CN108567980B - The CO controllable delivery system and its construction method of light power induction - Google Patents
The CO controllable delivery system and its construction method of light power induction Download PDFInfo
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- 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
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
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Abstract
The invention discloses the CO method for releasing of light power induction, CO controllable delivery system and its construction method.CO method for releasing of the invention under the irradiation of near infrared light, carries out the controlled release of CO by nearly infrared optical response type, the photosensitizer that can be used for optical dynamic therapy and carbon monoxide-releasing molecules CORM-401 mixing.The present invention is based on the CO method for releasing of light power induction, construct CO controllable delivery system, including near infrared light response type, it can be used for the photosensitizer of optical dynamic therapy, carbon monoxide-releasing molecules CORM-401, and load or the carrier for combining photosensitizer and carbon monoxide-releasing molecules CORM-401.CO controllable delivery system of the invention, the photochemical effect that near infrared light induction photosensitizer generates can promote CO controllable delivery system and enter cell, and nanogel disintegrates under the action of glutathione in the cell, releases CORM-401.Near infrared light activates while generating singlet oxygen and CO is respectively used to optical dynamic therapy and CO Gases for Treating, realizes combination therapy, and antitumous effect significantly improves.
Description
Technical field
The invention belongs to medical biomaterial technical fields, are related to a kind of CO method for releasing of smooth power induction, Yi Jiji
In the CO controllable delivery system and its construction method of the induction of light power.
Background technique
Carbon monoxide (CO) has very strong Hb BC hemoglobin binding capacity as a kind of colourless, tasteless gas, sucks people
It is easy to cause in blood after body and forms carbonyl haemoglobin, hemoglobin is made to lose oxygen carrying capacity, body is caused to be poisoned, therefore is long
CO is considered a type of " killer of silencing " since phase.People gradually recognize that CO plays important life in vivo in recent years
Reason and pathological effect, it is after nitric oxide (NO) and hydrogen sulfide (H2S after), the third gasotransmitter for being found
(gasotransmitters).CO has a variety of important physiological actions and potential pharmacological activity.Endogenous CO is maintaining body
It is played an important role in terms of interior self-balancing: can promote vasodilation, anti-apoptotic, anti-inflammatory, anti-oxidant etc..These discoveries are not
It is disconnected to have deepened people to the understanding of CO essence, make it in cardiovascular disease, organ transplant, shock, septicemia, inflammation, cancer etc.
Aspect has broad application prospects.Due to its intrinsic gas characteristic, CO precisely passing at lesion tissue position how is realized
Sending with controlled release is that CO is used for an important research direction of clinical treatment in recent years.
Available CO suction apparatus has clinically been had already appeared at present, it can be directly quantitative toward conveying in vivo by device
CO, but such device is faced with many problems: 1) sucking a large amount of CO and be easy to cause general toxicity；2) gas being directly sucked in
Lack targeting, life entity may be caused compared with havoc.Therefore, researchers have developed the medicine of a kind of releasable CO
Object, i.e. carbon monoxide-releasing molecules (CORMs), which, which provides, to discharge the method for a large amount of CO in privileged site, compensate for
The defect of CO suction apparatus realizes the accurate delivering of CO to a certain extent.
According to the difference of structure, CORMs has different CO releasing mechanisms.Such as CORM-2 and CORM-3 can match
CO is discharged by ligand exchange under the action of body such as glutathione (GSH)；CORM-A1 has sensitivity to acid, can be made by proton
With the rate of release for improving CO；CORMs (ET-CORMs) with enzyme responsiveness can fast quick-release under esterase effect in vivo
Put CO；In addition one kind CORMs (photoCORMs) then has light sensitivity, can pass through electronics under ultraviolet light or visible light action
Transfer release CO.
In recent years, although many novel CORMs developed successively, and it is applied to the treatment of various diseases.But
There is also some defects in terms for the treatment of by many CORMs.The ET-CORMs of release is responded with enzyme and there is ligand exchange to make
The uncontrollable problem of CO release is faced with the CORMs of release to be easy to occur in blood circulation after such CORMs enters in vivo
The release in advance of CO, the phenomenon that causing septicemia and drug effect to be lost.In addition, being easy when photoCORMs is recycled in vivo
The release that CO occurs under the irradiation of natural light, causes body to be poisoned, therefore generally require for patient to be maintained at during treatment
Under dark condition, inconvenience is brought to patient's life.Therefore, providing efficiently controllable delivery system for CORMs is CO therapy
A critical problem applied to disease treatment.CO not only may be implemented to be treated using the CORMs of controlled release CO
In the accurate delivering of lesion tissue, moreover it is possible to preferably performance therapeutic effect.The CORMs that developed at present is made a general survey of, it is most ideal
Selection be photoCORMs.PhotoCORMs can control the release of CO by regulation light application time, power, region, realize
Release time and space it is highly controllable.But most of photoCORMs is that release CO is stimulated using ultraviolet light, ultraviolet
Light is weak to the penetration power of tissue, it is difficult to reach the lesion tissue of depth areas, high-energy ultraviolet light will also produce tissue and cell
Third contact of a total solar or lunar eclipse toxic action.Therefore it designs and becomes current research emphasis using more excellent stimuli responsive condition to discharge CO.
Near infrared light (NIR light, 650-850nm) has tissue penetration more deeper than ultraviolet light, visible light, and not
Injury can be generated to tissue.Therefore, the controlled release that stimulation CO is induced using near infrared light, for carrying forward vigorously CORMs's
Clinical application has far-reaching significance.
Summary of the invention
It is limited to ultraviolet light and visible light for the stimulation corresponding conditions of existing light sensitivity CO release, present invention firstly provides
A kind of CO method for releasing of smooth power (PDT) induction.This method can utilize the light of photosensitizer generation under the irradiation of near infrared light
Chemical action stimulates the time induced carbon monoxide-releasing molecules release CO, realization CO under near infrared light induction, space can
Controlled release is put.
The CO method for releasing of light power induction of the invention, by nearly infrared optical response type, can be used for optical dynamic therapy
Photosensitizer and carbon monoxide-releasing molecules CORM-401 mixing, under the irradiation of near infrared light, carry out the controlled release of CO.
Specifically, above-mentioned photosensitizer can be Ce6 (chlorin e 6), Ce4 (dihydroquinone e4), HPPH
(Photochlor, light Crow), AlPcS4Deng the photosensitizer that can be used for optical dynamic therapy near infrared light stimuli responsive.
In a particular embodiment, the present invention is by mixing photosensitizer Ce6 and carbon monoxide-releasing molecules CORM-401,
Under the irradiation of near infrared light, the controlled release of CO is carried out.
In order to improve the burst size of CO, in a particular embodiment, the present invention passes through the light by molar ratio for 0.05~1:1
Quick dose of Ce6 is mixed with carbon monoxide-releasing molecules CORM-401, under the irradiation of near infrared light, carries out the controlled release of CO.
For the burst size for further improving CO, in a particular embodiment, the present invention is by being 0.1~1:1 by molar ratio
The release of photosensitizer Ce6 and carbon monoxide divide CORM-401 to mix, under the irradiation of near infrared light, carry out the controlled release of CO.
The present invention also provides the CO controllable delivery systems of the CO method for releasing based on above-mentioned smooth power induction.The delivering
System includes near infrared light response type, the photosensitizer that can be used for optical dynamic therapy, carbon monoxide-releasing molecules CORM-401, and
Load or the carrier for combining photosensitizer and carbon monoxide-releasing molecules CORM-401.
For the benefit of CO controllable delivery system enters intracellular, the partial size of the CO controllable delivery system 200nm with
Under.
In a particular embodiment, CO controllable delivery system provided by the invention is that CORM@G3DSP-Ce6 nanogel is passed
System is sent, the CORM@G3DSP-Ce6 nanogel delivery system includes nanogel G3DSP-Ce6 and is supported on nanometer
Carbon monoxide-releasing molecules CORM-401, the nanogel G3DSP-Ce6 in gel G3DSP-Ce6 cavity are with more
Face body oligomeric silsesquioxane POSS is that three generations's lysine dendrimer (G3-Lys) of core is obtained with photosensitizer Ce6 covalent coupling
It is cross-linked to form to conjugate G3-Ce6 crosslinked dose of 3,3'- dithiodipropionic acid two (N- hydroxysuccinimide) ester (DSP)
Nanogel.
Specifically, in above-mentioned CORM@G3DSP-Ce6 nanogel delivery system, the photosensitizer Ce6 and an oxygen
The molar ratio for changing carbon emissions molecule CORM-401 is 1:7.5~20.
As more preferably scheme, in above-mentioned CORM@G3DSP-Ce6 nanogel delivery system, described is photosensitive
The molar ratio of agent Ce6 and carbon monoxide-releasing molecules CORM-401 is 1:15~20.
More specifically, in embodiment, the present invention provides the system of above-mentioned CORM@G3DSP-Ce6 nanogel delivery system
Preparation Method first passes through macromolecular and photosensitizer Ce6 covalent coupling, then solidifying by being cross-linked to form the nanometer with abundant cavity structure
CORM-401 is loaded into the cavity of nanogel by glue G3DSP-Ce6 finally in the way of physical load, is prepared while being carried
There is a nanogel delivery system CORM@G3DSP-Ce6 of photosensitizer Ce6 and carbon monoxide-releasing molecules CORM-401, including with
Lower step:
It step 1, will be three generations's lysine dendrimer (G3- of core with polyhedral oligomeric silsesquioxane (POSS)
Lys) conjugate G3-Ce6 is obtained with photosensitizer Ce6 covalent coupling；
Step 2, by G3-Ce6 crosslinking agent 3, (N- hydroxysuccinimide) ester of 3'- dithiodipropionic acid two (DSP) is handed over
It is unified into nanogel G3DSP-Ce6 delivery system；
Step 3, in the way of physical load, CORM-401 is slowly dropped in G3DSP-Ce6 solution, is stirred to mixed
It closes uniformly, dialysis removes free CORM-401, and freeze-drying obtains CORM@G3DSP-Ce6 nanogel delivery system.
Specifically, step 1 are as follows: under nitrogen protection, by Ce6 and N, N'- dicyclohexylcarbodiimide (DCC), N- hydroxyl
Succinimide (NHS) is dissolved in anhydrous n,N-Dimethylformamide (DMF), and under room temperature, reaction overnight is with activated carboxyl, mistake
After filtering out dicyclohexylurea (DCU) (DCU), obtained activation Ce6 (Ce6-NHS) is slowly dropped in G3-Lys solution, is protected from light
Reaction, after then obtained solution is successively dialysed in DMF and water, freeze-drying obtains conjugate G3-Ce6.
Specifically, step 2 are as follows: G3-Ce6 is dissolved in DMF at room temperature, delays the DMF solution containing DSP under stirring
Slowly it is added drop-wise in the solution of G3-Ce6, after reaction, successively dialyses in DMF and water, freeze-drying obtains nanogel production
Object G3DSP-Ce6.
Specifically, step 3 are as follows: G3DSP-Ce6 and CORM-401 are dissolved separately in the PBS solution that pH is 7.4, are surpassed
Under sound, CORM-401 is slowly dropped in G3DSP-Ce6 solution, is stirred overnight at room temperature, CORM@G3DSP-Ce6 mixed molten
Liquid is dialysed in water removes free CORM-401, and freeze-drying obtains nanogel CORM@G3DSP-Ce6 delivery system.
More specifically, in each step, molecular cut off when dialysis is 1000Da.
More specifically, the molar ratio of the G3-Ce6 and DSP are 1:2~1:4 in step 2, the nanogel is produced
The partial size of object G3DSP-Ce6 is in 200nm or less.
More specifically, CORM-401 accounts for the 10~30% of CORM-401 and G3DSP-Ce6 gross mass in step 3.
Compared with prior art, the invention has the following advantages that
(1) the CO method for releasing of light power of the invention induction can be generated under the irradiation of near infrared light using photosensitizer
Photochemical effect, stimulation induction carbon monoxide-releasing molecules CORM-401 discharge CO, realize CO near infrared light induction under
Time, space controlled release；
(2) the CO controllable delivery system based on the induction of light power that the present invention constructs, near infrared light induce photosensitizer to generate
Photochemical effect can promote CO controllable delivery system and enter cell, improve photosensitizer and carbon monoxide-releasing molecules CORM-401
Enrichment degree in the cell can discharge CO in deeper lesion tissue, and CO burst size is big, and feasibility is strong；
(3) the CO controllable delivery system based on the induction of light power that the present invention constructs is capable of the work of glutathione in the cell
Disintegrated with lower nanogel, releases CORM-401.Near infrared light activation can generate simultaneously singlet oxygen and CO is respectively used to light
Dynamic therapy and CO Gases for Treating.Optical dynamic therapy and CO gas combination therapy system have good biological safety, compare
In simple optical dynamic therapy and CO Gases for Treating, combination therapy system has better inside and outside antitumous effect.
Detailed description of the invention
Fig. 1 is the mechanism choice for the CO method for releasing that light power of the invention induces.
Fig. 2 is that CORM-401 exists with 7.4 mixed solution of various concentration photosensitizer Ce6 and PBS respectively in embodiment 1
CO under 665nm near infrared light discharges figure.
Fig. 3 is that CORM@G3DSP-Ce6 method figure constructed by the present invention and light power induce CO method for releasing using delivering
System CORM@G3DSP-Ce6 method use for cancer treatment and schematic diagram.
Fig. 4 is that CO of the CORM@G3DSP-Ce6 under 665nm near infrared light discharges figure.
Fig. 5 is G3DSP-Ce6 and H of the CORM@G3DSP-Ce6 under 665nm near infrared light2O2Concentration variation diagram.
Fig. 6 is G3DSP-Ce6 and CORM@G3DSP-Ce6 under 665nm near infrared light1O2Generate figure.
Fig. 7 is the cellular uptake figure of CORM@G3DSP-Ce6.
Fig. 8 is the extracorporeal anti-tumor of CORM@G3DSP-Ce6-1, CORM@G3DSP-Ce6-2 and CORM@G3DSP-Ce6-3
Effect contrast figure.
Fig. 9 is the extracorporeal anti-tumor effect picture of CORM@G3DSP-Ce6-2.
Figure 10 is the internal antitumor process and effect picture of CORM@G3DSP-Ce6-2.
Figure 11 is safety evaluatio figure antitumor in CORM G3DSP-Ce6-2 body.
Specific embodiment
In order to make the objectives, technical solutions and advantages of the present invention clearer, below by accompanying drawings and embodiments, to this
Invention is described in further detail.However, it should be understood that described herein, specific examples are only used to explain the present invention, not
For limiting the scope of the invention.
Experimental methods as used in the following examples are conventional method unless otherwise specified.Institute in following embodiments
Material, reagent etc. commercially obtain unless otherwise specified.
Embodiment 1
The feasibility study of the method for light power induction release CO.
By the photosensitizer Ce6 of various concentration and carbon monoxide-releasing molecules CORM-401, (CORM-401 concentration is fixed as
1mM, Ce6 and CORM-401 concentration ratio are from 0.01:1 to 1:1) it is dissolved in the phosphate buffer (PBS 7.4) that pH is 7.4,
And be placed in a transparent cylinder together with CO gas detecting instrument and separate in closed container, closed system.665nm's
(optical energy density is 11.5 mW/cm near infrared light2) under prolonged exposure, pass through and read different time points CO gas detecting instrument
Registration records the concentration of CO, calculates the amount of each CORM-401 molecule release CO.
Assuming that both the gas phase and liquid phase in container reach balance, the pressure in container is 1 standard atmospheric pressure, then
Amount (the N of CORM-401 release COCO[mol]) it is calculated by following formula:
Wherein, p is the partial pressure of CO, VgAnd VlThe respectively volume of gas phase and liquid phase, R are gas constant (0.08205L
atm·mol-1·K-1), T is temperature, and c is the concentration of CO in the liquid phase, and k is the henry 's law constant of CO in water (at 25 DEG C
For 1052.63Latmmol-1).It is therefore possible for the detected that CO gas concentration can be scaled the partial pressure p of CO, to obtain CO's
Burst size.
Fig. 1 is that light power induces the drawing of CO machine for releasing.The hydrogen peroxide generated during optical dynamic therapy as we know from the figure
From the photosensitising processes of photosensitizer.Enter singlet excited after the irradiation of photosensitizer Ce6 light, by interaction between being
(Intersystem crossing), the Ce6 of singlet excited is changed into triplet excited state, then transfers an electron to oxygen molecule
On, generate superoxide anion.Superoxide anion finally generates stable hydrogen peroxide in conjunction with the proton hydrogen in solution.
And carbon monoxide-releasing molecules CORM-401 is in a relatively steady state in PBS 7.4. CORM-401
It is easy to lose a CO in the solution, the CO lost can be recombined on CORM-401 again, so that CORM-401 is in opposite
Stable state.If there are hydrogen peroxide in solution, the hydrogen peroxide ligand and oxidant active as one can promote
CORM-401 releases CO.CORM-401 is the metal carbonyl complex with 18 electronic structures, according to 18 electron Rules,
CORM-401 has more stable structure, and therefore, the lone electron pair that hydrogen peroxide molecule structure provides can not directly and CORM-
401 coordinations.A CO is lost and when in unsteady state (16 electronic structure) when CORM-401 is of short duration in the solution, solution
In hydrogen peroxide can be coordinated with its center Mn as ligand, while CO being prevented to recombine on the center Mn.Coordination
Hydrogen peroxide then aoxidizes CORM-401, and the electronics of complex is made to be transferred to H by central metallic ions2O2On ligand, weaken Mn with
Backdonation between CO eventually leads to σ fit key between Mn and CO to weaken backdonation to the firm effect of its σ fit key
Fracture, promotes the release of CO.
Fig. 2 is CORM-401 respectively with 7.4 mixed solution of various concentration photosensitizer Ce6 and PBS in 665 nm near-infrareds
CO under light irradiation discharges figure.Photosensitizer Ce6 induces carbon monoxide-releasing molecules under near infrared light as we know from the figure
The amount that CORM-401 discharges CO depends on the proportionate relationship of Ce6 and CORM-401.When Ce6:CORM-401 is greater than 0.05:1, CO
Burst size it is more obvious, the generation rate of CO is very fast.
Embodiment 2
The building of the nanogel delivery system of CO method for releasing based on the induction of light power.
Three generations the lysine dendrimer G3-Lys and photosensitizer Ce6 that by POSS be core, lysine is branch units
Between covalent coupling reaction, synthesized conjugate G3-Ce6.Specially under nitrogen protection, by Ce6 (83.53mg,
0.14mmol) and N, N'- dicyclohexylcarbodiimide (DCC) (433.29mg, 2.10mmol), n-hydroxysuccinimide
(NHS) (241.69mg, 2.10mmol) is dissolved in the anhydrous n,N-Dimethylformamide of 10mL (DMF), anti-overnight under room temperature
Acquired carboxylated Ce6 (Ce6-NHS) should be slowly dropped to activated carboxyl, after dicyclohexylurea (DCU) (DCU) is removed by filtration
It in G3-Lys (1.00g, 0.07mmol) solution, is protected from light for 24 hours, then by obtained solution successively in DMF and water
It dialyses after (dialysis bag retention molecular weight 1000Da), freeze-drying obtains blackish green floccule G3-Ce6.
G3-Ce6 is cross-linked into nanogel with crosslinking agent (DSP).G3-Ce6 is dissolved in DMF solvent at room temperature,
Under the revolving speed stirring of 1500r/min, the DMF solution containing DSP is slowly dropped in the solution of G3-Ce6, wherein G3-Ce6
Molar ratio with DSP is 1:2~1:4.After reaction for 24 hours, successively (dialysis bag retention molecular weight is for dialysis in DMF and water
1000Da), freeze-drying obtains blackish green cotton-shaped nanogel product G3DSP-Ce6.
Since there are numerous cavitys inside nanogel G3DSP-Ce6, it can be used for physical load small-molecule drug.It will
G3DSP-Ce6 and CORM-401 is dissolved separately in first in 7.4 solution of PBS, and under Yu Chaosheng state, CORM-401 is slowly dripped
It is added in G3DSP-Ce6 solution (wherein CORM-401 account for CORM-401 and G3DSP-Ce6 gross mass 10~30%), room temperature
It is stirred overnight.By dialysing in water, (dialysis bag retention molecular weight is resulting CORM@G3DSP-Ce6 mixed solution
Free CORM-401 1000Da) is removed, finally freeze-drying obtains CORM@G3DSP-Ce6 floccule.
CORM-401 is loaded into the internal cavities of G3DSP-Ce6 nanogel, constructs by the method coated by physics
Total load delivery system CORM@G3DSP-Ce6 with different Ce6 and CORM-401 ratios (is named as CORM@G3DSP-Ce6-
1, CORM@G3DSP-Ce6-2 and CORM@G3DSP-Ce6-3, Ce6:CORM-401 are respectively 1:7.5,1:15,1:20).
The schematic illustration of the method is as shown in Figure 3.Table 1 is G3DSP- obtained under G3-Ce6 and DSP different proportion
The size distribution data of Ce6, the molar ratio of G3-Ce6 and DSP be 1:2~1:4 in the case where, can get size 200nm with
Under G3DSP-Ce6 nanogel.This is because the nanoparticle under the size can enter cell by way of endocytosis, thus
Reach good cellular uptake rate, and then guarantees its therapeutic effect.
1 G3-Ce6 of table and the size of G3DSP-Ce6 obtained under DSP different proportion are distributed
Embodiment 3
The CO release behavior of CORM@G3DSP-Ce6 is detected using CO gas detecting instrument.Continued with the near-infrared of 665nm
CORM@G3DSP-Ce6 solution is irradiated, holding optical energy density is 11.5mW/cm2, detect the burst size of CO.
To probe into the mechanism that light power induces CO release, Amplex Red reagent and horseradish peroxidase (HRP) are utilized
The H that detection G3DSP-Ce6 and CORM@G3DSP-Ce6 solution generates under photoinduction2O2Concentration variation.By G3DSP-Ce6 (Ce6
0.68 μM of concentration) and CORM@G3DSP-Ce6 (0.68 μM of Ce6 concentration, 10 μM of CORM-401 concentration) be dissolved separately in PBS 7.4
In, and take in the solution to 96 orifice plates of 50 μ L, using after the near infrared light prolonged exposure solution of 665nm, (whole process keeps light
Energy density is 11.5mW/cm2), to each hole in the Amplex Red (100 μM) and HRP (0.2U/mL) work of 50 μ L is added
Make solution, the fluorescent value (excitation wavelength 560nm, launch wavelength 586nm) in every hole is measured with microplate reader.By comparing hydrogen peroxide
Standard curve calculates concentration of hydrogen peroxide.The standard curve concentration gradient of hydrogen peroxide is set as 0,0.5,1,2.5,5,10 μ
M。
As a result as shown in Figure 4 and Figure 5, under the irradiation of near infrared light, CORM@G3DSP-Ce6 can quick release it is a large amount of out
CO.And according to the comparative analysis of Fig. 5 it is found that under light conditions, the presence of CORM-401 consumes photosensitizer Ce6 generation
Hydrogen peroxide, it was demonstrated that the principle of smooth power induction release CO proposed by the present invention is to consume Photodynamic therapy generation
Hydrogen peroxide promotes CORM-401 to discharge CO.
Embodiment 4
To probe into optical dynamic therapy effect, singlet oxygen is utilized1O2Fluorescence probe (Singlet Oxygen Sensor
Green, SOSG) CORM@G3DSP-Ce6 and G3DSP-Ce6 is had detected under near infrared light induction1O2Generation ability, Jin Erfen
Whether the release of analysis CO can consume Ce6 generation1O2.By CORM@G3DSP-Ce6 (0.68 μM of Ce6 concentration, CORM-401 concentration
10 μM) and G3DSP-Ce6 (0.68 μM of Ce6 concentration) and SOSG (1 μM) mixed dissolution in quartz colorimetric utensil, it is close with 665nm
The Infrared irradiation mixed solution, holding optical energy density are 11.5mW/cm2.Point in different times, uses fluorescence spectrophotometry
The fluorescent value (excitation wavelength 488nm, launch wavelength 525nm) of meter measurement solution.7.4 solution of PBS of SOSG (1 μM) is set as empty
White group.
As a result as shown in fig. 6, CORM@G3DSP-Ce6 and G3DSP-Ce6 under the photoinduction of same dose have it is similar
Singlet oxygen generates ability, shows the release singlet oxygen that consumption Ce6 is not generated of CO.Since singlet oxygen is that light power is controlled
The Main Factors damaged in treatment to cell, tissue, CORM-401 have no the generation efficiency of singlet oxygen when discharging CO
While influencing, therefore can speculate that CORM@G3DSP-Ce6 delivery system generates CO gas under the induction of near infrared light, very well
The effect for remaining optical dynamic therapy.
Embodiment 5
Cell experiment
In order to probe into the cellular uptake rate of CORM@G3DSP-Ce6, examined using laser confocal microscope and flow cytometer
The cellular uptake situation of CORM@G3DSP-Ce6 is surveyed.
In order to select the optimal proportion of Ce6 and CORM-401, the present invention have studied first CORM@G3DSP-Ce6-1,
The effect of the anti-mouse breast cancer cell 4T1 proliferation of CORM@G3DSP-Ce6-2 and CORM@G3DSP-Ce6-3.By 100 μ L cells
Density is 5 × 103The cell suspending liquid in a/hole is placed in 96 orifice plates, the overnight incubation in incubator.After cell is adherent, abandon
Fall original culture medium.To have G3DSP-Ce6, the CORM@G3DSP-Ce6-1, CORM@of identical Ce6 concentration (2.72 μM)
Respectively with 4T1 cell culture 3h, the near infrared light for then carrying out low energy shines G3DSP-Ce6-2 and CORM@G3DSP-Ce6-3
(0.25J/cm2), continue after cultivating 1h, choose whether to carry out lighting process to cell further according to following grouping:
1) Control: blank cultures+dark
2) CO-1:CORM@G3DSP-Ce6-1+ is dark
3) CO-2:CORM@G3DSP-Ce6-2+ is dark
4) CO-3:CORM@G3DSP-Ce6-3+ is dark
5) PDT:G3DSP-Ce6-3+ illumination
6) PDT+CO-1:CORM@G3DSP-Ce6-1+ illumination
7) PDT+CO-2:CORM@G3DSP-Ce6-2+ illumination
8) PDT+CO-3:CORM@G3DSP-Ce6-3+ illumination
The dosage that near infrared light shines is 1J/cm2.After cell is continued culture for 24 hours, culture medium is discarded, with PBS 7.4
Solution cleans cell, and the serum free medium containing 10%CCK-8 is added, 1h is incubated in incubator, is measured with microplate reader every
OD value of a hole at 450nm, measures the cell survival rate in each hole in this approach.Cell survival rate passes through following formula
It is calculated:
Wherein, AxFor the absorption value of experimental group, AcFor the absorption value of negative control group, AbFor the absorption value of blank control group.
According to testing above as a result, CORM@G3DSP-Ce6-2 is selected to detect the antitumous effect under each concentration, have
As described above carry out is made in gymnastics.
As a result as Figure 7-9.As can be seen from Figure 7, cell has preferable intake effect to CORM@G3DSP-Ce6, and works as
After having carried out near infrared light photograph, the intake of cell is bigger, has reached 92%, and the CORM@G3DSP-Ce6 detected into the cell is flat
Equal fluorescence intensity (MFI) also significantly improves.Results showed that CORM@G3DSP-Ce6 can be rich well under near infrared light induction
Collection is in the cell.
As it can be observed in the picture that merely CORM@G3DSP-Ce6 is delivered in tumour cell without carrying out lighting process to it,
The survival rate of tumour cell shows simple CORM-401 to oncotherapy to no effect almost without any change.CORM@G3DSP-
The light power link CO gas that Ce6-1, CORM@G3DSP-Ce6-2 and CORM@G3DSP-Ce6-3 are generated under light conditions is controlled
Treating (PDT+CO-1, PDT+CO-2 and PDT+CO-3 group) has preferably treatment than simple optical dynamic therapy (PDT group)
Effect, and PDT+CO-2 and PDT+CO-3 have optimal tumor cytotoxicity effect, illustrate CORM@G3DSP-Ce6-2 and
CORM@G3DSP-Ce6-3 has the combination therapy effect become apparent under photoinduction.
The 4T1 Cytostatic to tumor cell effect (PDT+CO group) that CORM@G3DSP-Ce6 is generated as can be seen from Figure 9 depends on
The concentration of Ce6 and CORM-401, when the concentration of Ce6 and CORM-401 respectively reaches 1.36 and 20 μM, cell survival rate is obvious
It reduces.
Embodiment 6
Zoopery
The building of mouse breast cancer model is as follows:
Upgrowth situation good 4T1 cell centrifugation (1200rpm, 3min) is collected, and with after the washing of PBS 7.4, by institute
(cell density is 1 × 10 to obtained cell suspending liquid6A every mouse) it is subcutaneously injected into the back right lateral side of mouse, it infuses
The growing state of meaning observation tumour and the size for measuring tumour.The size of tumour is calculated with vernier caliper measurement, specific to count
It is as follows to calculate formula:
V=W2×L/2
Wherein V is represented tumor size (volume), and W is the width of tumour, and L is the length of tumour.
The present invention utilizes mouse 4T1 breast cancer tumour model, has detected the therapeutic effect of light power induction CO method for releasing.
Using BALB/c mouse, 4T1 breast cancer tumour model is subcutaneously established in mouse.When tumour is long to about 100mm3When, by mouse with
Machine is divided into 4 groups, is administered by way of intratumor injection, carries out the near infrared light of low energy according to (3.0J/ after 1 h is administered
cm2), and chosen whether to carry out lighting process to mouse according to group, specifically it is grouped as follows:
1) for blank control group, 7.4 solution of PBS, dark condition PBS: are injected；
2) CO: (Ce6 dosage is 1.0mg/kg to injection CORM@G3DSP-Ce6 solution, and CORM-401 dosage is 8.1mg/
Kg), dark condition；
3) PDT: injection G3DSP-Ce6 solution (Ce6 dosage is 1.0mg/kg) is carried out in administration 4h and for 24 hours afterwards respectively
12.0J/cm2Near infrared light shine；
4) PDT+CO: (Ce6 dosage is 1.0mg/kg to injection CORM@G3DSP-Ce6 solution, and CORM-401 dosage is
8.1mg/kg), 12.0J/cm is carried out afterwards in administration 4h and for 24 hours respectively2Near infrared light shine.
The above administration and phototherapy carry out 3 times respectively, are spaced 3 days.Continuous observation mouse body situation, measures it
Changes of weight and tumor size.After 18 days, mouse is put to death, takes its tumour and the heart, liver, spleen, lung, kidney, and clear with 7.4 solution of PBS
Bloodstain is washed off, and tumor size pattern is taken pictures and weighed.The tumour and main organs of taking-up are solid with 4% paraformaldehyde
It is fixed.
After tumour and main organs dehydration, trimming, embedding, slice, carries out H&E, TUNEL dyeing and CD31 exempts from
Epidemic disease histochemical staining, and sealing in glass plate finally with micro- sem observation and carries out Image Acquisition.
The present invention also utilizes the HbCO content in Enzyme-linked Immunosorbent Assay method (Elisa) measurement mice plasma, with assessment
The safety of CORM@G3DSP-Ce6.
The result of zoopery is as shown in Figure 10 and Figure 11.
Figure 10 a is the flow diagram of cell experiment.Figure 10 b-d shows CORM@G3DSP-Ce6 can under light induction
Generate combination therapy (PDT+CO) effect of optical dynamic therapy and CO Gases for Treating.The final size of mouse tumor in figure shows
PDT+CO combination therapy inhibits the proliferation of mouse breast cancer tumour well, tumor control rate reached 84% (* p in figure <
0.05).Figure 10 e shows the stained slice analysis result of mouse tumor tissue.In H&E stained slice, PDT+CO, which combines, to be controlled
The Tumor Tissue Tumors nucleus for the treatment of group reduces, tissue space increases, it is meant that tumor tissues receive biggish destruction.Tumour
The apoptosis situation of tissue is found after being detected with TUNEL cell apoptosis detection kit, in TUNEL stained slice, PDT+CO connection
The apoptosis of tumor cells rate for closing treatment group significantly improves.And the present invention utilizes target gene CD31 immunohistochemical method pair
Mouse tumor histotomy is dyed, and is observed and is determined the expression position target gene CD31 and signal strength or weakness, assessed with this small
Microvessel density in mouse tumor tissues.The microvessel density (MVD) of tumor tissues is combined by PDT+CO as can be known from the results
It is significantly reduced after treatment.Length of the scale in figure is 50 μm.
Figure 11 is shown to be assessed using the biological safety that CORM@G3DSP-Ce6 is treated under near infrared light.
As shown in fig. 11a, after CORM@G3DSP-Ce6 being injected into Mice Body, carbonyl haemoglobin in mouse blood is not caused
(HbCO) rising of content shows that CO intoxicating phenomenon will not be caused by injecting CORM@G3DSP-Ce6, it was demonstrated that the delivery system
Safety.As shown in figure 11b, when carrying out PDT+CO therapeutic process, mouse weight variation without exception, mouse main organs
The H&E stained slice (Figure 11 c, length of the scale be 100 μm) of (heart, liver, spleen, lung, kidney) have no the apparent tissue inflammation of discovery and
Necrosis phenomena shows and carries out optical dynamic therapy and CO Gases for Treating with good bio-safety using CORM@G3DSP-Ce6
Property.
In conclusion light power induction CO method for releasing of the invention has the quick release CO under near infrared light induction
Performance.The mixed solution of photosensitizer (such as Ce6) and CORM-401 under the irradiation of near infrared light (such as wavelength is 665nm),
It can release a large amount of CO, and with the increase of photosensitizer concentration ratio, the burst size of CO is higher.And what the present invention constructed
CORM@G3DSP-Ce6 under near infrared light, can quick release go out a large amount of CO.Wherein, the main reason for promotion CO release, is
Consume a large amount of H generated during PDT2O2.And CORM@G3DSP-Ce6 does not consume PDT mistake while discharging CO
It is generated in journey1O2。
Light power induction CO method for releasing of the invention has the performance of joint optical dynamic therapy and CO Gases for Treating, can use
In the treatment of a variety of diseases.The photochemical effect that near infrared light induction photosensitizer generates can promote CORM@G3DSP-Ce6 entrance
Cell improves the enrichment degree of photosensitizer and carbon monoxide-releasing molecules CORM-401 in the cell.And CORM@G3DSP-
Nanogel disintegrates Ce6 under the action of glutathione in the cell, releases CORM-401.Near infrared light activation can generate simultaneously
Singlet oxygen and CO are respectively used to optical dynamic therapy and CO Gases for Treating.Optical dynamic therapy and CO gas combination therapy system have
Good biological safety, compared to simple optical dynamic therapy and CO Gases for Treating, combination therapy system has better body
Inside and outside antitumous effect.
It is antitumor by H&E dyeing, the detection of TUNEL Apoptosis and CD31 immunohistochemical study, joint of the invention
Mechanism essentially consists in: under near infrared light induction, CORM@G3DSP-Ce6 produces CO gas and singlet oxygen simultaneously, causes
The extensive damage of tumor tissues reduces the microvessel density MVD of tumor tissues, is proliferated rapidly to cut off tumor tissues
Nutrition supply chain, cause the large area apoptosis of tumour cell, the final growth for inhibiting tumor tissues.
Claims (10)
1.CO controllable delivery system, which is characterized in that the CO controllable delivery system is CORM@G3DSP-Ce6 nanogel
Delivery system, including nanogel G3DSP-Ce6 and the carbon monoxide being supported in nanogel G3DSP-Ce6 cavity release point
Sub- CORM-401, the nanogel G3DSP-Ce6 are to rely ammonia by the three generations of core of polyhedral oligomeric silsesquioxane POSS
Sour dendrimer G3-Lys and photosensitizer Ce6 covalent coupling obtain crosslinked dose of 3,3'- dithio dipropyl of conjugate G3-Ce6
The nanogel that sour two (N- hydroxysuccinimide) esters are cross-linked to form.
2. CO controllable delivery system according to claim 1, which is characterized in that the photosensitizer Ce6 and carbon monoxide
The molar ratio for discharging molecule CORM-401 is 1:7.5~20.
3. CO controllable delivery system according to claim 1, which is characterized in that the photosensitizer Ce6 and carbon monoxide
The molar ratio for discharging molecule CORM-401 is 1:15~20.
4. the preparation method of any CO controllable delivery system according to claim 1~3, which is characterized in that including following
Step:
Step 1, by using polyhedral oligomeric silsesquioxane POSS as three generations's lysine dendrimer G3-Lys of core with it is photosensitive
Agent Ce6 covalent coupling obtains conjugate G3-Ce6；
Step 2, by G3-Ce6 crosslinking agent 3, it is solidifying that 3'- dithiodipropionic acid two (N- hydroxysuccinimide) ester is cross-linked into nanometer
Glue G3DSP-Ce6 delivery system；
Step 3, in the way of physical load, CORM-401 is slowly dropped in G3DSP-Ce6 solution, stirring is equal to mixing
Even, dialysis removes free CORM-401, and freeze-drying obtains CORM@G3DSP-Ce6 nanogel delivery system.
5. the preparation method of CO controllable delivery system according to claim 4, which is characterized in that step 1 are as follows: protected in nitrogen
Under shield, by Ce6 and N, N'- dicyclohexylcarbodiimide, n-hydroxysuccinimide are dissolved in DMF, under room temperature, reaction overnight
With activated carboxyl, after being filtered to remove dicyclohexylurea (DCU), obtained carboxylated Ce6 is slowly dropped in G3-Lys solution, is protected from light
Reaction, after then obtained solution is successively dialysed in DMF and water, freeze-drying obtains conjugate G3-Ce6.
6. the preparation method of CO controllable delivery system according to claim 4, which is characterized in that step 2 are as follows: at room temperature will
G3-Ce6 is dissolved in DMF, the DMF solution containing DSP is slowly dropped in the solution of G3-Ce6 under stirring, reaction terminates
Afterwards, it successively dialyses in DMF and water, freeze-drying obtains nanogel product G3DSP-Ce6.
7. the preparation method of CO controllable delivery system according to claim 4, which is characterized in that step 3 are as follows: by G3DSP-
Ce6 and CORM-401 is dissolved separately in the PBS solution that pH is 7.4, and under ultrasound, CORM-401 is slowly dropped to G3DSP-
It in Ce6 solution, is stirred overnight at room temperature, CORM@G3DSP-Ce6 mixed solution is dialysed in water and removes free CORM-401,
Freeze-drying obtains nanogel CORM@G3DSP-Ce6 delivery system.
8. the preparation method of CO controllable delivery system according to claim 4, which is characterized in that in each step, when dialysis
Molecular cut off be 1000Da.
9. the preparation method of CO controllable delivery system according to claim 4, which is characterized in that described in step 2
The molar ratio of G3-Ce6 and DSP is 1:2~1:4, and the partial size of the nanogel product G3DSP-Ce6 is in 200nm or less.
10. the preparation method of CO controllable delivery system according to claim 4, which is characterized in that described in step 3
CORM-401 accounts for the 10~30% of CORM-401 and G3DSP-Ce6 gross mass.
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