensitizer of the energy optical dynamic therapy of film targeting type
The ruthenium complex for weighing 3mg first, is dissolved in DMSO solution, configuration 1 × 10-3The mother liquor of the complex of mol/L is used
The DMEM difference diluted concentration of serum-free is to 3 μM, 5 μM and 17.5 μM.There are the copolymerization of HeLa and 3T3 cell burnt for being incubated for respectively
Ware takes out, and wash three times with PBS buffer solution, is separately added into 3 μM prepared, the ruthenium complex of 5 μM and 7.5 μM, placement later
In 20%O2, 5%CO2And 75%N2Normal oxygen incubator in, be incubated for 2.5h at 37 DEG C.Culture dish is taken out, it is slow with PBS
Fliud flushing is washed three times to remove dead cell and remaining ruthenium complex, and places it in microscopically observation, as a result such as Fig. 3 institute
Show.Experiment uses the exciting light of 458nm, collects the fluorescence signal of 600-650nm wave band.
As a result, it has been found that as shown in figure 3, the ruthenium complex under various concentration has targeted the cell membrane of HeLa cell, still
To normal cell 3T3 but always without targeting, after we select (3 μM) of ruthenium complex of moderate concentration to carry out in experiment
Continuous experiment.
In order to be more clearly observed position of the Ru complex in cell, the present invention joined cell in cell
Core indicator (Hoechst 33342).In experimentation, 3 μM of Ru complex is added and is placed in 20% in the burnt ware of copolymerization
O2, 5%CO2And 75%N2Normal oxygen incubator in, 37 DEG C culture under be incubated for 2.5h, be added after cleaning 3 times with PBS
Hoechst 33342 (10 μ g/mL) is incubated for 15min in Tissue Culture Dish, carries out being copolymerized burnt test after cleaning 3 times with PBS, knot
Fruit is as shown in Figure 4.
As shown in figure 4, nucleus indicator can be located in the nuclear location of cell, and under 405nm laser irradiation, issue
Blue-fluorescence can be clearly seen that the position of nucleus by being superimposed for core indicator and light field cell.By Ru complex
With being superimposed for core indicator, it can be seen that non-luminous black zones are cytoplasmic regions between cell membrane and nucleus.
Therefore, ruthenium complex of the invention has good cell membrane Targeting Effect.
Embodiment 5: the photosensitizer and cell membrane indicator of the energy optical dynamic therapy of film targeting type
In order to scientifically verify the target membrane characteristic of Ru complex, we have selected cell membrane green fluorescence indicator, can
Target cell membrane issues feux rouges under 635nm laser irradiation.As a result as shown in Figure 4.In experimentation, 3 μM of Ru is added and matches
It closes object and is placed in 20%O in the burnt ware of copolymerization2, 5%CO2And 75%N2Normal oxygen incubator in, 37 DEG C culture under be incubated for
Cell membrane green fluorescence indicator is added in 2.5h after cleaning 3 times with PBS.As a result as shown in Figure 5.
Further, by the analysis of Fig. 6 it is found that ruthenium complex and the almost be overlapped coefficient of dye altogether of cell membrane indicator are high
Up to 93%, ruthenium complex being capable of target cell membrane well.
A kind of embodiment 6: the singlet oxygen test of the photosensitizer of the energy optical dynamic therapy of film targeting type in the cell
The photosensitizer of the energy optical dynamic therapy of film targeting type of the invention is applied to intracellular tool as a kind of photosensitizer
There is good optical dynamic therapy effect.
The DCFH-DA used in the present embodiment is a kind of non-luminous active oxygen fluorescence probe, can pass freely through cell
Film.After entering cell, DCFH-DA is easy to be generated DCFH by intracellular esterase hydrolyzed, and DCFH cannot penetrate cell membrane,
It is trapped in intracellular.Non-blooming DCFH can be oxidized to the DCF to shine in 525nm by intracellular active oxygen, from DCF
Fluorescence power can judge the level of intracellular active oxygen indirectly.Itself can there are weak H in living cells2O2Substance,
Cell has weak fluorescence appearance after DCFH-DA activity oxygen indicator is added.After Ru complex is added, in the effect of illumination
Under, active oxygen is generated, cell has strong fluorescence appearance after DCFH-DA activity oxygen indicator is added.
The present embodiment has carried out 5 groups of parallel laboratory tests altogether.
Contain only the blank group of cell；
Blanc cell adds DCFH-DA (PBS)；
The cell for being incubated for material adds DCFH-DA；
The cell for being incubated for material adds DCFH-DA to add illumination；
The cell for being incubated for material adds active oxygen scavenger (VC) plus illumination.
Fig. 7 is the detection that complex generates active oxygen in the cell, using 405nm laser, is collected at 500-550nm
Fluorescence.By can be seen that in figure, blank group (only cell) does not detect fluorescence into the cell, has after addition DCFH-DA faint
Fluorescence occurs, it was demonstrated that contains a small amount of reactive oxygen species H in cell2O2Presence；Ruthenium complex adds DCFH-DA, and light group is not thin
Born of the same parents have faint fluorescence.When the xenon lamp using 475nm, 30mW irradiates after five minutes, intracellular Fluorescence enhancing can prove that Ru matches
It closes object and produces a large amount of active oxygen in the cell after illumination effect.In order to prove that the luminous of DCF is generated by Ru complex
Active oxygen caused by, we to be added Ru complex cell carried out VC pretreatment, can effectively be removed after VC is handled
Intracellular reactive oxygen species, fluorescence intracellular after VC effect weakens significantly as the result is shown.Illustrate that Ru complex is made in illumination
A large amount of singlet oxygen is produced under.First is classified as the green fluorescence channel image of collection, and second is classified as cell bright field image,
Third is classified as the stacking chart of fluorescent image Yu cell light field.Used ruthenium complex concentration and probe concentration is 3 μM.
The image of Ru complex is superimposed by the present embodiment with the active oxygen image of generation, can be more clearly observed
The imaging position of active oxygen and complex is as shown in Figure 8.
Embodiment 7: a kind of photosensitizer of the energy optical dynamic therapy of film targeting type and AnnexinV-FITC and PI (iodate third
Pyridine) double fluorescent stainings apoptosis test.
The present embodiment verifies the light power effect of ruthenium complex using cell apoptosis assay.Apoptosis refers to one kind
The death of the order of gene control, two stages are divided into apoptosis process: one is the early apoptosis stage: at this
Cell membrane turns up in one stage, but cell membrane is complete.The other is the late apoptic stage: cell membrane in this stage
It is destroyed, cell volume becomes smaller, and cytoplasm concentration, nucleus is cracked into fragment, generates apoptotic body.
The present embodiment mainly select the dyeing of apoptosis kit using copolymerization it is burnt come observe Apoptosis change over time it is complete
Process.We select.The exciting light of two kinds of fluorescent dyes is at 488nm, and cell in normal state will not be by two kinds of dyestuffs
Dyeing, after cell is by apoptosis induction, cell initially enter it is early withers the stage, PS (phosphatidylserine) is from cell membrane at this time
It is interior survey be transferred to outside, AnnexinV is the cardiolipin binding protein that a kind of pair of calcium has dependence, can in specific manner be exposed to film
The PS in outside is combined and is formed Annexin V-FITC, and green can be presented on cell membrane.Finally when cell enters apoptosis advanced stage
When, endonuclease (substrates of certain Caspase) can shear DNA between nucleosome, generate a large amount of length in 180-
The DNA fragmentation of 200bp.PI can be specifically in conjunction with DNA fragmentation, and then realizes the specific stain to nucleus.
The present embodiment has the cell of ruthenium complex to carry out time series imaging incubation, as a result as shown in figure 9, detecting respectively
The fluorescence signal of FITC and PI when 0h, 0.5h, 1h, 1.5h and 2h can obviously be seen by the variation of the fluorescence intensity of the two
Cell listens the state at place out, and cell only has faint FITC light in the early state of withering when 0h, over time
FITC fluorescence gradually increases, and is dyed by PI with a small amount of cell, illustrates to have at this time a small amount of cell to be in evening and withers state,
When the cell in 2h rearward vision is all dyed by PI, illustrate that cell has fully entered late state of withering.It follows that of the invention
The photosensitizer of the energy optical dynamic therapy of film targeting type has good smooth power effect.First be classified as collection FITC green it is glimmering
Optical channel image, second is classified as the PI red fluorescence channel image of collection, and third is classified as the stacking chart of FITC and PI.It is used
Ruthenium complex concentration and probe concentration be 3 μM, illumination 5 under the conditions of excitation wavelength 458nm, 475nm (power density 12mW/cm-2)
Minute.
Embodiment 8: a kind of photosensitizer of the energy optical dynamic therapy of film targeting type and Calcein-AM calcein and PI are bis-
Redye the apoptosis experiment of color.The present embodiment uses Calcein-AM calcein (live cell fluorescent probe) and PI (dead cell
Fluorescence probe) apoptosis test is carried out again, calcein is a kind of fluorescent dye that can permeate living cells film, AM group energy
The hydrophobicity for enough reinforcing molecule makes molecule readily penetrate through cell membrane, and AM group can close the molecule in conjunction with calcium ion
Part makes molecule itself not fluoresce, and can be calcein (Ex/ by intracellular esterase hydrolyzed after molecule enters cell
Em=488nm/515nm).Often with dead cell nuclear probe propidium iodide PI combined mark, the dual of living cells and dead cell is carried out
Dyeing.
As shown in Figure 10, it can be clearly seen that the fluorescence of calcein disappears after 2h, the fluorescence enhancement of PI, in the visual field
Cell, which is all adjusted, dies.First is classified as the Calcein-AM green fluorescence channel image of collection, second be classified as collection PI it is red
Color fluorescence channel image, third are classified as cell bright field image, and the 4th is classified as the stacking chart of fluorescent image Yu cell light field.Made
Ruthenium complex concentration and probe concentration is 3 μM, light under the conditions of excitation wavelength 488nm, 475nm (power density 12mW/cm-2)
According to 5 minutes.
The apoptotic state of cell can also be analyzed from the light field of cell, as shown in figure 11, normal HeLa cell has cell
Protrusion is in shuttle shape, and the cell membrane in apoptosis period is destroyed, and cell volume becomes smaller, and cytoplasm concentration, nucleus is cracked into fragment,
Generate apoptotic body.It is excellent that the above results all show that the photosensitizer of the energy optical dynamic therapy of film targeting type of the invention has
Light power effect.
Still there are many embodiment, all technical sides formed using equivalents or equivalent transformation by the present invention
Case is within the scope of the present invention.
Claims (10)
1. a kind of photosensitizer of the energy optical dynamic therapy of film targeting type, it is characterised in that: have following structure formula:
2. a kind of photosensitizer of the energy optical dynamic therapy of film targeting type according to claim 1, it is characterised in that:
Wherein, N ∧ N ligand is any type in following ligand:
3. a kind of preparation method of the photosensitizer of the energy optical dynamic therapy of film targeting type, characterized by the following steps:
S1: being added raw material bipyridyl, ruthenium trichloride and lithium chloride at 155 DEG C, and DMF reflux 8h, cold after reaction under nitrogen
But to room temperature, acetone is added, overnight, suction filtration obtains black solid for frost, washed with water and ether and be drying to obtain product a --- connection
Pyridine ruthenium dichloro bridge；
S2: water and ethyl alcohol being added in two mouth flask, nitrogen protection weighs 50mg a and 43mg b raw material respectively --- class joins pyrrole
Pyridine ligand, flow back 20h at a certain temperature, and solution becomes kermesinus from red, glows, and saturation KPF is then added6It is water-soluble
Liquid has a large amount of precipitatings to generate at this time, filters, be washed with water and wash, remove excessive KPF6 and KCl, be drying to obtain product c --- film
The ruthenium complex photosensitizer of the energy optical dynamic therapy of targeting type；
General structure are as follows:
。
4. a kind of preparation method of the photosensitizer of the energy optical dynamic therapy of film targeting type according to claim 3, feature
Be: the molar ratio of the bipyridyl, ruthenium trichloride and lithium chloride is 2: 1: 10, the yield 53% of product c.
5. a kind of preparation method of the photosensitizer of the energy optical dynamic therapy of film targeting type according to claim 3, feature
It is: in S1 step, acetone 50mL；In S2 step, water 10mL, ethyl alcohol 15mL, the certain temperature are 80 DEG C.
6. a kind of preparation method of the photosensitizer of the energy optical dynamic therapy of film targeting type according to claim 3, feature
It is: the photosensitizer product c that S2 step obtains is dissolved in DMSO and is tested, tests absorption and the hair of photosensitizer product c
It penetrates, in DMSO solution, ruthenium complex absorption maximum is at 458nm, and most hyperfluorescence emission peak is in 620nm.
7. a kind of application of the photosensitizer of the energy optical dynamic therapy of film targeting type, it is characterised in that: for Hela Execution
It is smaller, it can be used for the cell experiment in later period.
8. a kind of application of the photosensitizer of the energy optical dynamic therapy of film targeting type, it is characterised in that: there is specific target membrane effect,
It can be good at for cell membrane imaging.
9. a kind of application of the photosensitizer of the energy optical dynamic therapy of film targeting type, it is characterised in that: can be produced in the cell under illumination
Raw a large amount of active oxygens；The a large amount of active oxygens generated after illumination can destroy cell membrane, and light power effect is preferable.
10. a kind of application of the photosensitizer of the energy optical dynamic therapy of film targeting type, it is characterised in that: the application is vivo tumor
Optical dynamic therapy, there is good optical dynamic therapy effect, add a kind of new approaches for optical dynamic therapy.
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| CN113321687A (en) * | 2021-05-27 | 2021-08-31 | 广西医科大学 | Preparation method of ruthenium-based photosensitizer and application of ruthenium-based photosensitizer in photodynamic therapy of breast cancer |
| CN114315832A (en) * | 2022-01-11 | 2022-04-12 | 云南大学 | Fully conjugated bridged ligand and preparation method thereof, and fully conjugated binuclear ruthenium complex and preparation method and application thereof |
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