CN104548095B - A kind of PLGA/MoS2Composite medicament stent material and its preparation method and application - Google Patents
A kind of PLGA/MoS2Composite medicament stent material and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to a kind of PLGA/MoS2Composite medicament stent material and its preparation method and application, including：Nonaqueous solvents with biocompatibility and PLGA, the MoS being dispersed in the solvent2PEG nanometer sheets and chemotherapeutics.In the present invention, PLGA is a kind of strong hydrophobic high polymer, by the PLGA/MoS2Composite medicament stent material（" oleosol "）It is injected into after tumour, PLGA/MoS2" liquid is solid " phase transformation can occur at once for/chemotherapeutics, in intra-tumor formation PLGA/MoS2/ chemotherapeutics block, i.e. PLGA/MoS2/ chemotherapeutics support.
Description
Technical field
The invention belongs to the multi-mode therapy field of tumour, it is related to a kind of PLGA/MoS2Composite medicament stent material and its
Prepare and cancer therapeutic applications.Specifically, the present invention relates to photoacoustic imaging ability, and the heat of tumour can synchronously be realized
The timbering material for the treatment of/chemotherapy combined treatment and its preparation and oncotherapy.
Background technology
It is well known that malignant tumour has become the huge killer of current threat human health.Develop high curative effect, low toxicity pair
The tumour diagnosis and treatment material and method of effect, it is significant to the quality of life and developing national economy of the raising mankind etc..Light
Heat cure is a kind of emerging, minimally invasive oncotherapy means.In photo-thermal therapy field, near-infrared laser (NIR, wave-length coverage：
700-1100nm) there is a series of advantage, such as tissue penetration depths are deep, normal structure absorbs more low to it.NIR laser shines
Penetrate the optical-thermal conversion material for being enriched in tumor locus and raise tumor tissues temperature, and cause death of neoplastic cells.Based on NIR
The photo-thermal therapy research of laser, particularly develops the broad interest that new optical-thermal conversion material causes people.Current research
More optical-thermal conversion material includes gold nanorods, graphene oxide, copper sulfide, tungsten sulfide, palladium metal, indocyanine green, poly- pyrrole
Cough up.Transient metal sulfide (such as MoS2And WS2) because having the advantages that cost is low, biological safety is high, in biomedical sector
Research especially as optical-thermal conversion material gradually causes people to pay close attention to.
At present, the dispersion liquid of material is mainly injected to experimental animals by the application of optical-thermal conversion material by vein
It is interior, nano material is permeated retention effect (EPR effects) by means of the enhancing of tumor locus blood vessel and be passively enriched with to tumor locus；
Or nano material is injected to by intra-tumor by intratumor injection, to improve enriching quantity of the material in tumor locus.For tail vein
For injection, the material or medicine of overwhelming majority injection can enter whole body internal organs with blood circulation, and by reticular endotheliums such as liver, spleens
System organ catches, and the material for being enriched in tumor locus is seldom.Cause oncotherapy effect not good, and normal tissue and organ
Cause certain damage.Intratumor injection is a kind of with traumatic expectant treatment method, and it is needed by means of advanced swollen
Knurl diagnostic means are accurately positioned tumor focus position, and accurately carry out puncturing in knurl, injection.Although intratumor injection can make
More material is passively enriched in tumor locus, but due to the increase of tumor locus vasopermeability, the portion of material of intratumor injection
Blood circulation can be entered by Vascular permeability, it is equally possible to which damage is caused to normal tissue and organ.
The content of the invention
The problem of existing in face of prior art, it is an object of the invention to provide can realize photo-thermal therapy and chemotherapy combined
Treat and efficiently remove tumour, while the PLGA/MoS of the damage of normal tissue and internal organs can be reduced2/ chemotherapeutics branch
Frame and its preparation method and application.
The present inventor learn Poly(D,L-lactide-co-glycolide (PLGA) be one kind by U.S.'s food and FAD
(FDA) certification, the high molecular polymer that can slowly degrade in physiological conditions, are formally included into the U.S. as pharmaceutic adjuvant
Pharmacopeia.PLGA has strong hydrophobicity, and meeting strand after water can drastically roll up and separate out.Moreover, the present inventor has passed through
Experiment demonstrates MoS2- PEG nanometer sheets can absorb NIR laser and convert it to heat, and efficiently kill tumour cell.
Therefore, if preparing a kind of PLGA/MOS2/ chemotherapeutics " oleosol ", then it is at room temperature liquid to be somebody's turn to do " oleosol ", can be swollen
Local injection in knurl, met in knurl can form block timbering material after water and by MoS2- PEG nanometer sheets and chemotherapeutics are coated on
Wherein.And the PLGA/MoS2/ chemotherapeutics timbering material has MoS concurrently2- PEG photo-thermal kills the change of tumour and chemotherapeutics
Treat effect for the treatment of tumour.Importantly, MoS2- PEG and chemotherapeutics are tied in timbering material, are unlikely in large quantities
Into blood circulation.Based on this, the present inventor completes the present invention.
Herein, on the one hand, the present invention provides a kind of PLGA/MoS2Composite medicament stent material, including：With bio-compatible
The nonaqueous solvents of property and Poly(D,L-lactide-co-glycolide, the MoS being dispersed in the solvent2- PEG nanometer sheets and
Chemotherapeutics.
In the present invention, PLGA is a kind of strong hydrophobic high polymer, by the PLGA/MoS2(" oil is molten for composite medicament stent material
Glue ") it is injected into after tumour, PLGA/MoS2" liquid-solid " phase transformation can occur at once for/chemotherapeutics, in intra-tumor formation PLGA/
MoS2/ chemotherapeutics block, i.e. PLGA/MoS2/ chemotherapeutics support.PLGA/MoS2/ chemotherapeutics support possesses thermotherapy and change
Treat the dual activity for the treatment of tumour：MoS2- PEG nanometer sheets impart PLGA/MoS2The good photothermal deformation of/chemotherapeutics support
Ability, the photo-thermal therapy available for tumour；The chemotherapeutics of load can be discharged, and assign PLGA/MoS2/ chemotherapeutics branch
The ability of frame chemotherapeutic treatment tumour.Importantly, MoS2- PEG and chemotherapeutics are tied in timbering material, are unlikely to big
Amount ground enters blood circulation.While the utilization rate of material and medicine is largely increased, normal tissue and internal organs are reduced
Damage, effectively compensate for intravenous injection and intratumor injection deficiency.In addition, MoS2- PEG nanometer sheets possess optoacoustic radiography work(
Can, distribution situation of the material in knurl can be monitored in real time.
Therefore, the present invention is by providing a kind of PLGA/MoS2Composite medicament stent material (PLGA/MoS2/ chemotherapeutics oil
Colloidal sol), and then equivalent to also providing a kind of PLGA/MoS2Composite medicament stent (PLGA/MoS2/ chemotherapeutics support), should
PLGA/MoS2/ chemotherapeutics support is by the PLGA/MoS2It (is, for example, physiology in vitro that composite medicament stent Material injection, which enters water,
Salt solution, in vivo for example, tumor locus) in and formed, including PLGA supports and the MoS that is coated in the support2- PEG nanometers
Piece and chemotherapeutics.The PLGA/MoS of the present invention2/ chemotherapeutics support can realize photo-thermal therapy and chemotherapy combined treatment and it is high
Effect ground remove tumour, more after without recurrence, Small side effects, with important clinical conversion meaning.
It is preferred that the molecular weight of the Poly(D,L-lactide-co-glycolide is 1000~10000 dalton, wherein monomer
The mol ratio of lactic acid and hydroxyacetic acid is 10:90~90:10.
It is preferred that the concentration of the Poly(D,L-lactide-co-glycolide is 0.1g/mL~1.0g/mL.
It is preferred that the MoS2The concentration of-PEG nanometer sheets is 1~5mg/mL.
It is preferred that the concentration of the chemotherapeutics is 0.1mg/mL~1.0mg/mL.
It is preferred that the chemotherapeutics is at least one of doxorubicin hydrochloride, taxol, camptothecine and Combretastatin.
It is preferred that the nonaqueous solvents with biocompatibility is 1-METHYLPYRROLIDONE (NMP), dimethyl sulfoxide (DMSO)
(DMSO)。
On the other hand, the present invention also provides above-mentioned PLGA/MoS2The preparation method of composite medicament stent material, including：Press
According to the PLGA/MoS2The content ratio of each component in composite medicament stent material, by Poly(D,L-lactide-co-glycolide, MoS2-
PEG nanometer sheets and chemotherapeutics are dispersed in the nonaqueous solvents with biocompatibility, that is, the PLGA/MoS is made2/
Chemotherapeutics compound support frame material.And by the way that further dispersions obtained system's (timbering material) is injected into physiological saline, i.e.,
The PLGA/MoS is made2/ chemotherapeutics compound rest.
It is preferred that the Poly(D,L-lactide-co-glycolide by dispersed with stirring in the solvent, mixing time is 12
~24 hours, mixing speed was 100~400 revs/min；The MoS2- PEG nanometer sheets and/or the chemotherapeutics pass through super
Sound is scattered in the solvent, the MoS2The ultrasonic disperse time of-PEG nanometer sheets and/or the chemotherapeutics is 10~60
Minute, ultrasonic power is 50~500W.
Another further aspect, the present invention also provides above-mentioned PLGA/MoS2Composite medicament stent material is in antineoplastic is prepared
Application.The antineoplastic can be the medicine for tumour heat/chemotherapy combined treatment.
Brief description of the drawings
Fig. 1, (a) MoS2The TEM pictures of-PEG nanometer sheets, (b) PLGA/MoS2PLGA/MoS (c)2/ DOX supports
FESEM pictures, (d) is respectively from left to right C, O, Mo and S Element area profile；
Fig. 2, PLGA/MoS2(a) XPS collection of illustrative plates and (b) XRD spectra of support；
Fig. 3, L929 cell are in PLGA/MoS2The survival rate of/DOX rack surfaces, (b-e) is untreated (b＆d) and PLGA/
MoS2Cell morphology after the processing of/DOX supports after the L929 of (c＆e) (b＆c) cell morphology and (d＆e) Trypan Blue；
Under Fig. 4, the irradiation of different capacity density laser, (a) PLGA/MoS2/ DOX supports and (c) PLGA/MoS2/ DOX supports
It is immersed in the water variation relation of the water temperature with radiated time；(b) it is respectively (a) and (c) corresponding radiation after-poppet material with (d)
Thermal imaging picture；
Fig. 5, the μ L PLGA/MoS of intratumor injection 302/ DOX, NIR laser (0.6W/cm2) irradiation different time after tumour temperature
Degree and thermal imaging picture；
Fig. 6, PLGA/MoS2The DOX release profiles of/DOX timbering materials at different conditions；
Gross tumor volume versus time curve after Fig. 7, distinct methods treatment；
Fig. 8, the μ L PLGA/MoS of intratumor injection 302After/DOX, Mo content in each internal organs of different time points nude mice；
(the μ L PLGA/MoS of intratumor injection 30 after Fig. 9, treatment2/ DOX, and assign NIR laser (0.6W/cm2, irradiate 5 points
Clock)) the tumour photo of different time；
Figure 10, the μ L PLGA/MoS of intratumor injection 302Photoacoustic imaging image before and after/DOX.
Embodiment
The present invention is further illustrated below in conjunction with accompanying drawing and following embodiments, it should be appreciated that accompanying drawing and following embodiments
The present invention is merely to illustrate, is not intended to limit the present invention.
The present invention has strong hydrophobicity using PLGA, meets the characteristic that strand can drastically roll up and separate out after water, together
Shi Liyong MoS2- PEG nanometer sheets can absorb NIR laser and convert it to heat, and efficiently kill the property of tumour cell
There is provided a kind of PLGA/MOS for matter2/ chemotherapeutics compound, the compound is in vitro with the nonaqueous solvents with biocompatibility
For carrier, be formed as the form of " oleosol ", i.e. in the nonaqueous solvents with biocompatibility it is dispersed have PLGA,
MOS2And chemotherapeutics.It is at room temperature liquid to be somebody's turn to do " oleosol ", can carry out intra-tumor local injection, being met in knurl can after water
Block timbering material is formed, that is, is formed as PLGA/MOS2/ chemotherapeutics support.The PLGA/MOS2/ chemotherapeutics support includes
PLGA supports and the MoS being coated in PLGA supports2- PEG nanometer sheets and chemotherapeutics.The PLGA/MOS of the present invention2/ chemotherapeutic
Thing timbering material has MoS concurrently2- PEG photo-thermal kills effect of tumour and the chemotherapeutic treatment tumour of chemotherapeutics.It is prior
It is, MoS2- PEG and chemotherapeutics are tied in timbering material, are unlikely to enter blood circulation in large quantities.Material and medicine
While utilization rate is largely increased, reduce the damage of normal tissue and internal organs, effectively compensate for intravenous injection and
The deficiency of intratumor injection.In addition, MoS2- PEG nanometer sheets possess optoacoustic radiography function, and distribution of the material in knurl can be monitored in real time
Situation.
So far, this area is not yet developed a kind of from PLGA/MoS2/ chemotherapeutics " oleosol " prepares PLGA/MoS2/
Chemotherapeutics support, and thermotherapy and the method for chemotherapy combined treatment applied to tumour.Therefore, the present invention has filled up the blank.
The present invention is from PLGA/MoS2The method that/chemotherapeutics " oleosol " prepares support has simple technique, material and utilization ratio of drug
It is high, the advantages of oncotherapy effect is good, with larger clinical conversion meaning.
Specifically, PLGA/MoS of the invention2/ chemotherapeutics oleosol includes：Non-aqueous with biocompatibility
Agent and PLGA, the MoS being dispersed in the solvent2- PEG nanometer sheets and chemotherapeutics.
Wherein, the nonaqueous solvents with biocompatibility includes but is not limited to 1-METHYLPYRROLIDONE, dimethyl Asia
Sulfone.By choosing such solvent, PLGA, MoS can be both disperseed well2- PEG nanometer sheets and chemotherapeutics, and in note
There can be good biocompatibility after entering in vivo.
The PLGA molecular weight can be 1000~10000 dalton.Monomer lactic acid (LA) and hydroxyacetic acid (GA's) rubs
Your ratio can be 10:90~90:10.
In PLGA/MoS2In/chemotherapeutics oleosol, PLGA concentration can be 0.1g/mL~1.0g/mL；MoS2- PEG receives
The concentration of rice piece can be 1~5mg/mL；The concentration of chemotherapeutics can be 0.1mg/mL~1.0mg/mL.
Chemotherapeutics includes but is not limited to doxorubicin hydrochloride (DOX), taxol (PTX), camptothecine (CPT), Combretastatin
At least one of (CA4).
The PLGA/MoS of the present invention2/ chemotherapeutics support includes：PLGA supports and it is coated in PLGA supports
MoS2- PEG nanometer sheets and chemotherapeutics.Wherein, MoS2The mass fraction of-PEG nanometer sheets can be 0.1%~5%, chemotherapeutics
Mass fraction can be 0.01%~1%.MoS2The piece footpath of-PEG nanometer sheets can be 50~150nm.
＜ PLGA/MoS2The preparation method ＞ of/chemotherapeutics oleosol
The PLGA/MoS of the present invention2/ chemotherapeutics oleosol is by by PLGA, MoS2, chemotherapeutics be scattered in biology
The nonaqueous solvents (such as NMP) of compatibility can be prepared by.In one example, according to the concentration of each component in target product, take
Appropriate PLGA is dissolved in 1-METHYLPYRROLIDONE (NMP)；By MoS2- PEG nanometer sheets are scattered in gained PLGA nmp solution
In, stir to obtain PLGA/MoS2" oleosol "；Tumor chemotherapeutic drug is dissolved in above-mentioned " oleosol ", PLGA/MoS is obtained2/
Chemotherapeutics " oleosol ".
PLGA dissolving method can for stirring, mixing time can be 12~24 hours, mixing speed can for 100~400 turns/
Minute.MoS2The process for dispersing of-PEG nanometer sheets can be ultrasound, and ultrasonic time can be 10~60 minutes, ultrasonic power can for 50~
500W.The process for dispersing of chemotherapeutics can be ultrasound, and ultrasonic time can be 10~60 minutes, and ultrasonic power can be 50~500W.
Wherein MoS2- PEG nanometer sheets are in MoS2Nanometer sheet surface modification PEG is formed, and can be strengthened by modifying PEG
MoS2The stability of nanometer sheet, improves its blood compatibility and biocompatibility.MoS2The piece footpath of-PEG nanometer sheets can for 50~
150nm, for example, 100nm or so.MoS2The preparation method of-PEG nanometer sheets refers to prior art literature (for example
Biomaterials, 2015,39,206-217, or Chinese patent CN104030360A).
By PLGA/MoS2/ chemotherapeutics oleosol is injected into after tumour, PLGA/MoS2/ chemotherapeutics can be because of PLGA's
Strong hydrophobic effect and " liquid-solid " phase transformation occurs at once, in intra-tumor formation PLGA/MoS2/ chemotherapeutics support.It is injected into tumour
Volume can be 10~100 μ L.
The present invention from PLGA/MoS2/ chemotherapeutics " oleosol " prepare support method have technique simple, material and
The advantages of utilization ratio of drug is high, oncotherapy effect is good, with larger clinical conversion meaning.
The present invention is by PLGA, MoS2- PEG nanometer sheets and chemotherapeutics are scattered in NMP simultaneously, and PLGA/MOS is made2Chemotherapy
(concentration for preferably, choosing PLGA here is 0.5g/mL, MoS to medicine " oleosol "2- PEG concentration is 2.5mg/mL, chemotherapy
Medicine is DOX, and concentration is 1mg/mL).After intratumor injection, " oleosol " meet support is formed after water and by MoS2- PEG nanometer sheets
With DOX claddings wherein.The PLGA/MoS2/ DOX supports have MoS concurrently2- PEG photo-thermal kills tumour and DOX chemotherapeutic treatment swells
Effect of knurl, can efficiently kill tumour, more after without recurrence；And the damage of normal tissue and internal organs can be avoided, effectively
The deficiency of intravenous injection and intratumor injection material and chemotherapeutics is compensate for, with important clinical conversion meaning.
In one embodiment, 30 μ L PLGA/MoS of the present invention are taken2/ DOX " oleosol " is expelled to lotus 4T1 breasts
The intra-tumor of the Balb/c nude mices of adenocarcinoma tumor model.It is 0.6W/cm by power density2NIR laser (wavelength is 808nm,
Similarly hereinafter) irradiation tumour 5 minutes.Experimental result finds that the tumour of Balb/c nude mice by subcutaneous can form a scab because of high temperature, and growth is pressed down completely
System.Over time, tumour incrustation can be completely fallen off, wound healing, and rear tumour is without recurrence.Under equal conditions, note
The tumour growth for penetrating physiological saline is then unrestricted.It is worth noting that, 30 μ L PLGA/MoS of injection2And apply equality strength
With the NIR laser groups of time, and 30 μ L PLGA/MoS of injection2Growths of/the DOX " oleosol " without applying laser group tumour
Though suppressed, degree is relatively low, and this is test result indicates that PLGA/MoS2/ DOX intelligence implants can efficiently realize tumour
Thermotherapy and chemotherapy combined treatment.
Some exemplary embodiments are included further below the present invention is better described.It should be understood that the present invention is in detail
The above-mentioned embodiment stated, and following examples are only illustrative of the invention and is not intended to limit the scope of the invention, this area
Technical staff the protection of the present invention is belonged to according to some nonessential modifications and adaptations for making of the above of the present invention
Scope.In addition, specific proportioning, time, temperature in following technological parameters etc. is also only exemplary, those skilled in the art can be with
Suitable value is selected in the range of above-mentioned restriction.
Embodiment 1
Weighing 1g PLGA, (molecular weight is 10000 dalton, LA:GA=1：1, purchased from the limited public affairs of Jinan Mount Tai handle of the Big Dipper biotechnology
Department), mixed with 2mLNMP, stir 12 hours at room temperature, obtain clear transparent solutions.Take 5mgMoS2- PEG nanometer sheets (piece footpath
100nm, preparation method refers to Biomaterials, 2015,39,206-217), it is well mixed with above-mentioned PLGA solution, at room temperature
Ultrasonic disperse (power output is 500W) 0.5 hour, makes MoS2- PEG nanometer sheets are homogeneously dispersed in above-mentioned PLGA solution.Claim
2mgDOX (being purchased from Beijing Hua Feng drugmakers) is taken, with above-mentioned PLGA/MoS2" oleosol " is well mixed, at room temperature ultrasonic disperse
(power output is 500W) 0.5 hour, obtains PLGA/MoS2/ DOX " oleosol ".Respectively take 50 μ L PLGA, PLGA/MoS2And PLGA/
MoS2In/DOX " oleosol ", rapid injection water, after after " oleosol " completely phase transformation, PLGA, PLGA/MoS are produced2And PLGA/
MoS2/ DOX supports.
It will be seen from figure 1 that the MoS chosen here2- PEG be uniform sheet layer material, piece footpath in 100nm or so,
PLGA/MoS2And PLGA/MoS2/ DOX supports are the block timbering material (Fig. 1 b＆c) with loose structure.Elemental redistribution is swept
Retouch confirmation Mo and S elements to be distributed evenly in whole timbering material, show MoS2- PEG nanometer sheets are uniformly coated on
It is that further photo-thermal therapy tumour is laid a good foundation in timbering material.
Embodiment 2
The PLGA/MoS prepared in a little embodiment 1 is taken respectively2Support, analyzes the valence state and component of timbering material.Use
ESCAlab250 types high-performance imaging x-ray photoelectron spectroscopy instrument (Thermal Scientific) is constituted and former to material surface element
Sub- valence state is analyzed.The use of AlK α is excitaton source, incident electron energy is 1486.6eV, and exciting power is 15kW.Gained is composed
Figure is corrected with C1s (with reference to that can be 284.8eV).Use (the scanning of Japanese Rigaku D/MAX2200PC types X-ray diffractometer
Condition：Cu K alpha rays, wavelengthOperating voltage 40kV, electric current 40mA, scanning range：5 °~60 °) sample component is entered
Row analysis.
Such as Fig. 2, the energy of Mo 3d 3/2 (232eV) and Mo 3d 5/2 (228.2eV) track can be detected from sample
Amount change, illustrates MoS2- PEG nanometer sheets can stably be distributed in PLGA/MoS2In timbering material, do not occur valence state change.
XRD also detected MoS2- PEG diffraction maximum, further demonstrates MoS in timbering material2The presence of-PEG nano materials.
Embodiment 3
PLGA/MoS2The evaluation of its biocompatibility of/DOX timbering materials：It is sample, analysis and PLGA/ to select L929 cells
MoS2Cell survives situation after/DOX timbering materials are co-cultured 24 hours, to evaluate the biocompatibility of support.Specific experiment
Operating procedure is as follows：Logarithmic phase L929 cells are collected, according to 105The density of cells/well is inoculated in 6 porocyte culture plates, is put
In CO2(Heraeus BB15, Thermo Scientific, the U.S., condition of culture is 37 DEG C, 5%CO to incubator2) in cultivated
Night, make cell fully it is adherent, sprawl.Draw 50 μ L PLGA/MoS2" oleosol " is simultaneously injected into culture plate, control group injection
The physiological saline of equal volume.It is placed in CO2Continue to cultivate 24 hours in incubator, discard culture medium after terminating, use physiological saline
Cleaning 3 times, evaluates cell according to the operating procedure of CCK-8 kits and survives situation.After CCK-8 experiments terminate, physiology salt is used
Water is cleaned 3 times, and 1mL Trypan Blue liquid is then added per hole.After culture 15 minutes, Trypan Blue is cleaned with physiological saline
Liquid, the micromorphology of L929 before and after Trypan Blue is observed using phase contrast microscope (Leica DM IL LED, Germany), further
Evaluate the biocompatibility of timbering material.
As shown in figure 3, through PLGA/MoS2The L929 of/DOX timbering materials processing and the light absorption value of cellular control unit do not show
Difference is write, cell remains in that its complete pattern, and no apoptosis phenomenon finds (apoptotic cell can dye blueness by trypan blue), card
Understand PLGA/MoS2/ DOX supports have good biocompatibility.
Embodiment 4
With NIR laser, (power density is respectively 0.2,0.4,0.6,0.8 and 1.0W/cm2) irradiate what is prepared in embodiment 1
PLGA/MoS2/ DOX supports, changed with time relation with FLIRA320 types thermal infrared imager record backing temp.For preferably
Simulate PLGA/MoS2Ramp case of/DOX the supports in knurl, 0.5mL steamings are added into the single culture hole of 48 porocyte culture plates
Distilled water, then adds 50 μ L PLGA/MoS2" oleosol ", after the completion for the treatment of its phase transformation, with NIR laser, (power density is respectively
0.2,0.4,0.6,0.8 and 1.0W/cm2) irradiation gained support, water temperature is recorded with the time with FLIRA320 types thermal infrared imager
Situation of change.
The PLGA/MoS it can be seen from Fig. 4 (a)2/ DOX supports can effectively carry out photothermal deformation.When power density is
0.2w/cm2When, NIR laser irradiates 5 minutes, and backing temp is that can raise 10.2 DEG C.When power density is 0.4,0.6,0.8
And 1.0w/cm2When, backing temp can then raise 14.8,21.2,32.4 and 49.8 DEG C (Fig. 4 a＆b) rapidly respectively.In simulation
Under the conditions of tumour, PLGA/MoS2/ DOX supports have also showed that good photothermal deformation ability.When power density be 0.2,
0.4,0.6,0.8 and 1.0w/cm2When, irradiating support 5 minutes, water temperature is that can rapidly raise 8.2,14.8,16.5,22.1,
With 30.1 DEG C (Fig. 4 c＆d).And for PLGA supports (without MoS2- PEG nanometer sheets), even if the use of power density being 1.0w/
cm2Laser irradiate 5 minutes, the temperature change of support or distilled water still not substantially, absolutely proves MoS2- PEG nanometer sheets are imparted
PLGA/MoS2The good photothermal deformation ability of/DOX supports.
Embodiment 5
2 lotus knurl Balb/c nude mices (diameter of tumor is about 0.7-1.0cm) are taken, pass through the μ L PLGA/ of intratumor injection 30 respectively
MoS2/ DOX FLIR thermal infrared imagers record tumor temperature changes with time situation.
In animal level, PLGA/MoS2/ DOX supports show good photothermal deformation ability.As shown in figure 5, irradiation
After 10s, tumor surface temperature can just raise 8.8 DEG C.With the increase of irradiation time, tumor temperature continues to rise, and irradiates 5 points
56.5 DEG C are risen to after clock.Excellent photothermal deformation ability is laid a good foundation for follow-up efficiently photo-thermal therapy tumour.
Embodiment 6
Respectively by 150 μ L PLGA/MoS2/ DOX " oleosol " is injected into equipped with 3mL phosphate buffers (PBS, pH=
7.4) and in the reaction bulb of Acetic acid-sodium acetate buffer solution (pH=5.4), it is placed in 37 DEG C of shaking tables and is incubated.In each scheduled time
Point, draws 1mL and contains DOX buffer solution, and add the corresponding fresh buffers of 1mL.Determine to discharge by standard curve
DOX concentration, calculate DOX different time points accumulative total volume, analyze PLGA/MoS2/ DOX supports are released DOX
To one's heart's content condition.The relation irradiated for research drug releasing rate with laser, after release 24 hours, to pH=5.4 cushioning liquid
In PLGA/MoS2/ DOX timbering materials apply the irradiation of NIR laser, and (power density is 0.6W/cm2, irradiate 5 minutes), statistics is shone
Penetrate the insoluble drug release situation of after-poppet material.
As shown in fig. 6, PLGA/MoS under low pH conditions (pH=5.4 simulates tumor environment)2Releases of/the DOX to DOX
Speed is fast compared to the rate of release under high pH conditions (pH=7.4, simulate physiological condition), imply that support can will be more
DOX is discharged in tumor region.The insoluble drug release of this pH responses, can reduce it while DOX oncotherapy effects are improved
The toxic side effect of normal tissue.On the other hand, NIR irradiations can also significantly increase DOX rate of release.PLGA macromolecules
Glass transition temperature (Tg) at 42 DEG C or so.When temperature is more than Tg, PLGA can generating state change that (glassy transition is
Elastomeric state), PLGA strands spacing becomes big, causes the DOX molecules of internal stent to be more prone to discharge.Moreover, temperature liter
Height, DOX molecular motions aggravation, can also accelerate its rate of release.Sum it up, PLGA/MoS2Releases of/the DOX to DOX is a kind of
Controlled release with pH and NIR laser (temperature) double-response characteristic, this is to preferably improving PLGA/MoS2/ DOX chemotherapy
Effect, the toxic side effect for reducing DOX is most important.
Embodiment 7
30 lotus knurl Balb/c nude mices (diameter of tumor is about 0.7-1.0cm) are taken, 4 groups are randomly divided into.1. 30 μ is injected respectively
L physiological saline (blank control group, 6), 2. 30 μ L PLGA/MoS2" oleosol " and it is aided with NIR laser irradiation (power density
For 0.6W/cm2, irradiate 5 minutes, 6), 3. 30 μ L PLGA/MoS2/ DOX " oleosol " (6), 4. 30 μ L PLGA/MoS2/
DOX " oleosol " and be aided with NIR laser irradiation (power density is 0.6W/cm2, irradiate 5 minutes, 12).After treatment is finished, every
Day entry nude mouse tumor volume.3 nude mices, the heart are taken from every group at different time points (after treatment the 14th day and the 28th day)
Dirty puncture takes blood to test physiochemical indice；Histotomy is carried out to each major organs, and passes through inductively coupled plasma spectrum (ICP)
Analyze the Mo contents in above-mentioned organ.
Test result indicates that, blank control group tumour growth is unaffected, and tumour growth is by different journeys in other 3 groups
Degree ground suppresses (as shown in Figure 7).In the case where not applying laser irradiation, PLGA/MoS2DOX can slowly discharge in/DOX groups
Out, the growth of tumour is suppressed.When applying laser, PLGA/MoS2Photothermal deformation can be efficiently carried out, effectively suppresses tumour
Pernicious growth.Under the irradiation of laser, one side PLGA/MoS2/ DOX supports can produce high temperature and kill tumour；Other one
DOX in aspect, support can be discharged, and high temperature can accelerate the DOX releases in support, further kill tumour.Cause
This, PLGA/MoS2/ DOX supports can realize photo-thermal therapy and the chemotherapy combined treatment to tumour, and then completely inhibit tumour
Growth.As shown in figure 9, the 7th day after the treatment, tumour is complete necrosis, forms a scab and come off.Over time, tumour is complete
It totally disappeared mistake, wound healing, healing tumour is without recurrence.
By being found with healthy nude mice comparative analysis, the 4. in group (experimental group) every physiochemical indice of nude mice normal
In the range of, show that material has good blood compatibility；The heart, liver, spleen, lung and each organ of kidney, which had not both been shown, significantly should
Swash property toxicity, and without long-term tissue toxicity, it was demonstrated that PLGA/MoS2Hypotoxicity of/DOX the supports in live body level.It is worth note
Meaning, the PLGA/MoS of this local injection2/ DOX " oleosol " can be by the MoS being dispersed therein2Phase transformation is strapped in DOX
In the support formed, without entering blood circulation.As shown in figure 8, icp analysis result shows, Mo in each internal organs of nude mice
Content be far below tail vein injection and intratumor injection when content, i.e., major part material all concentrate in the bracket.Have reason to recognize
For, with PLGA slow degraded, the MoS in support2Little by little enter blood with DOX meetings and be metabolized, thus greatly
Reduce the damage of nano material and Chemotherapeutic Drugs On Normal tissue and organ.In a word, results of animal shows institute of the present invention
The PLGA/MoS stated2/ DOX supports have good internal photo-thermal therapy and chemotherapeutic treatment tumor effect, in therapeutic field of tumor
With potential application prospect.
Embodiment 8
Take 1 lotus knurl Balb/c nude mice (diameter of tumor is about 0.7-1.0cm), using Vevo LAZR toys optoacoustics into
As system carries out photoacoustic imaging experiment.PLGA/MoS must be injected2After image before and after/DOX " oleosol " (30 μ L), picture is chosen to
Region calculates the photoacoustic signal value of tumour.From fig. 10 it can be seen that can't detect photoacoustic signal in nude mouse tumor before injection
(signal value 0.105).Inject PLGA/MoS2After/DOX " oleosol ", obvious photoacoustic signal (signal value is detected in knurl
2.129), i.e. PLGA/MoS2/ DOX supports show good internal optoacoustic radiography performance.Because PLGA/MoS2/DOX
MoS in support2- PEG nanometer sheets can absorb NIR laser and be converted to heat, cause the thermal expansion of tumor tissues, produce super
Acoustic signals and photoacoustic signal.Therefore, it is possible to use optoacoustic radiography more accurately tracks PLGA/MoS2/ DOX timbering materials
Distribution and metabolism behavior in vivo.
Present invention process is simple, and product is easy to get, and pin administration can be achieved, the effect of tumour is cured.More without recurrence, secondary work after
With small, it is easy to which clinic conversion, the efficiently treatment to tumour is significant.
Claims (9)
1. a kind of PLGA/MoS2Composite medicament stent material, it is characterised in that including：Nonaqueous solvents N- with biocompatibility
Methyl pyrrolidone and the Poly(D,L-lactide-co-glycolide being dispersed in the solvent, MoS2- PEG nanometer sheets and
Chemotherapeutics, the PLGA/MoS2Composite medicament stent material forms PLGA/MoS after meeting water2Composite medicament stent, including PLGA
Support and the MoS being coated in the support2- PEG nanometer sheets and chemotherapeutics, the PLGA/MoS2Composite medicament stent has simultaneously
The dual activity and optoacoustic radiography function of standby thermotherapy and chemotherapeutic treatment tumour, and chemotherapeutics therein can be to pH and near red
Outer laser double-response controlled release.
2. PLGA/MoS according to claim 12Composite medicament stent material, it is characterised in that the polylactic acid-glycolic base
The molecular weight of acetate multipolymer is 1000~10000 dalton, and wherein the mol ratio of monomer lactic acid and hydroxyacetic acid is 10:90~
90:10。
3. PLGA/MoS according to claim 12Composite medicament stent material, it is characterised in that the polylactic acid-glycolic base
The concentration of acetate multipolymer is the g/mL of 0.1g/mL~1.0.
4. PLGA/MoS according to claim 12Composite medicament stent material, it is characterised in that the MoS2- PEG nanometers
The concentration of piece is 1~5mg/mL.
5. PLGA/MoS according to claim 12Composite medicament stent material, it is characterised in that the chemotherapeutics it is dense
Spend for the mg/mL of 0.1mg/mL~1.0.
6. PLGA/MoS according to claim 12Composite medicament stent material, it is characterised in that the chemotherapeutics is
At least one of doxorubicin hydrochloride, taxol, camptothecine and Combretastatin.
7. the PLGA/MoS any one of a kind of claim 1 to 62The preparation method of composite medicament stent material, its feature
It is, according to the PLGA/MoS2The concentration of each component, poly lactic-co-glycolic acid is total in/chemotherapeutics compound support frame material
Polymers, MoS2- PEG nanometer sheets and chemotherapeutics are dispersed in the nonaqueous solvents 1-METHYLPYRROLIDONE with biocompatibility
In, that is, the PLGA/MoS is made2/ chemotherapeutics compound support frame material.
8. preparation method according to claim 7, it is characterised in that the Poly(D,L-lactide-co-glycolide is by stirring
Mix and be scattered in the solvent, mixing time is 12~24 hours, mixing speed is 100~400 revs/min；The MoS2-
PEG nanometer sheets and/or the chemotherapeutics by ultrasonic disperse in the solvent, the MoS2- PEG nanometer sheets and/or institute
The ultrasonic disperse time for stating chemotherapeutics is 10~60 minutes, and ultrasonic power is 50~500W.
9. the PLGA/MoS any one of a kind of claim 1 to 62Composite medicament stent material is preparing antineoplastic
In application.
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