CN104548095A - PLGA/MoS2 composite drug stent material as well as preparation method and application thereof - Google Patents
PLGA/MoS2 composite drug stent material as well as preparation method and application thereof Download PDFInfo
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- CN104548095A CN104548095A CN201510051614.7A CN201510051614A CN104548095A CN 104548095 A CN104548095 A CN 104548095A CN 201510051614 A CN201510051614 A CN 201510051614A CN 104548095 A CN104548095 A CN 104548095A
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Abstract
The invention relates to a PLGA/MoS2 composite drug stent material as well as a preparation method and application thereof. The PLGA/MoS2 composite drug stent material comprises a non-aqueous solvent with biological compatibility, and a polylactic acid-glycolic acid copolymer, MoS2-PEG nano films and a chemotherapeutic drug, which are uniformly dispersed in the solvent. In the PLGA/MoS2 composite drug stent material provided by the invention, PLGA is a strongly-hydrophobic high polymer, and after the PLGA/MoS2 composite drug stent material ('oleosol') is injected into a tumor, the PLGA/MoS2/chemotherapeutic drug can generate 'liquid-solid' phase changes immediately to form a PLGA/MoS2/chemotherapeutic drug block, namely a PLGA/MoS2/chemotherapeutic drug stent.
Description
Technical field
The invention belongs to the multi-mode treatment field of tumor, relate to a kind of PLGA/MoS
2composite medicament stent material and preparation thereof and cancer therapeutic applications.Specifically, the present invention relates to and there is photoacoustic imaging ability, and synchronously can realize the timbering material of the thermotherapy of tumor/chemotherapy combined treatment and preparation thereof and oncotherapy.
Background technology
As everyone knows, malignant tumor has become the huge killer of current threat human health.Develop the tumor diagnosis and treatment materials and methods of high curative effect, low toxic and side effects, to improving, quality of life of the mankind and developing national economy etc. are significant.Photo-thermal therapy is a kind of oncotherapy means of emerging, Wicresoft.In photo-thermal therapy field, near-infrared laser (NIR, wave-length coverage: 700-1100nm) has a series of advantage, and as dark in tissue penetration depths, normal structure absorbs lower etc. to it.The irradiation of NIR laser is enriched in the optical-thermal conversion material of tumor locus and tumor tissues temperature is raised, and causes death of neoplastic cells.Photo-thermal therapy based on NIR laser is studied, and particularly the optical-thermal conversion material of development of new causes the broad interest of people.The more optical-thermal conversion material of current research comprises gold nanorods, graphene oxide, copper sulfide, tungsten sulfide, palladium metal, indocyanine green, polypyrrole etc.Transient metal sulfide is (as MoS
2and WS
2) because having, cost is low, biological safety advantages of higher, particularly causes people to pay close attention to gradually as the research of optical-thermal conversion material at biomedical sector.
At present, the dispersion liquid of material is mainly injected in experimental animals by vein by the application of optical-thermal conversion material, makes nano material passively be enriched to tumor locus by means of enhancing infiltration retention effect (EPR effect) of tumor locus blood vessel; Or by intratumor injection, nano material is injected in tumor, improve the enriching quantity of material at tumor locus.For tail vein injection, material or the medicine of overwhelming majority injection can enter whole body internal organs with blood circulation, and are caught by the reticuloendothelial system such as liver, spleen organ, and the material being enriched in tumor locus is little.Cause oncotherapy poor effect, and normal tissue and organ cause certain damage.Intratumor injection is that one has traumatic expectant treatment method, and it needs to carry out accurate positioning tumor lesions position by means of the diagnosing tumor means of advanced person, and accurately carries out puncture in tumor, injection.Although intratumor injection can make, more material is passive is enriched in tumor locus, and because tumor locus vascular permeability increases, the portion of material of intratumor injection can enter blood circulation by Vascular permeability, may cause damage equally to normal tissue and organ.
Summary of the invention
In the face of prior art Problems existing, the object of the present invention is to provide and can realize photo-thermal therapy and chemotherapy combined treatment and remove tumor efficiently, the PLGA/MoS of the damage of normal tissue and internal organs can be reduced simultaneously
2/ chemotherapeutics support and its preparation method and application.
The present inventor learns that Poly(D,L-lactide-co-glycolide (PLGA) is a kind of by U.S. food and FAD (FDA) certification, the high molecular polymer that can slowly degrade in physiological conditions, is formally included into American Pharmacopeia as pharmaceutic adjuvant.PLGA has strong hydrophobicity, and after meeting water, strand can sharply be rolled up and separate out.And the present inventor demonstrates MoS by experiment
2-PEG nanometer sheet can absorb NIR laser and convert it to heat, and kills tumor cell efficiently.Therefore, if prepare a kind of PLGA/MOS
2/ chemotherapeutics " oleosol ", then should " oleosol " be at room temperature liquid, and can carry out local injection in tumor, can form block timbering material and by MoS in tumor after meeting water
2-PEG nanometer sheet and chemotherapeutics are coated on wherein.And this PLGA/MoS
2/ chemotherapeutics timbering material has MoS concurrently
2the photo-thermal of-PEG kills effect of the chemotherapeutic treatment tumor of tumor and chemotherapeutics.The more important thing is, MoS
2-PEG and chemotherapeutics are tied in timbering material, are unlikely to enter blood circulation in large quantities.Based on this, the present inventor completes the present invention.
At this, on the one hand, the invention provides a kind of PLGA/MoS
2composite medicament stent material, comprising: the nonaqueous solvent with biocompatibility and the Poly(D,L-lactide-co-glycolide, the MoS that are dispersed in described solvent
2-PEG nanometer sheet and chemotherapeutics.
In the present invention, PLGA is a kind of high polymer hydrophobic by force, by this PLGA/MoS
2after composite medicament stent material (" oleosol ") is injected into tumor, PLGA/MoS
2can there is " liquid-solid " phase transformation in/chemotherapeutics, in tumor, form PLGA/MoS at once
2/ chemotherapeutics block, i.e. PLGA/MoS
2/ chemotherapeutics support.PLGA/MoS
2/ chemotherapeutics support possesses the dual activity of thermotherapy and chemotherapeutic treatment tumor: MoS
2-PEG nanometer sheet imparts PLGA/MoS
2the photothermal deformation ability that/chemotherapeutics support is good, can be used for the photo-thermal therapy of tumor; The chemotherapeutics of load can discharge, and gives PLGA/MoS
2the ability of/chemotherapeutics support chemotherapeutic treatment tumor.The more important thing is, MoS
2-PEG and chemotherapeutics are tied in timbering material, are unlikely to enter blood circulation in large quantities.While the utilization rate of material and medicine is largely increased, reduces the damage of normal tissue and internal organs, effectively compensate for the deficiency of intravenous injection and intratumor injection.In addition, MoS
2-PEG nanometer sheet possesses optoacoustic radiography function, can monitor the distribution situation of material in tumor in real time.
Therefore, the present invention is by providing a kind of PLGA/MoS
2composite medicament stent material (PLGA/MoS
2/ chemotherapeutics oleosol), and then be equivalent to also provide a kind of PLGA/MoS
2composite medicament stent (PLGA/MoS
2/ chemotherapeutics support), this PLGA/MoS
2/ chemotherapeutics support is by described PLGA/MoS
2composite medicament stent Material injection enters in water (being such as normal saline in vitro, is such as tumor locus in vivo) and is formed, and comprises PLGA support and is coated on the MoS in this support
2-PEG nanometer sheet and chemotherapeutics.PLGA/MoS of the present invention
2/ chemotherapeutics support can realize photo-thermal therapy and chemotherapy combined treatment and remove efficiently tumor, more after without recurrence, side effect is little, has important clinical conversion meaning.
Preferably, the molecular weight of described Poly(D,L-lactide-co-glycolide is 1000 ~ 10000 dalton, and wherein the mol ratio of monomer lactic acid and hydroxyacetic acid is 10:90 ~ 90:10.
Preferably, the concentration of described Poly(D,L-lactide-co-glycolide is 0.1g/mL ~ 1.0g/mL.
Preferably, described MoS
2the concentration of-PEG nanometer sheet is 1 ~ 5mg/mL.
Preferably, the concentration of described chemotherapeutics is 0.1mg/mL ~ 1.0mg/mL.
Preferably, described chemotherapeutics is at least one in doxorubicin hydrochloride, paclitaxel, camptothecine and Combretastatin.
Preferably, the nonaqueous solvent described in biocompatibility is N-Methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO).
On the other hand, the present invention also provides above-mentioned PLGA/MoS
2the preparation method of composite medicament stent material, comprising: according to described PLGA/MoS
2the content ratio of each component in composite medicament stent material, by Poly(D,L-lactide-co-glycolide, MoS
2-PEG nanometer sheet and chemotherapeutics are dispersed in be had in the nonaqueous solvent of biocompatibility, i.e. obtained described PLGA/MoS
2/ chemotherapeutics compound support frame material.And by further dispersions obtained system (timbering material) being injected in normal saline, i.e. obtained described PLGA/MoS
2/ chemotherapeutics compound rest.
Preferably, described Poly(D,L-lactide-co-glycolide is by dispersed with stirring in described solvent, and mixing time is 12 ~ 24 hours, and mixing speed is 100 ~ 400 revs/min; Described MoS
2-PEG nanometer sheet and/or described chemotherapeutics by ultrasonic disperse in described solvent, described MoS
2the ultrasonic disperse time of-PEG nanometer sheet and/or described chemotherapeutics is 10 ~ 60 minutes, and ultrasonic power is 50 ~ 500W.
Again on the one hand, the present invention also provides above-mentioned PLGA/MoS
2the application in antitumor drug prepared by composite medicament stent material.Described antitumor drug can be the medicine for neoplastic fevers/chemotherapy combined treatment.
Accompanying drawing explanation
Fig. 1, (a) MoS
2the TEM picture of-PEG nanometer sheet, (b) PLGA/MoS
2(c) PLGA/MoS
2the FESEM picture of/DOX support, (d) is from left to right respectively C, the Element area profile of O, Mo and S;
Fig. 2, PLGA/MoS
2(a) XPS collection of illustrative plates of support and (b) XRD spectra;
Fig. 3, L929 cell is at PLGA/MoS
2the survival rate of/DOX rack surface, (b-e) is untreated (b & d) and PLGA/MoS
2cell morphology after the process of/DOX support after (b & c) cell morphology of the L929 of (c & e) and (d & e) Trypan Blue;
Under Fig. 4, different capacity density laser irradiate, (a) PLGA/MoS
2/ DOX support and (c) PLGA/MoS
2/ DOX support is immersed in the water the variation relation of water temperature with radiated time; C () and (d) is respectively the thermal imaging picture of radiation after-poppet material corresponding to (b) and (b);
Fig. 5, intratumor injection 30 μ L PLGA/MoS
2/ DOX, NIR laser (0.6W/cm
2) irradiate temperature and the thermal imaging picture of tumor after different time;
Fig. 6, PLGA/MoS
2/ DOX timbering material DOX release profiles at different conditions;
Gross tumor volume curve over time after the treatment of Fig. 7, distinct methods;
Fig. 8, intratumor injection 30 μ L PLGA/MoS
2after/DOX, the content of Mo in each internal organs of different time points nude mice;
(intratumor injection 30 μ L PLGA/MoS after Fig. 9, treatment
2/ DOX, and give NIR laser (0.6W/cm
2, irradiate 5 minutes)) the tumor photo of different time;
Figure 10, intratumor injection 30 μ L PLGA/MoS
2photoacoustic imaging image before and after/DOX.
Detailed description of the invention
Further illustrate the present invention below in conjunction with accompanying drawing and following embodiment, should be understood that accompanying drawing and following embodiment are only for illustration of the present invention, and unrestricted the present invention.
The present invention utilizes PLGA to have strong hydrophobicity, meets strand after water and can sharply roll up and the characteristic separated out, utilize MoS simultaneously
2-PEG nanometer sheet can absorb NIR laser and convert it to heat, and kills the character of tumor cell efficiently, provides a kind of PLGA/MOS
2/ chemotherapeutics complex, this complex to have the nonaqueous solvent of biocompatibility for carrier, is formed as the form of " oleosol " in vitro, that is, dispersed in the nonaqueous solvent with biocompatibility have PLGA, MOS
2, and chemotherapeutics.Should " oleosol " be at room temperature liquid, and can local injection in tumor be carried out, block timbering material can be formed meet water in tumor after, namely be formed as PLGA/MOS
2/ chemotherapeutics support.This PLGA/MOS
2/ chemotherapeutics support comprises PLGA support and is coated on the MoS in PLGA support
2-PEG nanometer sheet and chemotherapeutics.PLGA/MOS of the present invention
2/ chemotherapeutics timbering material has MoS concurrently
2the photo-thermal of-PEG kills effect of the chemotherapeutic treatment tumor of tumor and chemotherapeutics.The more important thing is, MoS
2-PEG and chemotherapeutics are tied in timbering material, are unlikely to enter blood circulation in large quantities.While the utilization rate of material and medicine is largely increased, reduces the damage of normal tissue and internal organs, effectively compensate for the deficiency of intravenous injection and intratumor injection.In addition, MoS
2-PEG nanometer sheet possesses optoacoustic radiography function, can monitor the distribution situation of material in tumor in real time.
Up to now, this area is not yet developed a kind of from PLGA/MoS
2/ chemotherapeutics " oleosol " prepares PLGA/MoS
2/ chemotherapeutics support, and be applied to the thermotherapy of tumor and the method for chemotherapy combined treatment.Therefore, the present invention has filled up this blank.The present invention is from PLGA/MoS
2the method that/chemotherapeutics " oleosol " prepares support has that technique is simple, material and the advantage such as utilization ratio of drug is high, oncotherapy effect is good, has larger clinical conversion meaning.
Specifically, PLGA/MoS of the present invention
2/ chemotherapeutics oleosol comprises: the nonaqueous solvent with biocompatibility and PLGA, MoS of being dispersed in described solvent
2-PEG nanometer sheet and chemotherapeutics.
Wherein, the nonaqueous solvent described in biocompatibility includes but not limited to N-Methyl pyrrolidone, dimethyl sulfoxide.By choosing such solvent, both PLGA, MoS can be disperseed well
2-PEG nanometer sheet and chemotherapeutics, and good biocompatibility can be had after being injected in vivo.
Described PLGA molecular weight can be 1000 ~ 10000 dalton.The mol ratio of monomer whose lactic acid (LA) and hydroxyacetic acid (GA) can be 10:90 ~ 90:10.
At PLGA/MoS
2in/chemotherapeutics oleosol, the concentration of PLGA can be 0.1g/mL ~ 1.0g/mL; MoS
2the concentration of-PEG nanometer sheet can be 1 ~ 5mg/mL; The concentration of chemotherapeutics can be 0.1mg/mL ~ 1.0mg/mL.
Chemotherapeutics includes but not limited at least one in doxorubicin hydrochloride (DOX), paclitaxel (PTX), camptothecine (CPT), Combretastatin (CA4).
PLGA/MoS of the present invention
2/ chemotherapeutics support comprises: PLGA support and the MoS be coated in PLGA support
2-PEG nanometer sheet and chemotherapeutics.Wherein, MoS
2the mass fraction of-PEG nanometer sheet can be 0.1% ~ 5%, and the mass fraction of chemotherapeutics can be 0.01% ~ 1%.MoS
2the sheet footpath of-PEG nanometer sheet can be 50 ~ 150nm.
< PLGA/MoS
2the preparation method > of/chemotherapeutics oleosol
PLGA/MoS of the present invention
2/ chemotherapeutics oleosol passes through PLGA, MoS
2, chemotherapeutics is scattered in the nonaqueous solvent (such as NMP) with biocompatibility and can obtains.In one example, according to the concentration of component each in target product, get appropriate PLGA and be dissolved in N-Methyl pyrrolidone (NMP); By MoS
2-PEG nanometer sheet is scattered in the nmp solution of gained PLGA, and stir to obtain PLGA/MoS
2" oleosol "; Tumor chemotherapeutic drug is dissolved in above-mentioned " oleosol ", obtains PLGA/MoS
2/ chemotherapeutics " oleosol ".
The dissolving method of PLGA can be stirring, and mixing time can be 12 ~ 24 hours, and mixing speed can be 100 ~ 400 revs/min.MoS
2the process for dispersing of-PEG nanometer sheet can be ultrasonic, and ultrasonic time can be 10 ~ 60 minutes, and ultrasonic power can be 50 ~ 500W.The process for dispersing of chemotherapeutics can be ultrasonic, and ultrasonic time can be 10 ~ 60 minutes, and ultrasonic power can be 50 ~ 500W.
Wherein MoS
2-PEG nanometer sheet is at MoS
2nanometer sheet finishing PEG forms, and can strengthen MoS by modifying PEG
2the stability of nanometer sheet, improves its blood compatibility and biocompatibility.MoS
2the sheet footpath of-PEG nanometer sheet can be 50 ~ 150nm, such as, be about 100nm.MoS
2the preparation method of-PEG nanometer sheet can with reference to prior art document (such as Biomaterials, 2015,39,206-217, or Chinese patent CN104030360A).
By PLGA/MoS
2after/chemotherapeutics oleosol is injected into tumor, PLGA/MoS
2can there is " liquid-solid " phase transformation because of the strong hydrophobic interaction of PLGA in/chemotherapeutics, in tumor, form PLGA/MoS at once
2/ chemotherapeutics support.The volume being injected into tumor can be 10 ~ 100 μ L.
Of the present invention from PLGA/MoS
2the method that/chemotherapeutics " oleosol " prepares support has that technique is simple, material and the advantage such as utilization ratio of drug is high, oncotherapy effect is good, has larger clinical conversion meaning.
The present invention is by PLGA, MoS
2-PEG nanometer sheet and chemotherapeutics are scattered in NMP simultaneously, obtained PLGA/MOS
2(concentration preferably, choosing PLGA is here 0.5g/mL, MoS to chemotherapeutics " oleosol "
2the concentration of-PEG is 2.5mg/mL, and chemotherapeutics is DOX, and concentration is 1mg/mL).After intratumor injection, " oleosol " forms support and by MoS after meeting water
2-PEG nanometer sheet and DOX are coated on wherein.This PLGA/MoS
2/ DOX support has MoS concurrently
2the photo-thermal of-PEG kills effect of the chemotherapeutic treatment tumor of tumor and DOX, can kill tumor efficiently, without recurrence more; And the damage of normal tissue and internal organs can be avoided, effectively compensate for the deficiency of intravenous injection and intratumor injection material and chemotherapeutics, there is important clinical conversion meaning.
In one embodiment, 30 μ L PLGA/MoS of the present invention is got
2/ DOX " oleosol " is expelled in the tumor of the Balb/c nude mice of lotus 4T1 breast cancer tumour model.Be 0.6W/cm by power density
2nIR laser (wavelength is 808nm, lower with) irradiate tumor 5 minutes.Experimental result finds, the tumor of Balb/c nude mice by subcutaneous can form a scab by Yin Gaowen, and growth is totally constrained.As time goes on, tumor incrustation can come off completely, wound healing, and rear tumor is without recurrence.Under equal conditions, the tumor growth of injecting normal saline is then unrestricted.It should be noted that injection 30 μ L PLGA/MoS
2and apply the NIR laser group of equality strength and time, and injection 30 μ L PLGA/MoS
2/ DOX " oleosol " though and not apply the growth of laser group tumor suppressed, degree is lower, and this experimental result shows PLGA/MoS
2/ DOX intelligence implant can realize thermotherapy and the chemotherapy combined treatment of tumor efficiently.
Below some exemplary embodiments are listed further better the present invention to be described.Should understand; the above-mentioned embodiment that the present invention describes in detail; and following examples are only not used in for illustration of the present invention and limit the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.In addition, concrete proportioning, time, temperature etc. in following technological parameter are also only exemplary, and those skilled in the art can select suitable value in the scope of above-mentioned restriction.
Embodiment 1
Take 1g PLGA (molecular weight is 10000 dalton, LA:GA=1:1, purchased from Dai Gang bio tech ltd, Jinan), mix with 2mLNMP, stirred at ambient temperature 12 hours, obtains clear transparent solutions.Get 5mgMoS
2-PEG nanometer sheet (sheet footpath 100nm, preparation method is with reference to Biomaterials, 2015,39,206-217), mix homogeneously with above-mentioned PLGA solution, under room temperature, ultrasonic disperse (output is 500W) 0.5 hour, makes MoS
2-PEG nanometer sheet is scattered in above-mentioned PLGA solution equably.Take 2mgDOX (purchased from Beijing Hua Feng drugmaker), with above-mentioned PLGA/MoS
2" oleosol " mix homogeneously, under room temperature, ultrasonic disperse (output is 500W) 0.5 hour, obtains PLGA/MoS
2/ DOX " oleosol ".Respectively get 50 μ L PLGA, PLGA/MoS
2and PLGA/MoS
2/ DOX " oleosol ", injects water rapidly, after " oleosol " completely phase transformation, obtains PLGA, PLGA/MoS
2and PLGA/MoS
2/ DOX support.
As can be seen from Figure 1, the MoS chosen here
2-PEG is uniform sheet layer material, and sheet footpath is at about 100nm, PLGA/MoS
2and PLGA/MoS
2/ DOX support is the block timbering material (Fig. 1 b & c) with loose structure.Elemental redistribution scanning confirms that Mo and S element is distributed in whole timbering material equably, shows MoS
2-PEG nanometer sheet has been coated in timbering material equably, for further photo-thermal therapy tumor is laid a good foundation.
Embodiment 2
Get the PLGA/MoS of preparation in a little embodiment 1 respectively
2support, analyzes valence state and the component of timbering material.Use ESCAlab250 type high-performance imaging x-ray photoelectron spectroscopy instrument (Thermal Scientific) to material surface elementary composition and atomic valence analyze.Use AlK α to be excitaton source, incident electron energy is 1486.6eV, and exciting power is 15kW.Gained spectrogram C1s (combining can be 284.8eV) corrects.Use the Japanese Rigaku D/MAX2200PC type X-ray diffractometer (condition of scanning: Cu K alpha ray, wavelength
operating voltage 40kV, electric current 40mA, sweep limits: 5 ° ~ 60 °) sample component is analyzed.
As Fig. 2, the energy variation of Mo 3d 3/2 (232eV) and Mo 3d 5/2 (228.2eV) track can be detected from sample, MoS is described
2-PEG nanometer sheet stably can be distributed in PLGA/MoS
2in timbering material, there is not valence state and change.XRD also detected MoS
2the diffraction maximum of-PEG, further demonstrates MoS in timbering material
2the existence of-PEG nano material.
Embodiment 3
PLGA/MoS
2the evaluation of its biocompatibility of/DOX timbering material: select L929 cell to be sample, analyzes and PLGA/MoS
2/ DOX timbering material Dual culture 24 hours later cell survive situation, to evaluate the biocompatibility of support.Specific experiment operating procedure is as follows: collect logarithmic (log) phase L929 cell, according to 10
5the density of cells/well is inoculated in 6 porocyte culture plates, is placed in CO
2(condition of culture is 37 DEG C, 5%CO to incubator for Heraeus BB15, Thermo Scientific, the U.S.
2) in overnight incubation, make cell fully adherent, sprawl.Draw 50 μ L PLGA/MoS
2" oleosol " is also injected in culture plate, the normal saline of matched group injection equal volume.Be placed in CO
2continue cultivation in incubator 24 hours, after terminating, discard culture medium, clean 3 times with normal saline, according to CCK-8 test kit operating procedure evaluate cell survive situation.After CCK-8 experiment terminates, clean 3 times with normal saline, then every hole adds the Trypan Blue liquid of 1mL.Cultivate after 15 minutes, clean Trypan Blue liquid with normal saline, use phase contrast microscope (Leica DM IL LED, Germany) to observe the micromorphology of L929 before and after Trypan Blue, evaluate the biocompatibility of timbering material further.
As shown in Figure 3, through PLGA/MoS
2the L929 of/DOX timbering material process and the light absorption value of cellular control unit do not have significant difference, and cell still keeps its complete pattern, find (apoptotic cell can be dyed blueness by trypan blue), demonstrate PLGA/MoS without apoptosis phenomenon
2/ DOX support has good biocompatibility.
Embodiment 4
With NIR laser (power density is respectively 0.2,0.4,0.6,0.8 and 1.0W/cm
2) irradiate the PLGA/MoS prepared in embodiment 1
2/ DOX support, by FLIRA320 type thermal infrared imager record backing temp relation over time.For simulating PLGA/MoS better
2the ramp case of/DOX support in tumor, adds 0.5mL distilled water in the single culture hole of 48 porocyte culture plate, then adds 50 μ L PLGA/MoS
2" oleosol ", after its phase transformation completes, with NIR laser (power density is respectively 0.2,0.4,0.6,0.8 and 1.0W/cm
2) irradiate gained support, by FLIRA320 type thermal infrared imager record water temperature situation over time.
As can be seen from Fig. 4 (a), PLGA/MoS
2/ DOX support can carry out photothermal deformation effectively.When power density is 0.2w/cm
2time, NIR laser irradiates 5 minutes, and namely backing temp can raise 10.2 DEG C.When power density is 0.4,0.6,0.8 and 1.0w/cm
2time, backing temp then can raise rapidly 14.8,21.2,32.4 and 49.8 DEG C (Fig. 4 a & b) respectively.Under simulation tumor condition, PLGA/MoS
2/ DOX support shows good photothermal deformation ability equally.When power density is 0.2,0.4,0.6,0.8 and 1.0w/cm
2time, irradiating support 5 minutes, namely water temperature can raise 8.2,14.8,16.5,22.1 rapidly, and 30.1 DEG C (Fig. 4 c & d).And (MoS is not added for PLGA support
2-PEG nanometer sheet), even if use power density is 1.0w/cm
2laser irradiate 5 minutes, the variations in temperature of support or distilled water is still not obvious, absolutely proves MoS
2-PEG nanometer sheet imparts PLGA/MoS
2the photothermal deformation ability that/DOX support is good.
Embodiment 5
Get 2 lotus tumor Balb/c nude mices (diameter of tumor is about 0.7-1.0cm), respectively by intratumor injection 30 μ LPLGA/MoS
2/ DOX FLIR thermal infrared imager record tumor temperature situation over time.
In animal level, PLGA/MoS
2/ DOX support shows good photothermal deformation ability.As shown in Figure 5, after irradiating 10s, tumor surface temperature just can raise 8.8 DEG C.Along with the increase of irradiation time, tumor temperature continues to rise, and irradiates and rises to 56.5 DEG C after 5 minutes.Excellent photothermal deformation ability is that the follow-up tumor of photo-thermal therapy is efficiently laid a good foundation.
Embodiment 6
Respectively by 150 μ L PLGA/MoS
2/ DOX " oleosol " is injected in the reaction bulb that 3mL phosphate buffer (PBS, pH=7.4) and Acetic acid-sodium acetate buffer (pH=5.4) are housed, and is placed in 37 DEG C of shaking tables and hatches.In each predetermined point of time, draw the buffer that 1mL contains DOX, and add fresh buffer corresponding to 1mL.Determined the concentration of the DOX discharged by standard curve, calculate the accumulative total volume of DOX in different time points, analyze PLGA/MoS
2/ DOX support is to the release conditions of DOX.For drugs rate of release and sharp light-struck relation, in release after 24 hours, to the PLGA/MoS in the buffer solution of pH=5.4
2/ DOX timbering material applies the irradiation of NIR laser, and (power density is 0.6W/cm
2, irradiate 5 minutes), statistics irradiates the drug release situation of after-poppet material.
As shown in Figure 6, PLGA/MoS under low pH condition (pH=5.4, simulation tumor environment)
2/ DOX is fast compared to the rate of release under high pH condition (pH=7.4, simulation physiological condition) to the rate of release of DOX, imply that more DOX can be released in tumor region by support.The drug release of this pH response, while raising DOX oncotherapy effect, can reduce the toxic and side effects of its normal tissue.On the other hand, NIR irradiates the rate of release that also can improve DOX significantly.The high molecular glass transition temperature of PLGA (Tg) is at about 42 DEG C.When temperature is more than Tg, can there is state and change (glassy transition is elastomeric state) in PLGA, and PLGA strand spacing becomes large, causes the DOX molecule of internal stent to be more prone to discharge.And temperature raises, DOX molecular motion aggravates, and also can accelerate its rate of release.Generally speaking, PLGA/MoS
2the release of/DOX to DOX is the controllable release that one has pH and NIR laser (temperature) double-response characteristic, and this is to improving PLGA/MoS better
2the chemotherapy effect of/DOX, the toxic and side effects reducing DOX is most important.
Embodiment 7
Get 30 lotus tumor Balb/c nude mices (diameter of tumor is about 0.7-1.0cm), be divided into 4 groups at random.Inject 1. 30 μ L normal saline (blank group, 6), 2. 30 μ L PLGA/MoS respectively
2" oleosol " and be aided with NIR laser irradiate (power density is 0.6W/cm
2, irradiate 5 minutes, 6), 3. 30 μ L PLGA/MoS
2/ DOX " oleosol " (6), 4. 30 μ LPLGA/MoS
2/ DOX " oleosol " and be aided with NIR laser irradiate (power density is 0.6W/cm
2, irradiate 5 minutes, 12).After treatment, the next day record nude mouse tumor volume.From every group, get 3 nude mices at different time point (after treatment the 14th day and the 28th day), heart puncturing extracting blood tests physiochemical indice; Tissue slice is carried out to each major organs, and analyzes the Mo content in above-mentioned organ by inductively coupled plasma spectrum (ICP).
Experimental result shows, blank group tumor growth is unaffected, and in other 3 groups, tumor growth is all suppressed (as shown in Figure 7) to some extent.Do not applying in sharp light-struck situation, PLGA/MoS
2in/DOX group, DOX can slowly release, the growth of Tumor suppression.When applying laser, PLGA/MoS
2photothermal deformation can be carried out efficiently, effectively the pernicious growth of Tumor suppression.Under the irradiation of laser, PLGA/MoS on the one hand
2/ DOX support can produce high temperature and tumor be killed; In addition on the one hand, the DOX in support can discharge, and high temperature can accelerate the DOX release in support, kills tumor further.Therefore, PLGA/MoS
2/ DOX support can realize the photo-thermal therapy of tumor and chemotherapy combined treatment, and then the growth of Tumor suppression completely.As shown in Figure 9, the 7th day after the treatment, tumor was necrosis completely, forms a scab and come off.As time goes on, cases of complete remission, wound healing, healing tumor is without recurrence.
By finding with healthy nude mice relative analysis, the 4. in group (experimental group) every physiochemical indice of nude mice all within normal range, show that material has good blood compatibility; The each organ of the heart, liver, spleen, lung and kidney had not both demonstrated obvious irritability toxicity, again without long-term tissue toxicity, demonstrated PLGA/MoS
2/ DOX support is at the hypotoxicity of live body level.It should be noted that the PLGA/MoS of this local injection
2/ DOX " oleosol " can be scattered in MoS wherein
2be strapped in the support that phase transformation formed with DOX, and do not enter blood circulation.As shown in Figure 8, icp analysis result shows, in each internal organs of nude mice, the content of Mo is far below content when tail vein injection and intratumor injection, and namely most of material is all concentrated in the bracket.Have reason to think, along with the slow degraded of PLGA, the MoS in support
2little by little enter blood with DOX meeting and by metabolism, thus greatly reduce the damage of nano material and Chemotherapeutic Drugs On Normal tissue and organ.In a word, results of animal shows PLGA/MoS of the present invention
2/ DOX support has photo-thermal therapy and chemotherapeutic treatment tumor effect in good body, has potential application prospect at therapeutic field of tumor.
Embodiment 8
Get 1 lotus tumor Balb/c nude mice (diameter of tumor is about 0.7-1.0cm), use Vevo LAZR toy photoacoustic imaging system to carry out photoacoustic imaging experiment.PLGA/MoS must be injected
2after image before and after/DOX " oleosol " (30 μ L), imaging region is selected to calculate the photoacoustic signal value of tumor.As can be seen from Figure 10, can't detect photoacoustic signal (signal value 0.105) in nude mouse tumor before injection.Injection PLGA/MoS
2after/DOX " oleosol ", namely detect obvious photoacoustic signal (signal value 2.129) in tumor, i.e. PLGA/MoS
2/ DOX support shows optoacoustic radiography performance in good body.This is because PLGA/MoS
2moS in/DOX support
2-PEG nanometer sheet can absorb NIR laser and be converted to heat, causes the thermal expansion of tumor tissues, produces ultrasonic signal and photoacoustic signal.Therefore, optoacoustic radiography can be used to follow the tracks of PLGA/MoS more exactly
2the distribution in vivo of/DOX timbering material and metabolism behavior.
Present invention process is simple, and product is easy to get, and can realize a pin administration, cure the effect of tumor.Rear nothing recurs, side effect is little, is easy to clinical conversion, significant to the efficient treatment of tumor.
Claims (10)
1. a PLGA/MoS
2composite medicament stent material, is characterized in that, comprising: the nonaqueous solvent with biocompatibility and the Poly(D,L-lactide-co-glycolide, the MoS that are dispersed in described solvent
2-PEG nanometer sheet and chemotherapeutics.
2. PLGA/MoS according to claim 1
2composite medicament stent material, is characterized in that, the molecular weight of described Poly(D,L-lactide-co-glycolide 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 1 and 2
2composite medicament stent material, is characterized in that, the concentration of described Poly(D,L-lactide-co-glycolide is 0.1g/mL ~ 1.0 g/mL.
4. PLGA/MoS according to any one of claim 1 to 3
2composite medicament stent material, is characterized in that, described MoS
2the concentration of-PEG nanometer sheet is 1 ~ 5mg/mL.
5. PLGA/MoS according to any one of claim 1 to 4
2composite medicament stent material, is characterized in that, the concentration of described chemotherapeutics is 0.1mg/mL ~ 1.0 mg/mL.
6. PLGA/MoS according to any one of claim 1 to 5
2composite medicament stent material, is characterized in that, described chemotherapeutics is at least one in doxorubicin hydrochloride, paclitaxel, camptothecine and Combretastatin.
7. PLGA/MoS according to any one of claim 1 to 6
2composite medicament stent material, is characterized in that, described in there is biocompatibility nonaqueous solvent be at least one in N-Methyl pyrrolidone, dimethyl sulfoxide.
8. the PLGA/MoS according to any one of a claim 1 to 7
2the preparation method of composite medicament stent material, is characterized in that, according to described PLGA/MoS
2the concentration of each component in/chemotherapeutics compound support frame material, by Poly(D,L-lactide-co-glycolide, MoS
2-PEG nanometer sheet and chemotherapeutics are dispersed in be had in the nonaqueous solvent of biocompatibility, i.e. obtained described PLGA/MoS
2/ chemotherapeutics compound support frame material.
9. preparation method according to claim 8, is characterized in that, described Poly(D,L-lactide-co-glycolide is by dispersed with stirring in described solvent, and mixing time is 12 ~ 24 hours, and mixing speed is 100 ~ 400 revs/min; Described MoS
2-PEG nanometer sheet and/or described chemotherapeutics by ultrasonic disperse in described solvent, described MoS
2the ultrasonic disperse time of-PEG nanometer sheet and/or described chemotherapeutics is 10 ~ 60 minutes, and ultrasonic power is 50 ~ 500W.
10. the PLGA/MoS according to any one of a claim 1 to 7
2the application in antitumor drug prepared by composite medicament stent material.
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Cited By (8)
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| CN105641704A (en) * | 2015-12-30 | 2016-06-08 | 上海理工大学 | Bubble-producing polylactide acid-glycolic acid effervescence drug and preparation method and application thereof |
| CN106890333A (en) * | 2017-02-04 | 2017-06-27 | 上海理工大学 | A kind of polyaminoacid/MoS2The preparation method and application of nanocluster |
| CN108126199A (en) * | 2017-12-29 | 2018-06-08 | 青岛大学 | A kind of degradable double-bang firecracker answers the preparation method of intelligent macromolecule/molybdenum sulfide pharmaceutical carrier |
| CN108653730A (en) * | 2017-03-28 | 2018-10-16 | 深圳大学 | Long afterglow oleosol and preparation method thereof, purposes |
| CN109260476A (en) * | 2018-08-28 | 2019-01-25 | 湖北大学 | A kind of composite antibacterial coating and preparation method thereof of 808 nm near-infrared excitation |
| CN110496250A (en) * | 2019-09-25 | 2019-11-26 | 杨建安 | Light-operated degradable polymer bracket and preparation method thereof |
| CN111996677A (en) * | 2020-03-06 | 2020-11-27 | 上海塔科生物技术有限公司 | Antibacterial MoS2Preparation method of PLGA nanofiber membrane |
| CN116212095A (en) * | 2022-12-14 | 2023-06-06 | 广西医科大学 | Preparation method of molybdenum disulfide nanofiber membrane dressing |
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| CN105641704A (en) * | 2015-12-30 | 2016-06-08 | 上海理工大学 | Bubble-producing polylactide acid-glycolic acid effervescence drug and preparation method and application thereof |
| CN106890333A (en) * | 2017-02-04 | 2017-06-27 | 上海理工大学 | A kind of polyaminoacid/MoS2The preparation method and application of nanocluster |
| CN108653730A (en) * | 2017-03-28 | 2018-10-16 | 深圳大学 | Long afterglow oleosol and preparation method thereof, purposes |
| CN108653730B (en) * | 2017-03-28 | 2021-05-04 | 深圳大学 | Long-afterglow oil sol and preparation method and application thereof |
| CN108126199A (en) * | 2017-12-29 | 2018-06-08 | 青岛大学 | A kind of degradable double-bang firecracker answers the preparation method of intelligent macromolecule/molybdenum sulfide pharmaceutical carrier |
| CN108126199B (en) * | 2017-12-29 | 2021-04-06 | 青岛大学 | Preparation method of degradable dual-response intelligent polymer/molybdenum sulfide drug carrier |
| CN109260476A (en) * | 2018-08-28 | 2019-01-25 | 湖北大学 | A kind of composite antibacterial coating and preparation method thereof of 808 nm near-infrared excitation |
| CN110496250A (en) * | 2019-09-25 | 2019-11-26 | 杨建安 | Light-operated degradable polymer bracket and preparation method thereof |
| CN111996677A (en) * | 2020-03-06 | 2020-11-27 | 上海塔科生物技术有限公司 | Antibacterial MoS2Preparation method of PLGA nanofiber membrane |
| CN116212095A (en) * | 2022-12-14 | 2023-06-06 | 广西医科大学 | Preparation method of molybdenum disulfide nanofiber membrane dressing |
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