CN116549673B - Albumin-near infrared fluorescent dye nanoparticle and preparation method and application thereof - Google Patents
Albumin-near infrared fluorescent dye nanoparticle and preparation method and application thereof Download PDFInfo
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0056—Peptides, proteins, polyamino acids
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- A61K49/0089—Particulate, powder, adsorbate, bead, sphere
- A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
- A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
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Abstract
The invention discloses albumin-near infrared fluorescent dye nanoparticles, a preparation method and application thereof, and in particular discloses application of albumin and novel near infrared dye IR817 after covalent bonding into nanoparticles in imaging diagnosis and photothermal treatment of tumors. The albumin-IR 817 nanoparticle uses bovine serum albumin as a carrier, and the IR817 is adsorbed in the carrier through hydrophobic force, so that the nanoparticle with uniform dispersion and stable structure is formed, and the particle size of the nanoparticle is 120-220 nanometers. The invention not only overcomes the defects of poor water solubility, fluorescence aggregation quenching, toxic and side effects and the like of IR817, but also improves the absorption and fluorescence emission peak value in the near infrared region, and has stronger fluorescence in the visible light range. At the same time, the present invention can effectively convert light energy to heat energy for photothermal therapy in combination with laser 808 irradiation while reducing the toxicity of IR817. Therefore, the albumin-IR 817 nanoparticle has great application and popularization potential in imaging diagnosis and photothermal treatment.
Description
Technical Field
The invention relates to the field of biotechnology and materials, in particular to albumin-near infrared fluorescent dye nanoparticles, and a preparation method and application thereof.
Background
Malignant tumors have been the greatest threat to human health and longevity. Although most malignant tumors can be treated by surgical excision in early stage, the survival rate of 5 years is more than 95 percent. However, patients often reach late stages before they are found, with missed surgical occasions, and long-term survival and prognosis decline dramatically. Therefore, it is important for early diagnosis and treatment of malignant tumors.
In recent years, near infrared fluorescent dyes have become main biological imaging agents due to their excellent photophysical properties such as low background interference, deep tissue penetration, high image sensitivity, etc., such as indocyanine green (ICG) which has been approved by the U.S. Food and Drug Administration (FDA), IR-780, IR-820, IR-808, etc., which have been studied more recently. However, different chemical couplings may alter targeting ligand structure, fluorescence imaging capability, and therapeutic potential. Therefore, the applicant successfully synthesizes a novel near infrared fluorescent dye IR817 by coupling IR-808 with choline in the earlier study, wherein the IR817 has good targeting anti-tumor capability and has a strong fluorescence imaging effect (SunC, wangJ, xiaT, sunQ, heY, wangH, et al Mitocochncondition-TargetedNIRTherapeuticAgentSuppressesMelanomabyInducingApoptosisand CellCycleArrestviaE F/Cyclin/CDKPath.pharmaceuticals (Basel). 2022; 15.). However, since IR817 has problems of poor water solubility, short imaging time, aggregation quenching effect, and acute toxicity (high dose), we want to find a new method to improve IR817 so that it has better application prospects in the field of tumor diagnosis and treatment.
Albumin has good biocompatibility, no toxicity, easy production and good stability in vivo, and has been widely developed as a multifunctional drug delivery nano-carrier for many years. If albumin is combined with a small-molecule dye compound, a dynamically stable dye can be generated through the interaction of covalent coupling and supermolecule encapsulation, meanwhile, aggregation of the molecular dye is avoided, and the self-quenching problem is reduced. Notably, by confining the dye in the hydrophobic pocket of albumin, both the brightness of the albumin-dye probe is significantly improved, and the solubility and biocompatibility of the dye is greatly improved while toxicity is reduced.
In recent years, the development of photothermal therapies based on proteins has also received attention from more and more researchers. Photothermal therapy achieves the therapeutic purpose by heating the focal region by using a photothermal agent to perform local thermal ablation under the irradiation of laser, and has the advantages of high specificity and minimally invasive property. The ideal photothermal agent should have a strong absorbance in the near infrared window, allowing the absorbed light energy to be efficiently converted to heat rather than fluorescent emission. Therefore, it is very interesting to combine albumin with IR817 to prepare a new nanoparticle and to explore its efficacy in photothermal therapy.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, provides albumin-near infrared fluorescent dye nanoparticles, a preparation method and application thereof, and particularly discloses application of albumin and novel near infrared dye IR817 in imaging diagnosis and photothermal treatment in tumors after covalent bonding of the albumin and the novel near infrared dye IR817 into nanoparticles. The albumin-IR 817 nanoparticle uses bovine serum albumin as a carrier, and the IR817 is adsorbed in the carrier through hydrophobic force, so that the nanoparticle with uniform dispersion and stable structure is formed, and the particle size of the nanoparticle is 120-220 nanometers. The invention combines albumin with novel near infrared fluorescent dye IR817 to obtain an all-new nanoparticle for tumor imaging and photothermal treatment, which not only overcomes the defects of poor water solubility, fluorescence aggregation quenching, toxic and side effects and the like of IR817, but also improves the absorption spectrum and fluorescence emission spectrum of the nanoparticle in the near infrared region, and has stronger fluorescence in the visible light range. Meanwhile, the invention can effectively convert fluorescence into heat energy for photothermal treatment by combining laser 808 irradiation while reducing the toxicity of IR817. Therefore, the albumin-IR 817 nanoparticle has great application and popularization potential in imaging diagnosis and photothermal treatment.
In order to achieve the technical effects, the following technical scheme is adopted:
an albumin-near infrared fluorescent dye nanoparticle, comprising bovine serum albumin and near infrared fluorescent dye IR817, wherein the bovine serum albumin is used as a carrier of the near infrared fluorescent dye IR817, and the IR817 is adsorbed in the bovine serum albumin carrier through hydrophobic acting force to form the albumin-near infrared fluorescent dye nanoparticle; the mole ratio of bovine serum albumin to IR817 is 1-3:1, a step of; the molecular weight of the bovine serum albumin is 60-70kDa; the molecular weight of the IR817 is 1176.9Da; the particle size of the albumin-IR 817 nanoparticle is 120-220 nanometers; the structural formula of the IR817 is as follows:
the preparation method of the albumin-near infrared fluorescent dye nanoparticle comprises the following steps:
step S1: dissolving bovine serum albumin in phosphate buffer to obtain phosphate buffer solution of bovine serum albumin, and dissolving IR817 powder in dimethyl sulfoxide solution to obtain stock solution of IR 817;
step S2: mixing phosphate buffer solution of bovine serum albumin prepared in the step S1 with IR817 liquid storage in an oscillating way, transferring to a dialysis bag for dialysis, centrifuging to obtain supernatant, and placing in a freeze-drying cup overnight;
step S3: and (3) putting the mixture obtained in the step (S2) into a freeze dryer for freeze drying the mixture the next day to obtain the albumin-IR 817 nanoparticle freeze-dried powder.
Further, the molar ratio of bovine serum albumin to IR817 in the step S1 is 1-3:1.
further, the phosphate buffer solution of the bovine serum albumin in the step S2 and the IR817 solution are mixed uniformly by shaking, and then are vibrated for 2-4 hours in a water bath constant temperature vibrator at 60 ℃ in a dark place.
Further, in the step S2, the cut-off molecular weight of the dialysis bag is 2.0KMWCO, the dialysis solution is deionized water, and the dialysis time is 24-36 hours.
Further, the step S2 is placed in a freeze-drying cup at-20 ℃ overnight.
Further, the step S3 is placed in a freeze dryer for freeze drying for 20-40 hours to obtain albumin-IR 817 nanoparticle freeze-dried powder.
The prepared albumin-near infrared fluorescent dye nanoparticle is applied to the preparation of medicaments for tumor imaging diagnosis and/or tumor photothermal treatment.
Further, the tumor is melanoma.
Further, IR817 is a heptamethine cyanine organic small molecule derivative, the preparation method thereof belongs to the prior art (see: sunC, wangJ, xiaT, sunQ, heY, wangH, et al Mitocochnondion-TargetedNIR TherapeuticAgentSuppressesMelanomabyInducingApoptosisandCellCycleArrestvia E F/Cyclin/CDKPath. Pharmaceuticals (Basel). 2022; 15), the invention preferably adopts the following method:
IR-808 and dicyclohexylcarbodiimide were used as raw materials and dissolved together in N, N-dimethylformamide. The reaction mixture was subjected to thin layer chromatography using methylene chloride/methanol as a solvent. After completion of the reaction, the mixture was extracted with methylene chloride. The organic phase is concentrated by reduced pressure rotary evaporation, dichloromethane/methanol is used as an eluting solvent, silica gel column is used for purification, and target product IR817 can be collected after reduced pressure concentration.
In the above technical scheme, the molar ratio of IR-808 to dicyclohexylcarbodiimide is 1:4.
In the technical scheme, the ratio of dichloromethane to methanol is 10:1.
According to the invention, novel heptamethine cyanine organic small molecule derivative IR817 is loaded on Bovine Serum Albumin (BSA) to obtain BSA-IR817 nanoparticles. The BSA-IR817 greatly improves the absorption spectrum and the fluorescence emission spectrum of the IR817 in the near infrared region, and the fluorescence intensity of the BSA-IR817 is obviously stronger than that of the IR817 in vivo and in vitro, so that the BSA-IR817 is a very good biological imaging reagent. After irradiation of the solution containing BSA-IR817 with laser 808, the temperature can be raised up to 52.6 ℃, which is sufficient to kill tumor cells. Therefore, BSA-IR817 nanoparticles are also an ideal photothermal agent. Therefore, the invention also discloses application of the BSA-IR817 nanoparticle in tumor imaging and photothermal treatment.
Although IR817 is a good diagnostic and therapeutic agent in the invention, the invention has the advantages of cyanine dyes and also has a plurality of unavoidable defects, such as poor biocompatibility, short body circulation time, low tumor accumulation, aggregation quenching effect, toxic and side effects and the like. Therefore, to improve the properties of IR817, we synthesized BSA-IR817 nanoparticles using bovine serum albumin as a carrier. The solubility of IR817 is improved, and the fluorescence intensity of the bovine serum albumin is greatly improved, so that the bovine serum albumin has good absorption and emission peaks in a near infrared region. The BSA-IR817 can realize biological imaging through a living body imaging technology, detect the tumorigenic part in real time, and can effectively convert light energy into heat energy by combining laser 808 irradiation to play a good role in photothermal treatment. Notably, encapsulation of bovine serum albumin also greatly reduced toxicity of IR817, making BSA-IR817 safer biologically.
The beneficial effects of the invention are as follows:
1. the problems of poor water solubility, short in vivo circulation time, quenching of fluorescence aggregation, large toxic and side effects and the like of the near infrared fluorescent dye IR817 are solved by taking bovine serum albumin as a carrier, so that the potential of further application of the bovine serum albumin is greatly improved;
2. through covalent bonding of bovine serum albumin and IR817, the bovine serum albumin has a strong light absorption peak value in a near infrared region, and the absorbed light energy can be effectively converted into heat energy by irradiation of laser 808, so that the bovine serum albumin can be used as a novel ideal photothermal therapeutic reagent.
Drawings
FIG. 1 is a diagram showing absorption spectra of BSA-IR817 and IR817 according to an embodiment of the present invention;
FIG. 2 is a graph showing fluorescence emission spectra of BSA-IR817 and IR817 according to an embodiment of the present invention;
FIG. 3 is a bar graph of fluorescence intensity versus concentration for IR817 at different concentrations according to an embodiment of the present invention;
FIG. 4 is a bar graph of fluorescence intensity versus concentration for BSA-IR817 at different concentrations according to an embodiment of the present invention;
FIG. 5 is a Scanning Electron Microscope (SEM) image of particle size of BSA-IR817 according to an embodiment of the present invention;
FIG. 6 is a particle size distribution plot of BSA versus BSA-IR 817;
FIG. 7 is a graph showing the comparison of the absolute value of Zata potential of BSA-IR817 and IR817 according to an embodiment of the present invention;
FIG. 8 is a graph showing the change in particle size with time of BSA-IR817 according to an embodiment of the present invention.
FIG. 9 is a graph showing in vitro fluorescence intensity contrast of BSA-IR817 and IR817 according to an embodiment of the present invention;
FIG. 10 is a graph showing comparison of cell uptake capacities of BSA-IR817 and IR817 according to an embodiment of the present invention;
FIG. 11 is a graph showing comparison of tumor accumulation imaging capacities of BSA-IR817 and IR817 according to an embodiment of the present invention;
FIG. 12 is a graph showing the relative intensity of fluorescence signals at tumor sites as a function of time for BSA-IR817 and IR817 according to an embodiment of the present invention;
FIG. 13 is a diagram of the present inventionExamples of the invention BSA-IR817 and IR817 were obtained in vitro using a laser 808 (power 1W/cm) 2 ) A temperature change curve graph after irradiation for different times;
FIG. 14 shows the concentration of BSA-IR817 in the laser 808 (power 1W/cm) 2 ) A graph of temperature change after irradiation;
FIG. 15 shows the in vivo use of laser 808 (power 1W/cm) with BSA-IR817 and IR817 according to an embodiment of the present invention 2 ) Irradiating for 5min, and performing infrared thermal imaging contrast map;
FIG. 16 shows the in vivo use of laser 808 (power 1W/cm) with BSA-IR817 and IR817 according to an embodiment of the present invention 2 ) A temperature change curve graph after irradiation for different times;
FIG. 17 is a bar graph showing the effect of BSA-IR817 at various concentrations on the activity of A375, B16-F10 melanoma cells according to an embodiment of the present invention;
FIG. 18 is a bar graph showing the effect of varying concentrations of BSA-IR817 on A375, B16-F10 melanoma cell activity following illumination in accordance with an embodiment of the present invention;
FIG. 19 is a diagram of tumor entities of mice in different treatment groups according to an embodiment of the present invention;
FIG. 20 is a graph showing tumor growth in mice of different treatment groups according to the embodiment of the present invention;
FIG. 21 is a graph showing tumor weight statistics of mice in different treatment groups according to the embodiment of the present invention;
FIG. 22 is a graph showing comparison of body weights of mice in different treatment groups according to the embodiment of the present invention;
FIG. 23 is a graph showing comparison of survival rates of mice in different treatment groups according to an embodiment of the present invention;
FIG. 24 is a graph showing the hemolysis ratio of BSA-IR817 with different concentrations in the example of the present invention.
Detailed Description
The invention is further described below with reference to the accompanying drawings, the scope of the invention not being limited to the following:
example 1: BSA-IR817 nanoparticles of bovine serum albumin loaded with near infrared fluorescent dye are prepared.
The BSA-IR817 is formed by adsorbing IR-817 into BSA by hydrophobic interaction using bovine serum albumin BSA as a carrier.
The method specifically comprises the following steps:
1. a certain amount of near infrared fluorescent dye IR817 is synthesized, and the preparation method is as follows:
IR-808 (764 mg,1 mM) and dicyclohexylcarbodiimide (284 mg,4 mM) were dissolved in N, N-dimethylformamide (20 mL), and stirred at room temperature for 24 hours. The solvent was methylene chloride/methanol at a ratio of 10:1, and the mixture was subjected to thin layer chromatography. After completion of the reaction, quenching with saturated aqueous solution of sodium chloride, washing twice, and extracting with methylene chloride. The organic phase was concentrated by rotary evaporation under reduced pressure, and purified by silica gel column using dichloromethane/methanol as eluting solvent. The desired product IR817 (0.95 g, 81%) was collected after concentration under reduced pressure.
2. BSA-IR817 was synthesized as follows:
(a) 10mg of near infrared fluorescent dye IR817 is weighed and dissolved in 425 mu L of dimethyl sulfoxide to obtain IR817 stock solution, and the stock solution is stored at 4 ℃ in a dark place. 198mg of bovine serum albumin BSA was weighed and dissolved in 100mL of phosphate buffer solution, and thoroughly mixed. mu.L of the previously prepared IR817 stock solution was added to 100mL of the above albumin phosphate buffer solution. After being evenly mixed, the mixture is placed in a constant temperature water bath oscillator to be oscillated for 2 hours in a dark place, and the temperature is set to be 60 ℃.
(b) Cutting a dialysis bag with proper length, cleaning the inner and outer surfaces of the dialysis bag with deionized water, transferring the mixed solution heated by light-proof oscillation into the dialysis bag, dialyzing in the deionized water for 24-36 hours in the absence of light, and replacing the deionized water for 2-3 times. After dialysis was completed, the solution was collected back into a centrifuge tube and centrifuged at high speed (13000 rpm,10 minutes), and the supernatant was then placed in a freeze-drying cup (note that the liquid level was kept as high as 1 cm) overnight at-20 ℃.
(c) The next day the above freeze-dried cups were placed in a lyophilizer and lyophilized for 40 hours to obtain a BSA-IR817 lyophilized powder. Finally, the BSA-IR817 powder is dissolved in phosphate buffer solution, and is evenly mixed to obtain BSA-IR817 stock solution, and the stock solution is stored at 4 ℃ in a dark place. Characterization of basic properties is performed by dynamic light scattering, zata potential, ultraviolet absorption, fluorescence emission, and the like.
FIGS. 1 and 2 are graphs of absorption and fluorescence emission spectra of the above BSA-IR817 and IR817 dissolved in PBS and IR817 directly mixed with BSA solution, respectively, at the same concentration (10. Mu.M). As shown in FIGS. 1 and 2, the absorption and emission peaks of BSA-IR817 and IR817 are both in the near infrared wavelength range, but the fluorescence intensity of the BSA-IR817 is obviously lower due to the poor water solubility of the IR-817 and aggregation quenching. And the IR817 is simply mixed with BSA and cannot improve the property of the BSA obviously, and the advantages of the BSA can be fully highlighted after the BSA is further prepared into nano particles. In a word, after the BSA and the IR-817 are prepared into nanoparticles, the optical absorption and fluorescence emission of the IR-817 are greatly improved, and the further application of the BSA and the IR-817 in imaging diagnosis and photothermal treatment is facilitated.
Example 2: BSA-IR817 effectively improves the IR-817 aggregation quenching effect
Respectively dissolving BSA-IR817 or IR817 with different concentrations in H 2 In O, the fluorescence emission spectrum was detected, the fluorescence intensity corresponding to the maximum peak of 0.31. Mu. MBSA-IR817 was set to "1", and the fluorescence intensities at other concentrations were relative ratios, as shown in FIGS. 3 and 4. As can be seen from FIGS. 3 and 4, when the concentration of IR-817 is below 5. Mu.M, the fluorescence intensity increases with increasing concentration, but when the concentration exceeds 5. Mu.M, the fluorescence is significantly decreased because of aggregation quenching in water with high concentration of IR-817. Compared with BSA-IR817, the fluorescence intensity is stronger than that of IR-817, and the fluorescence is still increased under high concentration, so that the BSA serving as a carrier effectively improves the fluorescence aggregation quenching effect of the IR-817.
Example 3: characterization of basic characteristics of BSA-IR817 nanoparticles
Fig. 5 is a Scanning Electron Microscope (SEM) image of particle size of BSA-IR817, and fig. 6 is a particle size distribution diagram of BSA and BSA-IR817, and it can be seen from fig. 5 and 6 that BSA and IR817 can form uniformly dispersed nanoparticles, and the particle size is 120-220 nm, so that the nanoparticles with the size can generate a better high-permeation long retention (EPR) effect in tumor tissues, and can play a role in the tumor tissues. The Zata potential is a measure of the strength of the mutual repulsion or attraction between particles, the higher its absolute value (positive or negative), the more stable the system is. As can be seen from FIGS. 7 and 8, the absolute value of the Zata potential (-20.95.+ -. 2.15 mV) of BSA@IR-817 is largest compared to BSA (-8.77.+ -. 1.28 mV) and IR-817 (1.485.+ -. 0.05 mV). And the particle size of BSA-IR817 was continuously monitored for 12 days, and no significant change was found. Therefore, the above results indicate that BSA-IR817 nanoparticles are very stable, which is beneficial for further research in vivo.
Example 4: fluorescence contrast of BSA-IR817 with IR817 in vitro and in vivo
First, near infrared fluorescence images were taken under a near infrared imaging system in an EP tube with 10. Mu. MBSA-IR817 and IR817, and as shown in FIG. 9, the fluorescence intensity of BSA-IR817 was significantly higher than that of IR817 by about 6 times. Next, after incubation of BSA-IR817 and IR817 with B16-F10 melanoma cells for different times (0.5,1,2,4,8, 16 hours), the cell uptake capacity was observed under an inverted fluorescence microscope. As shown in FIG. 10, BSA-IR817 begins to fluoresce approximately 4 hours after entering the cell, and is most intense at 8 hours, more intense than IR817. Although IR-817 was able to enter the cells rapidly, fluorescence began to drop significantly after 4 hours, while BSA-IR817 had no significant change in fluorescence at 16 hours. The results show that BSA-IR817 increases both the fluorescence intensity and fluorescence stability of IR817 in cells. Finally, tumor accumulation imaging ability of the comparison BSA-IR817 and IR817 was observed in mice. BSA-IR817 and IR817 (5 mg/kg) were injected subcutaneously into C57BL/6J mice vaccinated with B16-F10 melanoma via tail vein, and fluorescence changes in the comparison tumor sites were observed by taking images at different time points under a small animal in vivo imaging system. As shown in FIG. 11, BSA-IR817 reached maximum accumulation of fluorescence at the tumor site at 6 hours, followed by progressive metabolism of nonspecific accumulation at other sites, but fluorescence at the tumor site remained visible for 24 hours. Although fluorescence was observed at the tumor site even 12 hours after the IR817 was taken in the body, the targeting accumulation ability was lower, the fluorescence was weaker, and the tumor retention time was also shorter than that of BSA-IR817. FIG. 12 is a graph of fluorescence signal relative intensity at tumor sites over time, further illustrating good imaging of BSA-IR817 in vivo and tumor targeting accumulation capacity.
Example 5: in vivo and in vitro temperature changes of BSA-IR817 and IR817 under irradiation of laser 808
First, BSA-IR817 and IR817 having the same concentration of 20. Mu.M were placed in an EP tube, respectively, and laser 808 (power 1W/cm was used 2 ) And monitoring the temperature change by using an infrared thermal imager after irradiation for different times. The temperature change curve is shown in FIG. 13, the temperature of BSA-IR817 increases rapidly under laser irradiation, the temperature increases by 27.6℃at the maximum in 5 minutes, and IR-817 increases by 15.9℃only. FIG. 14 shows the BSA-IR817 concentration at the laser 808 (power 1W/cm) 2 ) The temperature change after irradiation showed that the highest temperature change range increased with increasing concentration of BSA-IR817.
The photo-thermal effects explored in vitro were confirmed by the photo-thermal changes of BSA-IR817 in vivo in B16-F10 melanoma subcutaneous tumor-bearing mice. After injection of 5mg/kg BSA-IR817 and IR8176 hours or 12 hours, respectively, via the tail vein, laser 808 (power 1W/cm) 2 ) The irradiation was carried out for 5 minutes, and the temperature change was recorded every 30 seconds. As can be seen from fig. 15, which is an infrared thermogram of the mice after 5 minutes of irradiation, the temperature of the tumor region significantly increased. FIG. 16 shows a specific temperature profile of BSA-IR817 at various concentrations, which can rise in vivo up to 52.3℃which is fatal to tumor cells. In summary, BSA-IR817 is an ideal photothermal therapeutic agent having a good photothermal effect both in vivo and in vitro.
Example 6: BSA-IR817 significantly reduces the toxicity of IR-817 but significantly kills tumor cells after laser irradiation
A375, B16-F10 melanoma cells were inoculated into 96-well plates, incubated for 24 hours with different concentrations of BSA-IR817, and cell activity was detected with MTT reagent. As shown in FIG. 17, even at a high concentration of 80. Mu.M, the cell activity was about 60%, indicating that BSA-IR817 significantly reduced the toxicity of IR-817. When BSA-IR817 was incubated with cells for 6 hours, laser irradiation was performed (power 1W/cm 2 ) After a further incubation period of 24 hours for 5 minutes, it can be seen from FIG. 18 that the cell activity can be reduced by 80-90% in the low concentration range. Indicating the great photothermal potential of BSA-IR817.
Example 7: evaluation of the effects of BSA-IR817 photothermal treatment in mice
By subcutaneous inoculation of B16-F10 cells (4X 10) 8 Individual/individual) to right buttocks of the mice to construct a melanoma mouse model until the tumor grows to 50-100mm 3 The mice were randomly divided into 6 groups, namely Control (PBS injection), laser (Laser 808 irradiation after PBS injection), IR-817, BSA-IR817, IR-817+laser, BSA-IR817+laser, and 8-9 mice each. The administration mode is as follows: tail vein injection; IR-817 and BSA-IR817 drug doses: 4mg/kg, 200. Mu.L/kg; frequency of: 1 time every day. Wherein the irradiation time of the Laser 808 in the IR-817+Laser group is 8 hours after the tail vein administration, and the irradiation power of the BSA-IR817+Laser group is 1.6W/cm after the tail vein administration for 6 hours 2 And 5 minutes. The body weight of the mice was recorded every 2 days, and the tumor volume was measured. Tumor volume (mm) 3 ) =0.5×long diameter×short diameter 2 . The survival rate of each group of mice was recorded simultaneously when the tumor volume of the mice was greater than 2000mm 3 And determining that the patient is dead.
Fig. 19, 20 and 21 are tumor solid, tumor growth curve and tumor weight statistics of mice of different treatment groups, respectively. As can be seen from FIGS. 19-21, BSA-IR817 can only slightly inhibit tumor growth, and the growth of tumors can be effectively inhibited by photothermal treatment of BSA-IR817 after irradiation of laser 808, and the inhibition rate can reach more than 99%. Meanwhile, the inventors found that the body weight of the mice injected with BSA-IR817 is dead about 7 days after administration due to the large toxicity of IR-817, but the body weight of the mice injected with BSA-IR817 is not obviously different from that of the mice injected with BSA-IR817 (as shown in figure 22), which shows that the biological safety of the BSA-IR817 is extremely high, and the toxic and side effects of the IR-817 are greatly weakened. From the 18-day-recorded growth curves, mice in the groups other than the BSA-IR817+Laser group were also found to survive, and the remaining groups were gradually dying (as shown in FIG. 23).
Example 8: hemolysis experiment to evaluate the biocompatibility of BSA-IR817
Taking mouse venous blood into an anticoagulant tube, preparing BSA-IR817 with different concentrations into an EP tube, and simultaneously taking PBS as a negative control, H 2 O is a positive control. To each of them, 20. Mu.L of fresh venous blood of the mice was added, mixed well, left to stand for 24 hours, and then put in a centrifuge at 2000rpmAfter centrifugation for 5 minutes, the EP tube was removed and photographed. When the supernatant liquid after centrifugation was red, it was found that hemolysis occurred. Finally, the supernatant liquid is sucked into a 96-well plate, and absorbance at 542 nanometers is detected under an enzyme label instrument. The calculation formula of the hemolysis rate:
hemolysis ratio (%) = [ OD (sample) -OD (PBS group)]/[OD(H 2 O) -OD (PBS group)]
As shown in FIG. 24, BSA-IR817 hardly caused hemolysis, indicating that BSA-IR817 has high biosafety.
In summary, the invention discloses an albumin-near infrared fluorescent dye nanoparticle, a preparation method and application thereof, and in particular discloses application of albumin and a novel near infrared dye IR817 after covalent bonding into nanoparticles in imaging diagnosis and photothermal treatment of tumors. The albumin-IR 817 nanoparticle uses bovine serum albumin as a carrier, and the IR817 is adsorbed in the carrier through hydrophobic force, so that the nanoparticle with uniform dispersion and stable structure is formed, and the particle size of the nanoparticle is 120-220 nanometers. The invention not only overcomes the defects of poor water solubility, fluorescence aggregation quenching, toxic and side effects and the like of IR817, but also improves the absorption spectrum and fluorescence emission spectrum of the infrared fluorescent dye in the near infrared region, and has stronger fluorescence in the visible light range. Meanwhile, the invention can effectively convert fluorescence into heat energy for photothermal treatment by combining laser 808 irradiation while reducing the toxicity of IR817. Therefore, the albumin-IR 817 nanoparticle has great application and popularization potential in imaging diagnosis and photothermal treatment.
So far, those skilled in the art will recognize that while embodiments of the present invention have been shown and described in detail herein, many other variations or modifications that are in accordance with the principles of the present invention may be directly ascertained or inferred from the present disclosure without departing from the spirit and scope of the present invention. Accordingly, the scope of the present invention should be understood and deemed to cover all such other variations or modifications.
Claims (6)
1. An albumin-near infrared fluorescent dye nanoparticle, characterized in that the nanoparticle comprises bovine serum albumin and a near infrared fluorescent dye IR817, wherein the bovine serum albumin is used as a carrier of the near infrared fluorescent dye IR817, and the IR817 is adsorbed in the bovine serum albumin carrier through hydrophobic acting force to form the albumin-near infrared fluorescent dye nanoparticle; the mole ratio of bovine serum albumin to IR817 is 1-3:1, a step of; the molecular weight of the bovine serum albumin is 60-70kDa; the molecular weight of the IR817 is 1176.9Da; the particle size of the albumin-IR 817 nanoparticle is 120-220 nanometers; the structural formula of the IR817 is as follows:
the preparation method of the albumin-near infrared fluorescent dye nanoparticle comprises the following steps:
step S1: dissolving bovine serum albumin in phosphate buffer to obtain phosphate buffer solution of bovine serum albumin, and dissolving IR817 powder in dimethyl sulfoxide solution to obtain stock solution of IR 817;
step S2: mixing phosphate buffer solution of bovine serum albumin prepared in the step S1 with IR817 liquid storage, shaking in a water bath constant temperature shaker at 60 ℃ for 2-4 hours in a dark place, transferring to a dialysis bag for dialysis, centrifuging to obtain supernatant, and placing in a freeze-drying cup overnight;
step S3: the mixture obtained in the step S2 is placed in a freeze dryer for freeze drying the next day, and albumin-IR 817 nanoparticle freeze-dried powder is obtained;
the mole ratio of bovine serum albumin to IR817 in the step S1 is 1-3:1.
2. the method for preparing albumin-near infrared fluorescent dye nanoparticles according to claim 1, wherein the dialysis bag has a molecular weight cutoff of 2.0K MWCO, the dialysate is deionized water, and the dialysis time is 24-36 hours in step S2.
3. The method for preparing albumin-near infrared fluorescent dye nanoparticles according to claim 1, wherein the step S2 is carried out overnight at-20 ℃ in a freeze-drying cup.
4. The method for preparing albumin-near infrared fluorescent dye nanoparticles according to claim 1, wherein the step S3 is carried out in a freeze dryer for freeze drying for 20-40 hours to obtain albumin-IR 817 nanoparticle freeze-dried powder.
5. Use of albumin-near infrared fluorescent dye nanoparticles prepared by the preparation method of any one of claims 2-4 in the preparation of a medicament for tumor imaging diagnosis and/or tumor photothermal treatment.
6. The use of an albumin-near infrared fluorescent dye nanoparticle according to claim 5, wherein the tumor is melanoma.
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