CN115215996B - PDTP-TBZ and application of nano preparation thereof in treating brain glioma - Google Patents
PDTP-TBZ and application of nano preparation thereof in treating brain glioma Download PDFInfo
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- CN115215996B CN115215996B CN202210860709.3A CN202210860709A CN115215996B CN 115215996 B CN115215996 B CN 115215996B CN 202210860709 A CN202210860709 A CN 202210860709A CN 115215996 B CN115215996 B CN 115215996B
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Abstract
The invention discloses a PDTP-TBZ polymer which is a conjugated polymer constructed by dithienopyrrole and thiadiazole benzotriazole, and also discloses an application of the polymer in serving as or preparing a photo-thermal conversion agent. The invention also discloses a PDTP-TBZ coupled c (RGDfK) nano preparation and application thereof in serving as or preparing a photodiagnosis and treatment agent for treating brain glioma. The PDTP-TBZ polymer has wide absorption in NIR-II biological window, has the advantages of good light stability, large extinction coefficient and the like, and can be used as a photo-thermal conversion agent for photo-thermal treatment and photo-acoustic imaging. The PDTP-TBZ coupled c (RGDfK) nano preparation has good biocompatibility, water dispersibility, photothermal conversion capability and photoacoustic imaging capability, can cross BTB and target tumor neovasculature and tumor cells, and can be used as a photodiagnosis and treatment agent for treating brain glioma.
Description
Technical Field
The invention relates to PDTP-TBZ and a nano preparation thereof and application of the PDTP-TBZ polymer in treating brain glioma, in particular to a PDTP-TBZ polymer and application of the PDTP-TBZ polymer serving as a photo-thermal conversion agent in photo-thermal treatment and photo-acoustic imaging, a nano preparation of PDTP-TBZ coupling c (RGDfK) and application of the PDTP-TBZ coupling c (RGDfK) serving as or in preparing a photo-diagnosis and treatment agent for treating brain glioma, and belongs to the technical field of nano medicines.
Background
Glioblastoma (GBM) is the most common and invasive primary brain tumor in the cranium, accounting for more than half of cases of glioblastoma, and the incidence rises year by year, especially in elderly patients. The median survival time in GBM is 14 months, the prognosis is extremely poor, the recurrence risk is high, the death rate is high, and the survival rate in 5 years is less than 10%. At present, various treatment methods, such as surgical excision to the maximum under controllable conditions, can obviously relieve symptoms to a certain extent and prolong the survival time of patients, but because of the characteristics of glioma cell heterogeneity and wettability, the growth edge is unclear, and accurate excision is difficult to realize, so that prognosis is poor. Most current clinical treatment regimens combine radiation therapy and/or chemotherapy after surgery, but radiation therapy is associated with serious side effects such as post-radiation leukoencephalopathy, nerve damage, hair loss, vomiting, infertility and rash, while the effectiveness of chemotherapy is limited by toxic effects on healthy cells, chemotherapy resistance to tumor cells, and poor selectivity of anticancer drugs. Therefore, the development of safe in vitro imaging and accurate treatment methods is of great importance for improving survival of clinical glioblastoma multiforme patients.
Photothermal therapy (photothermal Therapy, PTT) is receiving increasing attention in clinical medicine as a non-invasive tumor treatment method that acts on tumor tissue with little damage to other organs. PTT utilizes the photo-thermal effect of photo-thermal converters (photothermal transduction agents, PTA) to extract energy from light and convert the energy to heat, thereby increasing the temperature of the surrounding environment and causing death of cancer cells. Compared with the traditional cancer treatment method, the photothermal therapy is a more attractive tumor replacement therapy, and the tumor can be precisely aimed by using the external laser irradiation with adjustable dose, so that the damage to surrounding healthy tissues can be reduced to the greatest extent, and the method has the advantages of low toxicity, high specificity, small invasiveness, no inherent or acquired drug resistance and the like. In particular, the second near infrared window (NIR-II, 900-1700 nm) has deeper laser penetration than the commonly used first near infrared window (NIR-I, 650-900 nm), the maximum allowable exposure (maximum permissible exposure, MPE) is larger, and PTT can treat deeper tumors in the body in the NIR-II window, so that the treatment result is improved.
Photoacoustic imaging (photoacoustic imaging, PAI) is an emerging hybrid imaging technique that produces acoustic signals by the photo-thermal effect that recombine to form a photoacoustic image. It combines the high contrast of optical imaging with the high spatial resolution of ultrasound imaging. It is well known that near infrared light has an incomparable advantage in terms of reduced scattering and absorption in biological tissue, remote manipulation, etc., compared to visible light. The higher spatial resolution of the NIR-II PAI allows for deeper tissue imaging than conventional NIR-I, which has prompted efforts to extend the wavelength to the NIR-II window to achieve deeper tissue penetration. In most cases, PTA can be used for both PTT and PAI at the same time, facilitating integration of both on a single platform for diagnostic imaging and treatment of cancer. Therefore, it is of great importance to design and develop new nano-platforms with excellent biocompatibility, photostability and NIR-ii photo-response.
The materials currently used for NIR-II photoresponsive are very limited, most of which are inorganic materials such as gold nanoparticles, plasmonic metal clusters, carbon nanotubes, etc., but their long-term biosafety remains to be questioned.
In early GBM, tumor cells grow through normal Blood vessels protected by the Blood-brain barrier (BBB), however as GBM progresses, new tumor vessels gradually disrupt the integrity of the Blood-brain barrier resulting in the formation of the Blood-Brain Tumor Barrier (BTB). Therefore, how to deliver an effective dose of therapeutic drug into tumor tissue via BTB is a very considerable problem. It has been found that tumour vascular endothelial cells express a number of different receptors and that integrin αvβ3/αvβ5 receptors play an important role in the early stages of angiogenesis, over-expression on tumour neovascular endothelial cells as well as tumour cells such as neuroblastoma, osteosarcoma, melanoma, glioblastoma and breast cancer, and low-level expression in healthy vascular cells. c (RGDfK) is composed of arginine, glycine, aspartic acid, D-phenylalanine and lysine, and the head and tail amide bonds form a ring, is RGD tumor targeting peptide, is a high-efficiency selective inhibitor of an alpha v beta 3 integrin receptor, is a 'tumor homing' cyclic peptide combined with alpha beta integrin, and is hopeful to become a very promising cancer therapeutic drug and imaging agent delivery technology by c (RGDfK) coupling nano-carrier targeting tumor blood vessels or tumor cells.
Disclosure of Invention
Aiming at the prior art, the invention provides a PDTP-TBZ polymer which has wide absorption in NIR-II biological window and can be used as a photo-thermal conversion agent for photo-thermal treatment and photo-acoustic imaging. The invention also provides a nano preparation of PDTP-TBZ coupling c (RGDfK), which has good biocompatibility, water dispersibility, photothermal conversion capability and photoacoustic imaging capability, can cross BTB and target tumor neovasculature and tumor cells, and can be used as a photodiagnosis and treatment agent for treating brain glioma and other tumors.
The invention is realized by the following technical scheme:
a PDTP-TBZ polymer is a conjugated polymer constructed by strong electron donor Dithienopyrrole (DTP) and strong electron acceptor Thiadiazole Benzotriazole (TBZ), and the standard name of the polymer is dithienopyrrole polythiadiazole benzotriazole, and the structural formula is shown as follows, wherein n is 60-70.
The PDTP-TBZ polymer can be prepared by the following method: 4- (2-ethylhexyl) -2, 6-bis (trimethylstannyl) -4H-thieno [3,2-B:2',3' -D ] pyrrole and 4, 8-dibromo-6- (2-ethylhexyl) - [1,2,5] thiadiazole [3,4-f ] benzotriazole are used as raw materials, and react for 60 to 80 hours under the protection of nitrogen under the action of chlorobenzene, triphenylphosphine and tris (dibenzylideneacetone) dipalladium (0) at the temperature of 100 to 120 ℃ to prepare the PDTP-TBZ polymer. The reaction process is as follows:
further, the molar ratio relationship of 4 substances of 4- (2-ethylhexyl) -2, 6-bis (trimethylstannyl) -4H-thieno [3,2-B:2',3' -D ] pyrrole, 4, 8-dibromo-6- (2-ethylhexyl) - [1,2,5] thiadiazole [3,4-f ] benzotriazol, triphenylphosphine and tris (dibenzylideneacetone) dipalladium (0) is as follows: 50:50:4-8:1-2.
Further, the preparation method specifically comprises the following steps: 4- (2-ethylhexyl) -2, 6-bis (trimethylstannyl) -4H-thieno [3,2-B:2',3' -D ] pyrrole (0.1 mmol,61.7 mg), 4, 8-dibromo-6- (2-ethylhexyl) - [1,2,5] thiadiazole [3,4-f ] benzotriazol (0.1 mmol,44.7 mg), triphenylphosphine (12. Mu. Mol,3.14 mg) and tris (dibenzylideneacetone) dipalladium (0) (3. Mu. Mol,2.75 mg) were added to a Schlenk tube to which dry chlorobenzene (5 mL) had been added beforehand and stirred under nitrogen at 110℃for 72 hours; and cooling the mixture to room temperature, precipitating in methanol, filtering, collecting the precipitate, and drying to obtain black solid, namely the PDTP-TBZ polymer.
The PDTP-TBZ polymer is applied to be used as or prepared into a photo-thermal conversion agent, and is applied to photo-thermal treatment and photo-acoustic imaging; the application of the composition in serving as or preparing a photodiagnosis and treatment agent for treating the glioma is applied to treating the glioma.
A nano-class PDTP-TBZ coupled c (RGDfK) is prepared from PDTP-TBZ nanoparticles (PTNPs) as carrier and coupling c (RGDfK).
Further, the PDTP-TBZ nanoparticle is prepared by the following method: and (3) placing the tetrahydrofuran solution of PDTP-TBZ in an ice bath for ultrasonic treatment, then adding the solution into an aqueous solution of distearoyl phosphatidyl acetamide (DSPE-PEG 2000-COOH), stirring until the solution is clear and transparent, and removing tetrahydrofuran by rotary evaporation to obtain the PTNPs solution.
Specifically, the operation is as follows: PDTP-TBZ was added to tetrahydrofuran to prepare a tetrahydrofuran solution (500. Mu.g/mL) of PDTP-TBZ, and the resultant solution was subjected to ultrasonic treatment in an ice bath for 30 minutes (300 mW); 2mL of PDTP-TBZ in tetrahydrofuran was added dropwise to 10mL of an aqueous solution of distearoyl phosphatidyl acetamide (at a concentration of 150. Mu.g/mL) under magnetic stirring (1000 rpm); and stirring the mixed solution for 10 minutes, removing tetrahydrofuran by rotary evaporation after the solution is clear and transparent, and obtaining the PTNPs solution, and concentrating until the concentration of PDTP-TBZ is 200 mug/mL.
Further, the specific mode of coupling c (RGDfK) is as follows: adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) to the PTNPs solution to obtain a PTNPs suspension; then adding the aqueous solution of c (RGDfK) into PTNPs suspension, stirring to obtain nano-particle suspension, and adding the nano-particles into ddH 2 Dialysis in O for two days to remove excess unreacted c (RGDfK); and freeze-drying to obtain the PDTP-TBZ coupled c (RGDfK) nanometer preparation.
Specifically, the operation is as follows: 0.67mg of EDC and 0.5mg ofNHS was added to PTNPs solution (5 mL, 200. Mu.g/mL) and stirred at room temperature for 2 hours to give PTNPs suspension; 1mL of an aqueous solution of c (RGDfK) (1 mg/mL, mw=603.7 g/mol) was then added to the PTNPs suspension and stirred at room temperature for 12 hours; nanoparticle suspension at ddH 2 Dialysis in O for two days (MWCO: 3500) to remove excess unreacted c (RGDfK); and freeze-drying to obtain the nano preparation of PDTP-TBZ coupled c (RGDfK), wherein the loading capacity of c (RGDfK) is 7.25%.
The nano preparation of PDTP-TBZ coupling c (RGDfK) is applied to the preparation of a photodiagnosis and treatment agent for treating brain glioma, and is applied to the treatment of brain glioma.
The PDTP-TBZ polymer has wide absorption in NIR-II biological window, good light stability, large extinction coefficient and the like, and has better biocompatibility. The invention prepares conjugated polymer PDTP-TBZ into nano particles (PTNPs) by a nano precipitation method (the nano reprecipitation method can effectively form organic nano particles with good water dispersibility), then c (RGDfK) with integrin specific targeting is modified on the surface of the nano particles, and finally the multifunctional nano photodiagnosis and treatment reagent cRGD@PTNPs with targeted tumor neovascularization and tumor cells is obtained. The nanometer preparation has good biocompatibility, water dispersibility, photothermal conversion capability and photoacoustic imaging capability, and can effectively kill tumor cells in vivo and in vitro photothermal treatment. The nano preparation provided by the invention has very important theoretical research significance and practical application value for improving the GBM treatment efficiency, reducing the recurrence probability, and comprehensively evaluating and analyzing GBM and other tumor diagnosis and treatment systems.
The invention has the following beneficial effects:
1. in the NIR-II light response nanomaterial, the biocompatibility of the inorganic nanomaterial such as gold nanoparticles, plasma metal clusters, carbon nanotubes, etc. used for a long time is not clear. And some small molecule photosensitizers, such as indocyanine green (ICG), chlorin e6 (Ce 6) and the like, have poor stability and obvious attenuation after laser irradiation. The photo-thermal material PDTP-TBZ belongs to conjugated polymers, has the advantages of good photostability and large extinction coefficient, and has good biocompatibility.
2. Photothermal therapy requires the accumulation of sufficient photothermal material at the target site to achieve therapeutic purposes under irradiation of an external laser. The photo-thermal nano material without targeting or with poor targeting efficiency cannot accumulate at the tumor part and is dispersed throughout the body, so that the safety is extremely uncertain. The invention uses the targeting molecule to connect the photo-thermal nanometer material, to accumulate nanometer particles in high concentration at the tumor position. In addition, the nano particles cRGD@PTNPs have excellent photothermal conversion capability, can realize remarkable temperature rise at a lower concentration to ablate tumor cells, and are safer and more effective than some materials with poorer photothermal capability.
3. Most of the photo-thermal materials are only excited in an NIR-I light region at present, and as the penetration depth of light is related to the wavelength, the longer the wavelength is, the deeper the penetration depth is, and the less scattering interference is caused by biological tissues, the photo-thermal materials are only used for treating superficial tumors in the NIR-I light excitation, and the effect is poor for some deep tumors. The nano material cRGD@PTNPs has wide absorption in an NIR-II window, can be excited by NIR-II light, so that laser penetrates deeper, and the PTT can treat deeper tumors in a body by carrying out the PTT in the NIR-II window, thereby improving the treatment result. Furthermore, the PAI of NIR-II exhibits a stronger imaging capability of deep tissues, a higher signal/background ratio, and a higher application power than the PAI of NIR-I.
4. Unlike available material with single performance, the nanometer particle cRGD@PTNPs of the present invention integrates excellent PTT and PAI and is favorable to diagnosis and treatment.
The various terms and phrases used herein have the ordinary meaning known to those skilled in the art.
Drawings
Fig. 1: schematic representation of the status of crgd@ptnps in different solutions.
Fig. 2: transmission electron microscope pictures of crgd@ptnps.
Fig. 3: ultraviolet visible light absorption spectrum of crgd@ptnps.
Fig. 4: photoacoustic image schematic diagrams of crgd@ptnps solutions of different concentrations in vitro.
Fig. 5: schematic of the photo-thermal warming capacity of crgd@ptnps solutions of different concentrations in vitro.
Fig. 6: schematic of heating/cooling cycles of crgd@ptnps and ICG solutions in vitro.
Fig. 7: tumor cell uptake assay results are schematically shown.
Fig. 8: the result of the killing effect of cRGD@PTNPs on tumor cells is schematically shown.
Fig. 9: fluorescence images of C6 cells subjected to different treatments.
Fig. 10: schematic representation of the results of crgd@ptnps mediated blockade of tumor angiogenesis under laser irradiation.
Fig. 11: photoacoustic images at different time points after tumor-bearing mice were injected with the PTNPs solution and cRGD@PTNPs solution (circles represent tumor sites).
Fig. 12: schematic of photothermal effects of crgd@ptnps in a nude mouse subcutaneous tumor model.
Fig. 13: results of HE section of mice heart, liver, spleen, lung and kidney are schematically shown.
Detailed Description
The invention is further illustrated below with reference to examples. However, the scope of the present invention is not limited to the following examples. Those skilled in the art will appreciate that various changes and modifications can be made to the invention without departing from the spirit and scope thereof.
The instruments, reagents and materials used in the examples below are conventional instruments, reagents and materials known in the art and are commercially available. The experimental methods, detection methods, and the like in the examples described below are conventional experimental methods and detection methods known in the prior art unless otherwise specified.
EXAMPLE 1 preparation of PDTP-TBZ Polymer
4- (2-ethylhexyl) -2, 6-bis (trimethylstannyl) -4H-thieno [3,2-B:2',3' -D ] pyrrole (0.1 mmol,61.7 mg), 4, 8-dibromo-6- (2-ethylhexyl) - [1,2,5] thiadiazole [3,4-f ] benzotriazol (0.1 mmol,44.7 mg), triphenylphosphine (12. Mu. Mol,3.14 mg) and tris (dibenzylideneacetone) dipalladium (0) (3. Mu. Mol,2.75 mg) were added to a Schlenk tube to which dry chlorobenzene (5 mL) had been added beforehand and stirred under nitrogen at 110℃for 72 hours; the mixture was cooled to room temperature and precipitated in methanol, the precipitate was collected by filtration and dried to give a black solid (46 mg, 59%) which was PDTP-TBZ.
And performing nuclear magnetic resonance hydrogen spectrum, fourier infrared spectrum and gel permeation chromatography detection on the product.
The results were: 1 H NMR(CDCl 3 ,400MHz,δ):9.01(br),7.28(br),7.15(br),7.00(br),5.60(br),4.67(br),4.14(br),3.75(br),2.29(br),1.58-1.61(m,br),1.32-1.45(m,br).IR(KBr):ν=2920cm -1 (m),2850cm -1 (m),1440cm -1 (w),1400cm -1 (m),1350cm -1 (m),1260cm -1 (m),1190cm -1 (w),1120cm -1 (w),1080cm -1 (m),1020cm -1 (m),987cm -1 (m),814cm -1 (w),729cm -1 (m) GPC mn=36927da, pdi=2.65. The detection result shows that the obtained product is the target product.
EXAMPLE 2 preparation of cRGD@PTNPs solution
The method comprises the following steps:
(1) Preparation of PDTP-TBZ nanoparticles (PTNPs solution): PDTP-TBZ (prepared in example 1) was added to tetrahydrofuran to prepare a tetrahydrofuran solution (500. Mu.g/mL) of PDTP-TBZ, and subjected to ultrasonic treatment in an ice bath for 30 minutes; 2mL of PDTP-TBZ in tetrahydrofuran was added dropwise to 10mL of an aqueous solution of distearoyl phosphatidyl acetamide (DSPE-PEG 2000-COOH) (at a concentration of 150. Mu.g/mL) under magnetic stirring (1000 rpm); the mixed solution is stirred for 10 minutes, after the solution is clear and transparent, tetrahydrofuran is removed by rotary evaporation, and then the PDTP-TBZ is concentrated until the concentration is 200 mug/mL.
(2) Coupling c (RGDfK): 0.67mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 0.5mg of N-hydroxysuccinimide (NHS) were added to the PTNPs solution (5 mL, PDTP-TBZ concentration 200. Mu.g/mL), and stirred at room temperature for 2 hours to give a PTNPs suspension; 1mL of an aqueous solution of c (RGDfK) (1 mg/mL, mw=603.7 g/mol) was then added to the PTNPs suspension and stirred at room temperature for 12 hours; nanoparticle suspension inddH 2 Dialysis in O for two days (MWCO: 3500) to remove excess unreacted c (RGDfK); and freeze-drying to obtain the PDTP-TBZ coupled c (RGDfK) nanometer preparation. The free c (RGDfK) in the dialysate was determined using the standard BCA protein assay. From the protein standard curve of c (RGDfK), it was found that there was 0.8044mg of unreacted c (RGDfK) in the dialysate. Thus 0.1956mg of c (RGDfK) reacted with activated carboxyl groups on the nanoparticle surface at a loading of 7.25% (PDTP-TBZ 1mg, DSPE-PEG2000-COOH 1.5 mg).
As shown in FIG. 1, the cRGD@PTNPs were prepared by using PBS solution, DMEM solution and FBS solution, and the results are clear and transparent in the different solutions, indicating that the water solubility of the cRGD@PTNPs is good.
FIG. 2 is a transmission electron microscope photograph of cRGD@PTNPs, and the size of nanoparticles is about 80nm.
FIG. 3 shows the ultraviolet-visible light absorption spectrum of cRGD@PTNPs, and the graph shows that the absorption is wide between 900 and 1100 nm.
Experiment in vitro photoacoustic imaging experiment of 1cRGD@PTNPs solution
The preparation of a plurality of concentrations of cRGD@PTNPs aqueous solutions (0, 25, 50, 75 and 100 mug/mL) is carried out in a micro centrifuge tube, and the detection is carried out by a small animal photoacoustic imager to obtain a photoacoustic image, as shown in a figure 4, the signal intensity is enhanced along with the increase of the concentration, which shows that the photoacoustic signal intensity is positively correlated with the concentration of the solution. The photo-thermal heating capacity in vitro is shown in FIG. 5, and it is clear from the graph that the temperature rise is positively correlated with the solution concentration.
The specific operation of the in vitro photoacoustic imaging experiment of crgd@ptnps solution is as follows:
(1) cRGD@PTNPs solution (100. Mu.g/mL, 1 mL) was introduced into a quartz cuvette and laser light of 1064nm was used at different power densities (0.25,0.5,0.75,1.0W/cm 2 ) Irradiation was carried out for 5 minutes.
(2) cRGD@PTNPs solutions with a range of concentrations (0, 25, 50, 75, 100. Mu.g/mL, 1 mL) were added to quartz cuvettes and laser light at 1064nm at 1W/cm 2 Is used for the irradiation of the power intensity of the (c).
(3) Through 1064nm (1W/cm) 2 ) RepeatingThe light stability of crgd@ptnps was measured by irradiating on/off laser light for 4 cycles. Further, particle diameters and ultraviolet absorption spectra of crgd@ptnps before and after laser irradiation were measured.
To further determine the photostability of crgd@ptnps. In the use of 1064nm laser (1W/cm) 2 ) The temperature change in the crgd@ptnps solution (100 μg/mL,1 mL) was continuously monitored after 5 minutes of irradiation, and then naturally cooled to room temperature, and four heating/cooling cycles were performed, as shown in fig. 6, the crgd@ptnps sample had a stronger photothermal conversion ability, and the photothermal conversion performance did not significantly decrease after a plurality of heating/cooling cycles, while the FDA-approved NIR dye ICG (100 μg/mL,1 mL) showed significant degradation under the same conditions, and the photothermal conversion performance was greatly affected after four cycles.
Experiment 2 cell uptake experiment
To demonstrate the tumor targeting ability of crgd@ptnps, dishes were inoculated. PTNPs and cRGD@PTNPs were added to the chamber at a concentration of 25. Mu.g/mL after cell adhesion, respectively, and incubated at 37℃for different times. Subsequently, the cells were fixed with Hoecht33342 for 30 minutes to stain the nuclei. After incubation, cells were washed three times with PBS solution and imaged under confocal microscopy. Finally, the cells were analyzed for fluorescence intensity using Image J software. The results are shown in FIG. 7, which shows that nanoparticles modified with cRGD polypeptides cRGD@PTNPs can be internalized into cells more rapidly.
Experiment of killing of tumor cells by 3cRGD@PTNPs
And detecting the activity state of the tumor cells before and after the laser irradiation of the added nano particles by using a CCK-8 method. The C6 cells were first resuspended in DMEM medium and adjusted to 6X 10 after cell counting 4 Individual cells/ml. C6 cells (6X 10 per well) 3 Individual cells) were inoculated in 96-well plates and incubated with different concentrations of PTNPs and crgd@ptnps (0, 6.25, 12.5, 25, 50 μg/mL) for 4h after attachment. Laser group was set at 1W/cm 2 Exposed to 1064nm laser for 5 minutes. After an additional 12 hours incubation, cell viability was determined by standard CCK-8 methods. As shown in FIG. 8, the PTNPs and cRGD@PTNPs can kill tumor cells effectively under laser irradiation, but cytotoxicity of the non-irradiated group is unknownAnd (5) displaying.
And (3) observing the killing effect on tumor cells by a laser confocal microscope after calcein-AM/PI double-dyeing. The C6 cells were first resuspended in DMEM medium and adjusted to 5X 10 after cell counting 5 Individual cells/ml. C6 cells (1X 10 per well) 5 Individual cells) were seeded in 24-well plates and cultured for 12 hours, after cell attachment, incubated with cRGD@PT NPs (30. Mu.g/mL) for 4 hours, and then laser irradiated with 1064nm (laser irradiated with 1W/cm) 2 ) Treatment was carried out for 5 minutes. The medium was replaced with fresh DMEM medium containing 10. Mu.g/ml PI and 5. Mu.g/ml calcein-AM, after further incubation for 30 minutes, the cells were washed and then photographed by observation on a fluorescent inverted microscope. Live and dead cells were stained with calcein-AM (green) and PI (red), respectively. As a result, as shown in FIG. 9, after incubation with cRGD@PTNPs without laser irradiation, the C6 cells showed strong green fluorescence, indicating that the cell activity was hardly affected, the toxicity of the cRGD@PTNPs was not large, and the effect of the simple laser irradiation on the cells was negligible. In addition, little green fluorescence was seen in the crgd@ptnps group after treatment with 1064nm laser irradiation, indicating that crgd@ptnps-directed photothermal therapy can effectively kill tumor cells.
Experimental ability of 4cRGD@PTNPs to inhibit angiogenesis
HUVEC cells were resuspended in DMEM medium and adjusted to 5X 10 after cell counting 5 Individual cells/ml. HUVEC cells (5X 10 per well) 5 Individual cells) were inoculated into 6-well plates, attached, and then subjected to 5% CO at 37 ℃ 2 Incubated with cRGD@PTNPs (30. Mu.g/mL) for 4 hours. Blank DMEM medium served as a blank control. After 8 hours the culture medium was removed, the cells were digested with pancreatin and after cell counting at 5X 10 4 The individual cell/well densities were seeded into 96-well culture plates coated with Matrigel. The cells are then irradiated with or without a laser. And the culture was continued for 6 hours, and the formation of voids was observed under a microscope for each group, as shown in FIG. 10. In the control group, HUVECs were able to spontaneously form tubular structures on Matrigel gel. However, under NIR-II irradiation, the tubular structure in the group of cRGD@PTNPs was damaged and the cells were loose. The result shows that the PTT mediated by cRGD@PTNPs can effectively block tumor angiogenesis, thereby inhibiting tumorAnd (5) cell proliferation.
Experiment 5cRGD@PTNPs in vivo photothermal therapy experiment
Will be 1X 10 6 The nude mice were inoculated with C6 cells on their back to construct a mouse model of the transplanted tumor (subcutaneous tumor model). Firstly, detecting aggregation distribution of nano particles at a tumor part through photoacoustic imaging, and verifying targeting of cRGD@PTNPs. Tumor-bearing mice were anesthetized with isoflurane after injection of PTNPs solution (100. Mu.L, 200. Mu.g/mL) or cRGD@PTNPs solution (100. Mu.L, 200. Mu.g/mL). At different time points after injection, the collected photoacoustic images are excited by 1064nm laser, and the result is shown in fig. 11, so that the photoacoustic signals of the tumor sites of the crgd@ptnps group can be seen to be obvious, compared with PTNPs, cRGD@PTNPs, the photoacoustic signals can be rapidly collected to the tumor sites, and a higher concentration can be maintained, which means that c (RGDfK) can promote more nano particles to enter the tumor.
Tumors grow to 100mm 3 The C6 tumor-bearing mice were randomly divided into three groups (6 mice per group, with a body weight of approximately 20 g), each:
(1) Control (PBS solution + laser): 100. Mu.L of PBS solution was injected, and laser irradiation was performed at 1064nm (1W/cm 2 5 minutes).
(2) crgd@ptnps group (1 mg/Kg): mu.L of 200. Mu.g/ml cRGD@PTNPs solution was injected.
(3) crgd@ptnps (1 mg/Kg) +laser group: mu.L of 200. Mu.g/ml cRGD@PTNPs solution was injected and irradiated with 1064nm laser light (1W/cm 2 5 minutes).
After the mouse tail is intravenous injected with cRGD@PTNPs, aggregation distribution of the nano particles at the tumor site is monitored in real time through photoacoustic imaging. After 1 hour of drug injection, the tumor was irradiated with laser light, and the temperature change was detected by a thermal imager. The mental state of the mice, the body weight of the mice, and the growth of the tumor tissue (grasping the measurement of tumor volume with a vernier caliper as the mice survive) were observed throughout the experimental period, and as shown in fig. 12, it was seen that the tumors were substantially disappeared after the treatment day 7, while the tumor volume was increasing in the light-only and dosing-only groups.
Mice were sacrificed after the end of treatment (15 days), peripheral blood was collected, and blood biochemistry and blood normative were detected; the results of collecting heart, liver, spleen, lung and kidney of mice and performing HE staining and slicing treatment on tissue organs of tumor-bearing mice after administration and illumination are shown in fig. 13, and the results show that HE staining has no obvious change in main organs, and show that cRGD@PTNPs have good biocompatibility.
The foregoing examples are provided to fully disclose and describe how to make and use the claimed embodiments by those skilled in the art, and are not intended to limit the scope of the disclosure herein. Modifications that are obvious to a person skilled in the art will be within the scope of the appended claims.
Claims (10)
2. the PDTP-TBZ polymer of claim 1, wherein: the preparation method comprises the following steps: 4- (2-ethylhexyl) -2, 6-bis (trimethylstannyl) -4H-thieno [3,2-B:2',3' -D ] pyrrole and 4, 8-dibromo-6- (2-ethylhexyl) - [1,2,5] thiadiazole [3,4-f ] benzotriazole are used as raw materials, and react for 60 to 80 hours under the protection of nitrogen under the action of chlorobenzene, triphenylphosphine and tris (dibenzylideneacetone) dipalladium (0) at the temperature of 100 to 120 ℃ to prepare the PDTP-TBZ polymer.
3. A method of preparing a PDTP-TBZ polymer as defined in claim 1, wherein: 0.1mmol of 4- (2-ethylhexyl) -2, 6-bis (trimethylstannyl) -4H-thieno [3,2-B:2',3' -D ] pyrrole, 0.1mmol of 4, 8-dibromo-6- (2-ethylhexyl) - [1,2,5] thiadiazole [3,4-f ] benzotriazol, 12. Mu. Mol of triphenylphosphine and 3. Mu. Mol of tris (dibenzylideneacetone) dipalladium (0) were added to a Schlenk tube to which 5mL of dry chlorobenzene had been added beforehand, and stirred under nitrogen at 110℃for 72 hours; and cooling the mixture to room temperature, precipitating in methanol, filtering, collecting the precipitate, and drying to obtain black solid, namely the PDTP-TBZ polymer.
4. The use of a PDTP-TBZ polymer according to claim 1 for the preparation of a photothermal conversion agent, or for the preparation of a photodiagnostic agent for the treatment of brain glioma.
5. A nano-formulation of PDTP-TBZ coupled c (RGDfK), characterized by: the PDTP-TBZ nanoparticle is used as a carrier, and c (RGDfK) is coupled to the PDTP-TBZ nanoparticle; the nanoparticle of PDTP-TBZ is a nanoformulation of the PDTP-TBZ polymer of claim 1.
6. The PDTP-TBZ coupled c (RGDfK) nanoformulation of claim 5, wherein the PDTP-TBZ nanoparticles are prepared by: and (3) placing the tetrahydrofuran solution of PDTP-TBZ in an ice bath for ultrasonic treatment, then adding the solution into the water solution of distearoyl phosphatidyl acetamide, stirring until the solution is clear and transparent, and removing tetrahydrofuran by rotary evaporation to obtain the PTNPs solution.
7. A nano-formulation of PDTP-TBZ coupled c (RGDfK) as defined in claim 6, wherein: adding PDTP-TBZ into tetrahydrofuran to prepare PDTP-TBZ tetrahydrofuran solution with the concentration of 500 mu g/mL, and placing the PDTP-TBZ into ice bath for ultrasonic treatment for 30 minutes; dropwise adding a tetrahydrofuran solution of PDTP-TBZ of 2mL into an aqueous solution of distearoyl phosphatidyl acetamide of which the concentration is 150 mu g/mL of 10mL under the condition of magnetic stirring; stirring the mixed solution, and removing tetrahydrofuran by rotary evaporation after the solution is clear and transparent to obtain the PTNPs solution.
8. The nano-preparation of PDTP-TBZ coupled c (RGDfK) of claim 5, wherein the specific manner of coupling c (RGDfK) is: adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide to the PTNPs solution to obtain a PTNPs suspension; then adding the aqueous solution of c (RGDfK) into PTNPs suspension, stirring to obtain nano-particle suspension, and adding the nano-particles into ddH 2 Dialysis against O to remove excess unreactedc (RGDfK); and freeze-drying to obtain the PDTP-TBZ coupled c (RGDfK) nanometer preparation.
9. A nano-formulation of PDTP-TBZ coupled c (RGDfK) as defined in claim 8, wherein: adding 0.67mg EDC and 0.5mg NHS to a PTNPs solution having a concentration of 5mL of 200 μg/mL to obtain a PTNPs suspension; then 1mL of an aqueous solution of c (RGDfK) at a concentration of 1mg/mL was added to the PTNPs suspension and stirred at room temperature for 12 hours; nanoparticle suspension at ddH 2 Dialysis in O to remove excess unreacted c (RGDfK); and freeze-drying to obtain the nano preparation of PDTP-TBZ coupled c (RGDfK), wherein the loading capacity of c (RGDfK) is 7.25%.
10. Use of a nano-preparation of PDTP-TBZ coupled c (RGDfK) according to any of claims 5-9 for the preparation of a photodiagnosis and treatment agent for treating glioma.
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