CN114601925B - Hyaluronic acid and RSL3 co-modified photosensitive nanomaterial, preparation method and application thereof - Google Patents
Hyaluronic acid and RSL3 co-modified photosensitive nanomaterial, preparation method and application thereof Download PDFInfo
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- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
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Abstract
The invention relates to the technical field of biomedical nano materials, in particular to a photosensitive nano material jointly modified by hyaluronic acid and RSL3, a preparation method and application thereof, and solves the problems that the existing nano material carrying a photosensitizer has biotoxicity, complex preparation process, poor uniformity of the material, low light absorption efficiency of the material, poor capability of generating active oxygen and the like. The material is composed of an iron death medicament RSL3, a photosensitive nano material FeTBP and hyaluronic acid, wherein the iron death medicament RSL3 is carried in the photosensitive nano material FeTBP, and the hyaluronic acid is coated on the outer layer of the photosensitive nano material FeTBP carrying the iron death medicament RSL3. Iron death and PDT are combined to synergistically promote ROS, just like a powerful ROS engine, for accurate targeting and efficient tumor treatment. The preparation is completed by adding a photosensitive nanomaterial FeTBP solution and an iron death drug RSL3 solution into the hyaluronic acid solution.
Description
Technical Field
The invention relates to the technical field of biomedical nano materials, in particular to a photosensitive nano material jointly modified by hyaluronic acid and RSL3, a preparation method and application thereof.
Background
Bladder tumors are the most common malignancy of the urinary system, and the eleventh common malignancy in humans worldwide (9.0/10 ten thousand for age-standardized men and 2.2/10 ten thousand for women). Fortunately, most of these (about 75%) patients are non-myotic invasive bladder tumors (NMIBC) that can be preserved by resecting the tumor by transurethral minimally invasive techniques. Transurethral bladder tumor electrotomy (TURBt) is currently still the first line treatment for NMIBC. However, the biological properties of bladder tumors themselves determine that 50-70% of patients will have tumor recurrence within two years after TURBt surgery, not only significantly prolonging the treatment time of the patient, but also severely affecting the prognosis of the patient. More importantly, microscopic tumor lesions, such as Carcinoma In Situ (CIS), which are not visible for cystoscopy, cannot be resected effectively, and these microscopic lesions play a very important role in tumor recurrence.
Photodynamic therapy (photodynamic therapy, PDT) is a technique for treating diseases using photodynamic reactions. The photosensitizer is selectively absorbed by tumor cells, and after the photosensitizer is irradiated by excitation light with specific wavelength, the photosensitizer can absorb energy of laser, and is converted into an excited state from a ground state, when the photosensitizer is converted into the ground state from an unstable excited state, the photosensitizer can transfer the energy to oxygen molecules around the cells to generate a large amount of Reactive Oxygen Species (ROS), so that the cells die, and the purpose of treating tumors is achieved. PDT has some significant advantages over traditional therapeutic approaches, especially its minimally invasive and space-time controllable nature, with greatly reduced side effects. In addition to the direct killing mechanism, PDT can also cause other therapeutic effects in target tissues, including vascular injury and immune activation. However, photosensitizers are not ideal because of their low absorbance at the wavelengths of commonly used lasers. In addition, the tumor microenvironment (tumor microenvironment, TME) and rapid oxygen consumption during PDT significantly affect its anti-tumor efficacy. More importantly, apoptosis is the primary pathway of PDT-induced cell death, and some refractory tumors are resistant to apoptosis. Thus, for refractory tumors, metastatic tumors, etc., PDT can be combined with a complementary therapeutic modality for the purpose of complete eradication.
Iron death (ferroptosis) is a newly discovered mode of programmed cell death in recent years that is different from apoptosis and necrosis. It is mainly through inactivation of the antioxidant enzyme glutathione peroxidase 4 (GPX 4), causing intracellular lipid peroxide accumulation, causing disruption of the cytoplasmic membrane and ultimately leading to cell death. This process is termed iron death because it requires the participation of iron ions. Various research results prove that the induction of iron death can obviously inhibit the proliferation of tumors in vivo and in vitro, and especially drug-resistant and apoptosis-resistant tumor cells are sensitive to the iron death inducer. Furthermore, epithelial-mesenchymal transformed tumor cells that are susceptible to metastasis are also susceptible to iron death due to alterations in lipid metabolism and oxidative stress. The induction of cell iron death is a promising method, which can avoid cell apoptosis paths and improve the treatment effect of PDT. Thus, combining PDT and iron death can complementarily synergistically inhibit tumor cell growth by generating multiple ROS sources, and can be a very effective combination therapy.
In recent years, nanomaterials have received increasing attention for tumor PDT. The nanometer material is used for carrying the photosensitizer, so that the stability and targeting property of the photosensitizer can be obviously improved, and the defects of weak targeting property and low bioavailability of the photosensitizer when the photosensitizer is directly applied are overcome. The modified nanomaterial may perform multiple biological functions, such as: PDT, photothermal therapy, immune activation, chemotherapy, radiation therapy, and tumor microenvironment remodeling, etc., this effect is incomparable for clinically common small molecule photosensitizer-mediated PDT.
Currently, many nanostructures such as gold nanoparticles, mesoporous silica nanoparticles, carbon nanotubes, graphene, fullerenes, etc. have been used as photosensitizers for modification. In general, the nanomaterial will carry a photosensitizer and a chemotherapeutic agent, an immune activator or a protein inhibitor to achieve the combination therapy of PDT and other therapeutic means, and simultaneously improve biocompatibility and targeting by surface modification of a water-soluble polymer. Second, some nanomaterials may focus on improving the deficiencies of PDT itself, such as: improving the hypoxic environment of tumor, enhancing PDT, enhancing optical properties of material, being excited by near infrared light (NIR), enhancing active oxygen generation, and enhancing fluorescence diagnosis. However, current material designs suffer from a number of disadvantages: (1) the biotoxicity caused by doping of a plurality of metal elements is to be solved (2) the uniformity of the material is poor due to the complex preparation process (3) the absorption efficiency of the material under the irradiation of laser with specific wavelength is low, the capability of generating active oxygen is low (4) the required laser irradiation power is often high, and side effects during treatment, such as skin burn caused by photo-thermal effect, and the like, can be caused.
The metal-organic framework (MOF) is a novel organic-inorganic hybrid crystalline porous material, and compared with the traditional material, the metal-organic framework (MOF) has the characteristics of larger pores, high porosity, larger surface area and the like, which are beneficial to improving the efficiency of loading small molecular medicines, and has the characteristics of easy functional modification, good biocompatibility, biodegradability, water solubility and the like. More importantly, the photoactive material can be used as an organic ligand for the synthesis of the organic framework of MOFs, and thus, MOFs themselves can be used as photoactive materials for PDT. The MOF is used as a photosensitizer and an iron death drug carrying platform, so that the combined treatment of PDT and iron death can be realized, and meanwhile, the MOF can be irradiated by laser with short wavelength and shallower penetration of 450nm, so that a stronger PDT effect can be generated compared with the traditional near infrared laser, and the MOF has a very good application prospect for treating superficial tumors such as non-myogenic invasive bladder tumors, skin cancers, cervical cancers and the like.
Disclosure of Invention
The invention aims to provide a photosensitive nanomaterial jointly modified by hyaluronic acid and RSL3, a preparation method and application thereof, and solve the problems that the existing nanomaterial carrying a photosensitizer has biotoxicity, complex preparation process, poor uniformity of the material, low light absorption efficiency of the material, poor capability of generating active oxygen and the like.
The technical scheme of the invention is to provide a photosensitive nanomaterial modified by hyaluronic acid and RSL3, which is characterized in that: the iron death medicine RSL3 is carried in the photosensitive nano material FeTBP, and the hyaluronic acid is coated on the outer layer of the photosensitive nano material FeTBP carrying the iron death medicine RSL3.
Further, both hyaluronic acid and iron death drug RSL3 are bound to FeTBP by electro-electrostatic adsorption.
The invention also provides a preparation method of the photosensitive nanomaterial jointly modified by hyaluronic acid and RSL3, which is characterized by comprising the following steps:
step 1, preparing a photosensitive nano material FeTBP;
step 2, under ultrasonic treatment, adding a photosensitive nano material FeTBP solution and an iron death drug RSL3 solution into a hyaluronic acid solution, and stirring the mixed solution in the dark at room temperature for a set time;
step 3, carrying out liquid-solid separation on the reaction liquid in the step 2, collecting precipitate and washing with water; and drying to obtain the final novel photosensitive nanomaterial HAFeR jointly modified by hyaluronic acid and RSL3.
Further, the step 1 specifically includes the following steps:
step 1.1, preparation of Fe 3 O(OAc) 6 (H 2 O) 3 (OAc)；
Fe (NO) 3 ) 3 ·9H 2 O and CH 3 CO 2 Na·3H 2 Grinding O into paste in a mortar, dissolving the paste in methanol, transferring to a round bottom flask, refluxing and stirring for 12 hours; filtering the reaction mixture and standing for crystallization to obtain Fe 3 O(OAc) 6 (H 2 O) 3 (OAc)；
Step 1.2, preparing a photosensitive nanomaterial FeTBP;
fe is added to 3 O(OAc) 6 (H 2 O) 3 (OAc) solution, H 4 The TBP solution and formic acid were mixed and the reaction mixture was kept in an 80 degree oven for 24 hours; the violet precipitate was collected by centrifugation and washed with DMF and ethanol; finally, drying at room temperature to obtain FeTBP.
Further, in step 2:
the photosensitive nano material FeTBP solution is DMF solution of the photosensitive nano material FeTBP, and the concentration of the photosensitive nano material FeTBP solution is 50mg/mL;
the iron death medicine RSL3 solution is DMF solution of the iron death medicine RSL3, and the concentration of the iron death medicine RSL3 solution is 2mM;
the hyaluronic acid solution is double distilled water solution of hyaluronic acid, and the concentration of the hyaluronic acid solution is 2mg/mL;
the volume ratio of the photosensitive nano material FeTBP solution to the iron death drug RSL3 solution to the hyaluronic acid solution is as follows: 10:1:500.
Further, in step 1.1:
Fe(NO 3 ) 3 ·9H 2 o and CH 3 CO 2 Na·3H 2 The molar ratio of O is 1:2;
in step 1.2:
Fe 3 O(OAc) 6 (H 2 O) 3 (OAc) solution of Fe 3 O(OAc) 6 (H 2 O) 3 DMF solution of (OAc), fe 3 O(OAc) 6 (H 2 O) 3 (OAc) the concentration of the solution was 2.2mg/mL;
H 4 TBP solution is H 4 DMF solution of TBP, H 4 The concentration of the TBP solution is 1.32mg/mL;
Fe 3 O(OAc) 6 (H 2 O) 3 (OAc) solution, H 4 The volume ratio of TBP-DMF solution to formic acid is: 5:5:1.
the invention also provides an application of the hyaluronic acid and RSL3 co-modified photosensitive nanomaterial in preparing a medicine for treating tumors.
Further, the treatment is a disease treatment method using photodynamic therapy or using photodynamic therapy in combination with other treatment means.
Further, the tumor is a non-myogenic invasive bladder tumor.
Further, the upper photodynamic therapy uses 450nm laser irradiation.
The invention also provides a medicine for treating tumors, which is characterized by comprising the photosensitive nanomaterial modified by hyaluronic acid and RSL3.
Further, the tumor is a non-myogenic invasive bladder tumor.
The beneficial effects of the invention are as follows:
1. the HAFeR designed by the invention is of MOF type structure, and firstly, the HAFeR is enriched at a tumor site and selectively internalized into tumor cells through enhanced biocompatibility and specific targeting capacity mediated by an HA-CD44 receptor. Second, when receptor-mediated endocytosis occurs, the acidic lysosomal environment can cause HAFeR degradation while releasing ferrous ions in the framework structure and the onboard RSL3. Both will significantly amplify oxidative stress in the cell by increasing the accumulation of lipid peroxides. In particular, RSL3 can directly inhibit the activity of GPX4, a key enzyme that regulates redox homeostasis. On the other hand, ferrous ions can synergistically promote the inhibiting effect of RSL3. Meanwhile, the released ferric ions can be used as a bionic nano catalyst to carry out H 2 O 2 Conversion to O 2 To relieve tumor hypoxia. Due to high concentration of H in Tumor Microenvironment (TME) 2 O 2 (50-100. Mu.M) environment, this oxygen production effect can be maintained for a long period of time to enhance the therapeutic effect of PDT. Finally, HAFeR can produce oxygen independent type I and oxygen dependent type II PDT under 450nm laser irradiation, exhibiting excellent killing properties. Exquisite TME-regulatable HAFeR provides a promising therapeutic strategy that combines iron death with PDT to synergistically promote ROS, just like a powerful ROS engine, for accurate targeting and efficient tumor treatment.
2. FeTBP can be used as an exogenous iron source to promote the killing effect of RSL3, so that the dosage of RSL3 in vivo can be reduced, and the toxicity of RSL3 is reduced;
3. the preparation process of the FeTBP is simple, and the electron microscope result of the FeTBP shows that the material has good uniformity, uniform morphology and characteristics, presents rice grains, has smooth surface and basically has the size of about 350 nm;
4. the FeTBP material has high absorption efficiency on 450nm laser and strong capability of generating active oxygen; compared with the near infrared laser and the infrared laser which are commonly used at present, the laser irradiation power is higher, and side effects caused by the higher laser irradiation power are avoided.
Drawings
FIG. 1A is a transmission electron microscope image of FeTBP, HAFe and HAFeR; scale bar = 100nm.
FIG. 1B is a scanning transmission electron microscope and element mapping image of HAFeR; scale bar = 200nm.
FIG. 1C shows HAFeR (200. Mu.g/mL) at 450nm with laser irradiation (30 mW/cm) 2 15 minutes) TEMP +. 1 O 2 Electron paramagnetic resonance spectrum of (a) is provided.
FIG. 1D shows HAFeR (200. Mu.g/mL) at 450nm with laser irradiation (30 mW/cm 2 15 minutes) electron paramagnetic resonance spectrum of DMPO/.oh.
FIG. 1E shows the laser irradiation of HAFeR at 450nm (30 mW/cm 2 1 minute) using SOSG detection 1 O 2 (n=3).
FIG. 1F shows the laser irradiation of HAFeR at 450nm (30 mW/cm 2 1 minute) was measured for the formation of OH using APF (n=3).
FIG. 1G shows the laser irradiation of HAFeR at 450nm (30 mW/cm 2 1 min) total ROS production was detected using DPBF (n=3).
FIG. 1H is a schematic diagram of the use of ROSGreen TM Detection of different concentrations of HAFeR consumption H 2 O 2 (n=3).
FIG. 1I shows the detection of HAFeR at different concentrations by laser irradiation at 450nm (30 mW/cm 2 15 minutes) of GSH consumption capacity.
FIG. 1J is a graph of time-dependent O of HAFeR detection by an oximeter 2 And (3) generating.
* p <0.05, < p <0.01, < p <0.001 and p <0.0001.
Fig. 2A shows cell viability (n=4) of 253J cells after 24h incubation with 200nm RSL3 with different concentrations of FeTBP.
FIG. 2B shows 5637 cells incubated with FeTBP, HAFe and HAFeR (25 or 50. Mu.g/mL) for 4 hours with 450nm laser irradiation (30 mW/cm 2 15 minutes) cell viability after this. (n=3).
FIG. 2C is an Annexin-V/PI double staining apoptosis assay for 5637 cells by flow cytometry after the same treatment described in (B).
FIG. 2D is a photograph of a dead-living stain of Calcein-AM and PI after various treatments. Scale bar = 200 μm.
FIG. 2E shows the incubation of 5637 cells with different concentrations of HAFeR for 4 hours with laser irradiation at 450nm or 630nm (30 mW/cm 2 10 minutes) cell viability assay. (n=3).
FIG. 2F shows incubation of HAFeR and 5637 cells at different concentrations for 4 hours under anaerobic and normoxic conditions with laser irradiation at 450nm (30 mW/cm 2 10 minutes) cell viability assay. (n=3).
* p <0.05, < p <0.01, < p <0.001 and p <0.0001.
FIG. 3 shows the in vivo antitumor activity of HAFeR. (A) Total ROS production in tumor tissue was detected using DCFH-DA fluorescent probe. (B) Representative photographs of different groups of anatomical tumors at the end of the experiment. (C) tumor growth curves for all groups. (D) Weight statistics of tumors collected at the end of the experiment.
Detailed Description
So that the manner in which the above recited objects, features and advantages of the present invention can be understood in detail, a more particular description of the invention, briefly summarized above, may be had by reference to the embodiments, some of which are illustrated in the appended drawings. All other embodiments, which can be made by one of ordinary skill in the art based on the embodiments of the present invention without making any inventive effort, shall fall within the scope of the present invention.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the specific embodiments disclosed below.
According to the invention, an iron death drug RSL3 is loaded into a photosensitive nanomaterial FeTBP, and Hyaluronic Acid (HA) is modified on the outer layer of the FeTBP, so that a novel photosensitive nanomaterial which is more biocompatible, targeted and killing effective for non-muscular-layer invasive bladder tumors is formed. Wherein hyaluronic acid and iron death medicine RSL3 are combined on FeTBP through electronic electrostatic adsorption, wherein macromolecular hyaluronic acid is coated on the surface of FeTBP, and meanwhile, the porous internal structure provides a good carrying platform for the iron death medicine RSL3. The whole structure takes FeTBP as the main component, the proportion of hyaluronic acid and iron death medicine RSL3 is small, the mass of hyaluronic acid is about 1.57% of the whole mass, RSL3 is a small molecular medicine, and the input mass is in microgram level.
Example 1: preparing and characterizing a photosensitive nano material HAFeR jointly modified by hyaluronic acid and an iron death drug RSL 3;
the photosensitive nanomaterial co-modified by hyaluronic acid and iron death drug RSL3 is prepared through the following steps:
step 1), fe preparation 3 O(OAc) 6 (H2O) 3 (OAc). Fe (NO) 3 ) 3 ·9H 2 O (10 mmol,4.04 g) and CH 3 CO 2 Na·3H 2 O (20 mmol,2.72 g) was ground to a paste in a mortar, then the orange paste was dissolved in methanol (30 mL) and transferred to a round bottom flask with stirring at reflux for 12 hours. Filtering the reaction mixture and standing for crystallization;
step 2), preparing FeTBP. Into a 4mL glass vial was added 0.5mL Fe 3 O(OAc) 6 (H2O) 3 (OAc) solution [2.2mg/mL, dissolved in N, N-Dimethylformamide (DMF)]、0.5mL H 4 TBP solution [1.32mg/mL dissolved in DMF]And 100. Mu.L formic acid. The reaction mixture was kept in an 80 degree oven for 24 hours. The violet precipitate was collected by centrifugation (15000G) for 15 min and washed with DMF and ethanol. Finally, feTBP is prepared by drying at room temperature;
step 3), preparing the final product HAFeR. 4mg of sodium hyaluronate was dissolved in 2mL double distilled water to prepare a hyaluronic acid solution (2 mg/mL) and transferred to a 20mL glass bottle. 40. Mu.L of FeTBP (50 mg/mL, DMF) and 4. Mu.L of RSL3 (2 mM, DMF) were added under sonication for 5 minutes. The mixed solution was then stirred at room temperature in the dark for 24 hours. The precipitate was collected by centrifugation (15000G) and washed with water. The final HAFeR was obtained by lyophilization.
FIGS. 1A-1J are characterization graphs of HAFeR, and it can be seen from FIGS. 1A and 1B that HAFeR is prepared as a rice-grain nanoparticle with a size of about 350 nm.
FIGS. 1C-G respectively demonstrate that HAFeR can produce significant singlet oxygen 1 O 2 ) And hydroxyl radicals (. OH), which are two different active oxygen species.
1. Detection using electron paramagnetic resonance spectroscopy 1 O 2 And OH production;
2, 6-tetramethyl-4-piperidone (TEMP) and 5, 5-dimethyl-1-pyrroline-N-oxide (DMPO) are respectively selected as capturing agents to identify singlet oxygen 1 O 2 ) And hydroxyl radicals (. OH). Specifically, 200 μg of HAFeR was dispersed in 2mL of PBS and mixed with 20 μl of TEMP or dispersed in 2mL of absolute ethanol and dissolved in H 2 O 2 (100. Mu.M) was mixed with 10. Mu.L of DMPO in the presence of a laser of 450nm (30 mW/cm) 2 ) Irradiating for 15 minutes. Characteristic peak signals were immediately detected using an ESR spectrometer. The laser non-irradiated group and HAFeR-free solution group were set as controls. As can be seen from FIGS. 1C and 1D, HAFeR can be produced by irradiation with 450nm laser 1 O 2 And OH.
2. Singlet oxygen [ ] 1 O 2 ) Is detected;
detection using SOSG (singlet oxygen sensor green) 1 O 2 HAFeR (2 mL) at various concentrations was mixed with SOSG (2. Mu.L, 5 mM) in PBS, followed by laser light at 450nm (30 mW/cm) 2 ) The liquid was irradiated for 60 seconds. 100. Mu.L of the liquid was taken out every 15 seconds, and the fluorescence intensity at 530nm was recorded, with an excitation wavelength of 488nm. The laser non-irradiated group and HAFeR-free solution group were set as controls. From FIG. 1EAs can be seen (ordinate is the ratio of the fluorescence intensity F1 of the treatment group to the fluorescence intensity F0 of the control group), HAFeR can be generated after irradiation with a laser of 450nm 1 O 2 And the higher the HAFeR concentration, the more 1 O 2 The greater the amount of (2); the longer the irradiation time at the same concentration, the more 1 O 2 The greater the amount of (2).
3. Detection of hydroxyl radicals (·oh);
hydroxyl radical OH was detected using APF (aminophenyl fluorescein). HAFeR (2 mL) at various concentrations was mixed with APF (2. Mu.L, 5 mM) in PBS, followed by a 450nm laser (30 mW/cm) 2 ) The liquid was irradiated for 60 seconds. 100. Mu.L of the liquid was taken out every 15 seconds, and the fluorescence intensity at 515nm was recorded, and the excitation wavelength was 488nm. The laser non-irradiated group and HAFeR-free solution group were set as controls. As can be seen from fig. 1F, HAFeR can generate OH after irradiation with 450nm laser, and the higher the HAFeR concentration, the more amount of generated OH; the longer the irradiation time, the more OH is generated at the same concentration.
4. Detecting the total ROS production;
total ROS production was detected using the following method. DPBF (1, 3-diphenoxyzofuran) is susceptible to oxidation by ROS, resulting in a decrease in its absorption at 415 nm. In the experiment, different concentrations of HAFeR (2 mL) were mixed in PBS with DPBF dissolved in ethanol (20 μl,10 mM) and continuously shaken. Then using 450nm laser (30 mW/cm) 2 ) The liquid was irradiated for 60 seconds. 100 μl was taken every 15 seconds and the absorbance of DPBF at 415nm was recorded. The laser non-irradiated group and HAFeR-free solution group were set as controls. As can be seen from FIG. 1G (the ordinate in the figure is the absorption intensity A of the treatment group) 1 Absorption intensity A from control group 0 Ratio of (2) of HAFeR to a laser of 450 nm) to generate ROS. The higher the HAFeR concentration, the greater the amount of total ROS produced; the longer the irradiation time, the greater the amount of total ROS produced at the same concentration.
FIGS. 1H-1J demonstrate that HAFeR has the ability to deplete antioxidant GSH and deplete H in vivo 2 O 2 Oxygen generation function.
1. With RosGreen H 2 O 2 Detection of extracellular H by probes 2 O 2 ；
HAFeR (1 mL) was combined with RosGreenH at various concentrations 2 O 2 The probe (2. Mu.L, 5 mM) was mixed in PBS and the liquid was then taken up in 100. Mu. M H 2 O 2 Treatment is carried out for 4 hours. Finally, 100. Mu.L of the mixture was taken out, and the fluorescence intensity at 515nm was recorded, with an excitation wavelength of 488nm. PBS group and H 2 O 2 The groups served as negative and positive controls, respectively. As can be seen from FIG. 1H, HAFeR can degrade H 2 O 2 . The higher the HAFeR concentration, the degradation of H 2 O 2 The greater the amount of (2).
2. Detecting extracellular GSH using a GSH detection kit;
HAFeR (2 mL) at various concentrations was mixed with GSH (final concentration 100. Mu.g/mL) in PBS, followed by laser light at 450nm (30 mW/cm) 2 ) The liquid was irradiated for 15 minutes. Thereafter, the supernatant was collected by centrifugation (15000G) and the GSH content in the supernatant was measured according to the procedure of the cartridge instructions. As can be seen from fig. 1I, HAFeRPDT produced active oxygen can consume antioxidant GSH, and the higher the HAFeR concentration, the more GSH is consumed.
3. Detecting the production of oxygen.
To study degradation of intracellular H by HAFeR 2 O 2 And oxygen generating capacity, H 2 O 2 (100. Mu.M) was incubated with HAFeR (50. Mu.g/mL) in PBS and then dissolved O was measured with an oximeter every 5 minutes 2 Concentration was monitored for 1 hour. As can be seen from FIG. 1J, HAFeR has catalase activity and can degrade H 2 O 2 Production of O 2 。
Example 2: intracellular synergistic PDT and iron death killing effects of hyaluronic acid and RSL3 co-modified photosensitive nanomaterial HAFeR;
in order to prove that FeTBP can be used as exogenous iron to promote the killing effect of RSL3, in the embodiment, feTBP with different concentrations is incubated with 200nM RSL3, after 253J cells are treated for 24 hours, cell viability is observed (n=4), and the result is shown in fig. 2A, it can be seen from the graph that when pure FeTBP and RSL3 treat cells, the cell activity is not influenced, when the pure FeTBP and the RSL3 are incubated together, the killing effect of the RSL3 is obviously improved, and the killing of the RSL3 has the concentration dependence characteristic of the FeTBP; the FeTBP can be used as exogenous iron to promote the killing effect of RSL3, so that the dosage of RSL3 in vivo can be reduced, and the toxicity of RSL3 is reduced.
To demonstrate the successful preparation of the final material HAFeR and its more pronounced killing effect compared to the initial material FeTBP and the mere coating of hyaluronic acid, the intermediate material HAFe without RSL3 was incubated with FeTBP, HAFe and HAFeR (25 or 50. Mu.g/mL) for 4 hours in this example with 5637 cells incubated with or without 450nm laser irradiation (30 mW/cm 2 15 minutes), the cell viability was checked. The results are shown in fig. 2B to 2D, from which it can be seen that FeTBP and HAFe show negligible dark cytotoxicity. In contrast, HAFeR containing similar concentrations of RSL3 showed moderate cell mortality (25.3% and 39.2%) as self-supplementation of exogenous iron promoted iron death of RSL3. HAFe shows a higher PDT efficiency compared to FeTBP after 15 min of 450nm laser irradiation, due to enhanced cellular uptake mediated by hyaluronic acid (22.1% and 33.7% versus 49.6% and 59.0%). HAFeR showed the most pronounced killing (77.4% and 86.5%) due to the synergistic effect of PDT with iron death (fig. 2B). Furthermore, apoptosis assays after different MOF treatments and irradiation demonstrated this killing trend, indicating that HAFeR has the strongest ability to induce apoptosis in tumor cells (fig. 2C). The calcein-AM (green, living cells) and propidium iodide (red, dead cells) double staining assays also showed similar results. The results demonstrate that HAFeR has a better killing capacity than the initial material FeTBP and the intermediate material HAFe.
To demonstrate that the 450nm laser has better PDT effect than the commonly used near infrared 630nm laser, the experimental example was incubated with HAFeR at different concentrations with 5637 cells for 4 hours, irradiated with either 450nm or 630nm laser (30 mW/cm 2 10 minutes) cell viability was measured. (n=3). The results are shown in FIG. 2E, where 450nm laser-mediated PDT killing is significantly better than 630nm laser.
In order to prove that HAFeR still has good PDT killing effect in an anoxic environment, the experimental example uses HAFe with different concentrations in the anoxic environment and the normoxic environmentR was incubated with 5637 cells for 4 hours, irradiated with a laser at 450nm (30 mW/cm 2 10 minutes) cell viability was measured. (n=3). As shown in FIG. 2F, the effect of 450nm laser-mediated PDT in hypoxic environments is not significantly different from that in normoxic environments.
Example 3: in vivo antitumor activity of the photosensitive nanomaterial HAFeR co-modified by hyaluronic acid and RSL 3;
in order to prove the killing effect of HAFeR in a small animal tumor model, the embodiment constructs a MB49 mouse subcutaneous tumor model until the tumor volume is increased to 75-150mm 3 Mice were randomly divided into experimental groups (8 per group) of: (I) Saline +450nm laser irradiation, (II) RSL3, (III) HAFeR, (IV) FeTBP +450nm laser irradiation, (V) HAFeR +450nm laser irradiation. On day 0, for the RSL3 and HAFeR groups, 100. Mu.L of RSL3 (12. Mu.M, the same concentration as RSL3 contained in HAFeR) and 3mg/mL of HAFeR saline solution were injected around the tumors of MB49 tumor-bearing mice. In the case of saline+450 nm laser irradiation, feTBP+450nm laser irradiation and HAFeR+450nm laser irradiation groups, saline, feTBP and HAFeR (300. Mu.g FeTBP and HAFeR were dissolved in 100. Mu.L saline) were injected around tumor, and after 4 hours, mice were anesthetized with 2% (v/v) isoflurane, and anesthetized with 450nm laser at 100mW/cm 2 Is irradiated to the tumor for 10 minutes. The mice were covered with a disposable sterile surgical towel with holes (d=1.5 cm) and only the tumor area was exposed to laser irradiation. One mouse was randomly selected and the probe DCFH-DA was used to detect ROS production in tumor tissue following irradiation. Tumor size and mouse body weight were measured every other day after treatment for 14 days (tumor volume= (length x width) 2 )/2。)
Confocal fluorescence images of tumor sections (fig. 3A) showed that high-intensity and broad green fluorescence (+.25-fold) was observed in HAFeR PDT group compared to control group, indicating that a large amount of ROS was generated. As shown in fig. 3B-C, tumor growth was inhibited in the FeTBP and HAFeR PDT groups, whereas mice treated with HAFeR alone had only partially delayed tumor growth in the early stage and had observed rapid growth in the later stage, with no difference in volume from the control group. The average tumor weight (fig. 3D) also demonstrates that HAFeR PDT has the greatest anti-tumor efficacy. From these data, it can be seen that the combined treatment pattern of HAFeR and PDT with 450nm laser irradiation produced a significant amount of ROS in tumor tissue to inhibit tumor growth, whereas neither the unbound RSL3 drug group nor the group not receiving 450nm laser irradiation achieved the most significant treatment.
Claims (12)
1. A photosensitive nanomaterial co-modified with hyaluronic acid and RSL3, characterized in that: the iron death medicament RSL3 is carried in the photosensitive nano material FeTBP, and the hyaluronic acid is coated on the outer layer of the photosensitive nano material FeTBP carrying the iron death medicament RSL 3; the preparation process of the photosensitive nano material FeTBP comprises the following steps: fe is added to 3 O(OAc) 6 (H 2 O) 3 (OAc) solution, H 4 The TBP solution and formic acid were mixed and the reaction mixture was kept in an 80 degree oven for 24 hours; the violet precipitate was collected by centrifugation and washed with DMF and ethanol; finally, drying at room temperature to obtain FeTBP.
2. The photosensitive nanomaterial co-modified with RSL3 and hyaluronic acid according to claim 1, characterized in that: hyaluronic acid and iron death drug RSL3 are both bound to FeTBP by electro-electrostatic adsorption.
3. A method for preparing the photosensitive nanomaterial co-modified with RSL3 by hyaluronic acid according to claim 1 or 2, comprising the steps of:
step 1, preparing a photosensitive nano material FeTBP;
step 2, under ultrasonic treatment, adding a photosensitive nano material FeTBP solution and an iron death drug RSL3 solution into a hyaluronic acid solution, and stirring the mixed solution in the dark at room temperature for a set time;
step 3, carrying out liquid-solid separation on the reaction liquid in the step 2, collecting precipitate and washing with water; and drying to obtain the final photosensitive nanomaterial HAFeR modified by hyaluronic acid and RSL3.
4. The method for preparing a photosensitive nanomaterial co-modified with hyaluronic acid and RSL3 as claimed in claim 3, wherein the step 1 specifically comprises the following steps:
step 1.1, preparation of Fe 3 O(OAc) 6 (H 2 O) 3 (OAc)；
Fe (NO) 3 ) 3 •9H 2 O and CH 3 CO 2 Na•3H 2 Grinding O into paste in a mortar, dissolving the paste in methanol, transferring to a round bottom flask, refluxing and stirring for 12 hours; filtering the reaction mixture and standing for crystallization to obtain Fe 3 O(OAc) 6 (H 2 O) 3 (OAc)；
Step 1.2, preparing a photosensitive nanomaterial FeTBP;
fe is added to 3 O(OAc) 6 (H 2 O) 3 (OAc) solution, H 4 The TBP solution and formic acid were mixed and the reaction mixture was kept in an 80 degree oven for 24 hours; the violet precipitate was collected by centrifugation and washed with DMF and ethanol; finally, drying at room temperature to obtain FeTBP.
5. The method for preparing a photosensitive nanomaterial co-modified with hyaluronic acid and RSL3 according to claim 3, wherein in step 2:
the photosensitive nano material FeTBP solution is DMF solution of the photosensitive nano material FeTBP, and the concentration of the photosensitive nano material FeTBP solution is 50mg/mL;
the iron death medicine RSL3 solution is DMF solution of iron death medicine RSL3, and the concentration of the iron death medicine RSL3 solution is 2mM;
the hyaluronic acid solution is double distilled water solution of hyaluronic acid, and the concentration of the hyaluronic acid solution is 2mg/mL;
the volume ratio of the photosensitive nano material FeTBP solution to the iron death drug RSL3 solution to the hyaluronic acid solution is as follows: 10:1:500.
6. The method for preparing the photosensitive nanomaterial co-modified with hyaluronic acid and RSL3 according to claim 4, wherein in step 1.1:
Fe(NO 3 ) 3 •9H 2 o and CH 3 CO 2 Na•3H 2 The molar ratio of O is 1:2;
in step 1.2:
Fe 3 O(OAc) 6 (H 2 O) 3 (OAc) solution of Fe 3 O(OAc) 6 (H 2 O) 3 DMF solution of (OAc), fe 3 O(OAc) 6 (H 2 O) 3 (OAc) the concentration of the solution was 2.2mg/mL;
H 4 TBP solution is H 4 DMF solution of TBP, H 4 The concentration of the TBP solution was 1.32mg/mL;
Fe 3 O(OAc) 6 (H 2 O) 3 (OAc) solution, H 4 The volume ratio of TBP-DMF solution to formic acid is 5:5:1.
7. use of a photosensitive nanomaterial co-modified with hyaluronic acid according to claim 1 or 2 and RSL3 for the preparation of a medicament for the treatment of tumors.
8. The use according to claim 7, characterized in that: the treatment is a disease treatment method using photodynamic therapy or using photodynamic therapy in combination with other treatment means.
9. The use according to claim 8, characterized in that: the tumor is a non-myogenic invasive bladder tumor.
10. The use according to claim 9, characterized in that: photodynamic therapy uses 450nm laser irradiation.
11. A medicament for treating tumors, which comprises the photosensitive nanomaterial co-modified with RSL3 and hyaluronic acid according to claim 1 or 2.
12. The medicament for treating tumors as claimed in claim 11, wherein: the tumor is a non-myogenic invasive bladder tumor.
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