CN110251672B - Nano diagnosis and treatment agent and preparation method and application thereof - Google Patents
Nano diagnosis and treatment agent and preparation method and application thereof Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
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- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- 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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- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- 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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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a nano diagnosis and treatment agent and a preparation method and application thereof, wherein the nano diagnosis and treatment agent comprises the following components: albumin, sodium porphyrazin adsorbed on the surface of albumin. The nano diagnosis and treatment agent provided by the invention utilizes the strong adsorption effect of albumin and sodium porphyrine (DVDMS) to adsorb a large amount of sodium porphyrine on the surface of albumin, can be produced in large scale, is easy to realize industrialization, and has a good application prospect in the field of tumor diagnosis and treatment.
Description
Technical Field
The invention relates to the field of medical nano materials, in particular to a nano diagnosis and treatment agent and a preparation method and application thereof.
Background
Chemotherapy of tumors is a widely used clinical method, and although the systemic side effects of the drugs are obvious, the chemotherapy still has irreplaceable importance. Paclitaxel (PTX) is considered to be the most elegant natural anticancer drug found so far, and has been widely used clinically for the treatment of breast cancer, ovarian cancer, and partial head and neck cancer and lung cancer. However, a single paclitaxel molecule is not favorable for circulation in blood and delivery to the tumor site, and thus a drug delivery vehicle is required to achieve drug delivery to the tumor.
Photodynamic therapy (PDT) of tumors occurred in the early 20 th century and was the first drug and device combination approved by the FDA 20 years ago. PDT consists of three major factors: photosensitizers (photosenizer, PS), light and oxygen. In clinical practice, the patient is first injected or orally administered the photosensitizer and then given light of a specific wavelength at the site of the lesion to activate the photosensitizer. The activated photosensitizer transfers the energy of light to molecular oxygen, producing Reactive Oxygen Species (ROS), mainly Singlet oxygen (SO,1O2）。1O2can oxidize key biological macromolecules required by cells, thereby rapidly causing apoptosis and necrosis. Since this reaction requires excitation by light, ROS are not generated at a portion where light cannot be irradiated. PDT uses three non-toxic substances to achieve site-specific killing of tumor cells, so that the systemic toxicity is less than that of chemotherapeutic drugs, and normal tissues cannot be damaged like radiotherapy. However, the existing nano diagnosis and treatment agent has the problems of poor binding capacity of a photosensitizer and a carrier and complex preparation process.
Accordingly, the prior art is yet to be improved and developed.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a nano diagnosis and treatment agent, a preparation method and application thereof, and aims to solve the problem that the existing nano diagnosis and treatment agent has poor binding force between a photosensitizer and a carrier.
A nano-diagnostic, comprising: albumin, sodium porphyromonas bound to the surface of said albumin.
The nano diagnosis and treatment agent comprises the following components in a molar ratio of 5:1-3: 1.
The nano diagnostic and therapeutic agent further comprises paclitaxel bonded to the hydrophobic center of the albumin.
The nano diagnosis and treatment agent comprises the paclitaxel and the albumin, wherein the molar ratio of the paclitaxel to the albumin is 8:1-6: 1.
The nano diagnosis and treatment agent has the particle size of 100-120 nm.
The preparation method of the nano diagnosis and treatment agent comprises the following steps:
stirring and mixing the sodium porphyranthin and the albumin to obtain the nano diagnosis and treatment agent.
The preparation method of the nano diagnosis and treatment agent comprises the following steps:
mixing beta-mercaptoethanol, albumin and a solvent, then adding paclitaxel and stirring to obtain a mixed solution, and dialyzing the mixed solution in water to obtain albumin-paclitaxel nanoparticles;
stirring and mixing the sodium porphyranthin and the albumin-paclitaxel nano particles to obtain the nano diagnosis and treatment agent.
The preparation method of the nano diagnosis and treatment agent comprises the step of carrying out dialysis for 12-24 hours.
The preparation method of the nano diagnosis and treatment agent comprises the step of stirring and mixing the porphyromonas sodium and the albumin-paclitaxel nanoparticles for 2-6 hours.
An application of the nano diagnosis and treatment agent in preparing a preparation for treating tumors.
Has the advantages that: the nano diagnosis and treatment agent is a compound formed by combining albumin and sodium porphyromonas, wherein the albumin and the sodium porphyromonas have strong binding force, and the nano diagnosis and treatment agent can simultaneously realize photodynamic therapy and fluorescence imaging.
Drawings
FIG. 1 is a thermogram showing binding of albumin and DVDMS in example 1 of the present invention.
FIG. 2 is a TEM image of HSA-PTX-DVDMS in example 2 of the present invention.
FIG. 3 is a graph showing the killing of 4T1 tumor cells by the photodynamic/chemotherapeutic combination therapy of example 3 of the present invention.
FIG. 4 is a fluorescence image of HSA-PTX-DVDMS at a tumor site in example 4 of the present invention.
FIG. 5 is a graph showing the comparison of fluorescence intensity of ultrasonic irradiation and non-ultrasonic irradiation in example 4 of the present invention.
FIG. 6 is a graph of the inhibition of 4T1 tumor growth by the photodynamic/chemotherapeutic combination therapy of example 5 of the present invention.
Detailed Description
The invention provides a nano diagnosis and treatment agent, a preparation method and application thereof, and the invention is further described in detail below in order to make the purpose, technical scheme and effect of the invention clearer and more clear and definite. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The invention provides a nano diagnosis and treatment agent, which comprises the following components: albumin, sodium porphyromonas bound to the surface of said albumin.
Albumin (albumin) is the most prominent protein in human plasma. Human serum albumin is a kind of blood product, commonly called "life product". It is extracted from blood of healthy people, and is injected into patient's body via intravenous injection, and has the main function of strengthening immunity and resistance. The nano-carrier of albumin is easy to manufacture, stable, biodegradable and non-toxic.
Sodium porphyrine (DVDMS) is used as a new-generation photosensitizer independently developed in China, has quite stable property and high singlet oxygen yield, and is expected to become a more ideal photosensitizer than a commercial photosensitizer Photofrin.
In experimental tests, the inventor firstly finds that albumin and sodium porphyrine (DVDMS) have a strong adsorption effect, and the nano diagnosis and treatment agent can be obtained by adsorbing a large amount of sodium porphyrine on the surface of albumin-paclitaxel nano particles. The nano diagnosis and treatment agent is a compound formed by combining albumin and sodium porphyromonas, wherein the albumin and the sodium porphyromonas have stronger binding force.
The nano diagnosis and treatment agent is a compound combined by albumin-porphyrazine sodium, and simultaneously realizes photodynamic therapy and fluorescence imaging.
Preferably, the molar ratio of the porphyrazine sodium to the albumin is 5:1-3:1, so that the utilization rate of the carrier albumin is improved, and a good treatment effect is achieved.
Preferably, the nano-diagnostic further comprises paclitaxel bound to the hydrophobic center of the albumin, that is, the nano-diagnostic comprises: albumin, paclitaxel bound to the hydrophobic center of the albumin, sodium porphyrazin adsorbed on the albumin surface.
The preferable nano diagnosis and treatment agent is a nano diagnosis and treatment agent combining chemotherapy and photodynamic therapy, albumin-paclitaxel nanoparticles are used as a carrier material, and the surface of the carrier material (albumin-paclitaxel nanoparticles) is combined with sodium porphyromonas pallidum (DVDMS). In other words, the photosensitizer sodium porphyrinoid (DVDMS) is bound to albumin of albumin-paclitaxel nanoparticles.
The albumin-paclitaxel (HSA-PTX) obtained by combining albumin and paclitaxel not only can improve the water solubility of paclitaxel, but also can improve the circulation time of the drug in blood by being prepared into nanoparticles, and is beneficial to the accumulation of the drug to tumor parts.
The molar ratio of the paclitaxel to the albumin is 8:1-6:1, and improves the utilization rate of the carrier albumin.
The nano diagnosis and treatment agent has the particle size of 100-120 nm. Nanoparticles in this size range have the high permeability and retention (EPR) effect of solid tumors.
The preparation method of the nano diagnosis and treatment agent comprises the following steps:
stirring and mixing the sodium porphyranthin and the albumin to obtain the nano diagnosis and treatment agent.
The preparation method of the nano diagnosis and treatment agent utilizes the good binding force of the sodium porphyranthin and the albumin, and the preparation of the nano diagnosis and treatment agent can be realized by mixing and stirring.
The preparation method of the nano diagnosis and treatment agent comprises the following steps:
mixing beta-mercaptoethanol, albumin and a solvent, then dropwise adding paclitaxel and stirring to obtain a mixed solution, and dialyzing the mixed solution in water to obtain albumin-paclitaxel nanoparticles;
stirring and mixing the sodium porphyranthin and the albumin-paclitaxel nano particles to obtain the nano diagnosis and treatment agent.
Preferably, the method for preparing albumin-paclitaxel-porphyromonas sodium (HSA-PTX-DVDMS) nanoparticles comprises:
a) preparation of albumin-paclitaxel nanoparticles: mixing beta-mercaptoethanol, albumin (HSA) and an aqueous solution, then slowly dropwise adding a Paclitaxel (PTX) solution and stirring to obtain a mixed solution, and dialyzing the mixed solution in water for 24 hours to obtain albumin-paclitaxel nanoparticles.
b) Preparing an albumin-paclitaxel-porphyrazine sodium nano diagnosis and treatment agent: adding sodium porphyrinoid (DVDMS) into the albumin-paclitaxel nanoparticles prepared in the step a) and stirring to obtain albumin-paclitaxel nanoparticles (diagnosis and treatment agent) with the surface combined with the sodium porphyrinoid.
More specifically, the method comprises the following steps:
a) preparation of albumin-paclitaxel nanoparticles: to 9.9 mL of ultrapure water was added 100. mu.L of 0.2g/mL albumin (HSA) so that the concentration of albumin in the mixture was (2 mg/mL), beta-mercaptoethanol was added with stirring, then 300. mu.L of 10mg/mL Paclitaxel (PTX) was slowly added dropwise, and the above mixture was dialyzed in water for 24 hours to obtain albumin-paclitaxel nanoparticles.
b) Binding photosensitizer porphyrazine sodium (DVDMS) on the surface of albumin-paclitaxel nanoparticles: and adding 74 mu L of 5 mg/mL porphyromonas sodium (DVDMS) into the dialyzed albumin-paclitaxel nano particles, and stirring for 2 hours to obtain the albumin-paclitaxel-porphyromonas sodium (HSA-PTX-DVDMS) nano diagnosis and treatment agent.
The albumin-paclitaxel nanoparticles are formed by paclitaxel bound to the hydrophobic center of the albumin.
The nano diagnosis and treatment agent prepared by the preparation method can simultaneously realize the combined treatment of the fluorescence imaging of the tumor and the combination of the photodynamic therapy and the chemotherapy of the tumor, thereby having good application prospect in the field of diagnosis and treatment of the tumor. Meanwhile, the preparation process is simple, the operation is convenient, complex and expensive equipment is not needed, and the industrial production is easy to realize.
Preferably, the albumin in step a) is human blood albumin.
Preferably, the solvent is ultrapure water. Except water molecules, the ultrapure water has almost no impurities, and has no organic matters such as bacteria, viruses, chlorine-containing dioxin and the like, so that the ultrapure water is particularly suitable for preparing a solvent of a nano diagnosis and treatment agent.
Preferably, the dialysis time is 12-24 h. The invention concentrates the sample by dialysis technology, and obtains albumin-paclitaxel nano particles from the mixed solution.
Preferably, the molar ratio of the porphyromonas sodium to the albumin is 3:1, which is beneficial to improving the utilization rate of the porphyromonas sodium and the albumin.
Preferably, the stirring and mixing time of the sodium porphyrinoid and the albumin-paclitaxel nanoparticles is 2-6 h. During the stirring time, the process of binding the sodium porphyrins and the albumin-paclitaxel nanoparticles is substantially completed.
The invention also provides application of the nano diagnosis and treatment agent in preparation of a preparation for treating tumors. The nano diagnosis and treatment agent can also be used for preparing tumor medicinal preparations together with other medicines.
The nanometer diagnosis and treatment agent is applied to tumor treatment, and particularly the tumor treatment is a combined therapy of simultaneously adopting photodynamic therapy and chemotherapy.
The invention has the following advantages: the nano diagnosis and treatment agent prepared by the preparation method can simultaneously realize the combined treatment of the fluorescence imaging of the tumor and the combination of the photodynamic therapy and the chemotherapy of the tumor, thereby having good application prospect in the field of diagnosis and treatment of the tumor. Meanwhile, the preparation process is simple, the operation is convenient, complex and expensive equipment is not needed, and the industrial production is easy to realize.
The technical solution of the present invention will be described below by specific examples.
Example 1
Detection of affinity (binding force) of Albumin to sodium Porphyrinate (DVDMS)
Respectively preparing PBS buffer solutions (phosphate buffer saline solutions) of albumin and DVDMS, adjusting the concentrations to the molar ratio of approximately 1:10, slowly titrating 200 mu L of the sodium porphyrine solution into the albumin solution in an isothermal titration calorimeter, and monitoring a heat release curve in the titration process for 45 minutes in real time. The parameters associated with the binding process of albumin and DVDMS obtained by data fitting are shown in fig. 1. The combination constant of the two is 2.34 multiplied by 105±1.348 ×105 M-1The binding constant is at a higher level, indicating that the two have stronger binding force. The number of binding sites was on average about 4.56, and Δ S for the reaction was greater than 0, indicating that the binding process is enthalpy and entropy co-driven.
Example 2
Synthesis of Albumin-paclitaxel-porphyrinoid (HSA-PTX-DVDMS)
100 μ L of 0.2g/mL albumin (HSA) was added to 9.9 mL of ultrapure water so that the concentration of the albumin in the mixed solution was 2 mg/mL, β -mercaptoethanol was added with stirring, then 300 μ L of 10mg/mL Paclitaxel (PTX) was slowly added dropwise to obtain a mixed solution, and the above mixed solution was dialyzed in water for 24 hours to obtain albumin-paclitaxel nanoparticles. And adding 74 mu L of 5 mg/mL porphyromonas sodium (DVDMS) into the dialyzed albumin-paclitaxel nano particles, and stirring for 2 hours to obtain the albumin-paclitaxel-porphyromonas sodium (HSA-PTX-DVDMS) nano diagnosis and treatment agent.
The TEM image of the synthesized albumin-paclitaxel-porphyrazin sodium nano diagnostic agent (HSA-PTX-DVDMS) is shown in FIG. 2. As can be seen from fig. 2, the synthesized albumin-paclitaxel-porphyrazin sodium nano diagnostic agent is in a spherical shape, and the particle size of the nano diagnostic agent is between 100nm and 120 nm.
Example 3
Evaluation of toxicity of photodynamic therapy and chemotherapy combination therapy on 4T1 tumor cells
The effect of the combination of photodynamic therapy and chemotherapy on the survival of 4T1 cells was evaluated using standard MTT methods. 4T1 cells at 5X 10 per well3Inoculating into 96-well plate at a density of 37 deg.C and 5% CO2Incubate for 24h under conditions. Next, the old medium in the 96-well plate was aspirated, and the medium containing 3. mu.g/mL HSA-PTX-DVDMS DMEM was added thereto, respectively. After further culturing for 24 hours, the old medium was aspirated from the 96-well plate, 100. mu.L of DMEM medium was added to each well, and then the cells were irradiated with a 660 nm laser at a power of 200 mW/cm for 5 minutes for each well of the irradiated wells2. After irradiation, the old medium was aspirated from the 96-well plate, and 100. mu.L of a medium solution containing 10% CCK8 was added to each well, and incubation was continued for 1 hour. Then, the OD value of each well (detection wavelength: 450 nm) was measured on a Bio-Tel EL X800 type microplate reader, and the cell viability was calculated by the following equation. Cell viability (cell viability) (%) = (OD 450 value of sample/blank OD450 value) × 100%, and the experimental results are shown in fig. 3.
As shown in FIG. 3, the cell viability (cell viability) of 4T1 decreased gradually with the increase of the concentration of HSA-PTX-DVDMS drug due to the effect of the chemotherapeutic drug Paclitaxel (PTX). The cell viability (cell viability) of the cells after the light irradiation is more remarkably reduced, which indicates that the light irradiation causes the photosensitizer (DVDMS) to generate active oxygen to kill a large number of tumor cells.
Example 4
Evaluation of Effect of Low-frequency ultrasonic irradiation on promotion of accumulation of Nano diagnostic agent in bilateral subcutaneous tumors
Female Balb/c mice (3 weeks, 15-20 g) were injected subcutaneously into the left and right hind legs of 2X 10 mice64T1 tumor cells, and establishing a mouse subcutaneous tumor model. When the volume of bilateral tumors exceeds 100 mm3Fluorescence imaging experiments were performed. Tumor-bearing mice were randomly divided into two groups: (1) blank (control); (2) injecting the group of HSA-PTX-DVDMS; (3) HSA-PTX-DVDMS + unilateral ultrasound group was injected. Changes in tumor accumulation were observed by fluorescence imaging of DVDMS 0, 1, 2, 4, 24h after injection and quantified, and the results are shown in fig. 4.
In fig. 4, the accumulation of the drug in the tumor gradually increased with time after the administration. Whereas in tumors after ultrasound irradiation the concentration of the drug is relatively higher (the larger the corresponding fluorescence area in fig. 4, the stronger the fluorescence). FIG. 5 is the mean value of the change in tumor fluorescence intensity of three mice, and it can be seen that the fluorescence value of the tumor treated by ultrasound at 24h point is significantly different from the fluorescence value of the tumor on the other side when the effects of ultrasound irradiation and non-ultrasound irradiation are compared.
Example 5
Evaluation of the Effect of photodynamic/chemotherapeutic combination therapy on the inhibition of 4T1 tumor growth
Female Balb/c mice (3 weeks, 15-20 g) were injected subcutaneously into the hind legs of 2X 10 mice64T1 tumor cells, and establishing a mouse subcutaneous tumor model. When the tumor volume reaches 60 mm3Therapy experiments were performed. Tumor-bearing mice were randomly divided into five groups: (1) blank (control); (2) the HSA-PTX group was injected; (3) injecting the group of HSA-PTX-DVDMS; (4) the HSA-PTX-DVDMS + laser set was injected. Tumor volume was measured every other day with a vernier caliper while monitoring the body weight of the mice and according to the formula V = AB2Tumor volume (Tumor volume) was calculated where A is the long diameter of the Tumor and B is the short diameter (mm) of the Tumor. Each measurement was normalized by the starting tumor volume before treatment. The results of the experiment are shown in FIG. 6.
FIG. 6 shows the tumor volume (Normalized tumor volume) over time (days) in different treatment groups, the HSA-PTX-DVDMS + laser injection group can significantly inhibit the tumor growth, and the HSA-PTX injection group and the HSA-PTX-DVDMS injection group have equivalent tumor inhibition effects; after 15 days, the tumor weights of mice in HSA-PTX-DVDMS + laser injection group were significantly lower than those in blank group (control), HSA-PTX injection group and HSA-PTX-DVDMS injection group.
The albumin-paclitaxel-sodium porphyrazin (HSA-PTX-DVDMS) nano diagnosis and treatment agent can simultaneously realize the combined treatment of the fluorescence imaging of the tumor and the combination of the photodynamic treatment and the chemotherapy of the tumor.
In the invention, the HSA-PTX-DVDMS has good clinical application prospect, the HSA-PTX is a medicament which is approved to be applied to clinic, and the DVDMS is also a medicament which is subjected to a first-stage clinical experiment. PTX in HSA-PTX-DVDMS is a chemotherapeutic drug which is widely applied in clinic, and is widely used for treating breast cancer, ovarian cancer, partial head and neck cancer and lung cancer. The DVDMS is a new-generation photosensitizer, has stable property and high singlet oxygen yield, and has good photodynamic treatment effect.
The invention has the following advantages: the HSA-PTX-DVDMS nano diagnosis and treatment agent prepared by the preparation method can simultaneously realize the combined treatment of the combination of the fluorescence imaging of the tumor and the photodynamic therapy and chemotherapy of the tumor, and has good application prospect in the field of diagnosis and treatment of the tumor. Meanwhile, the preparation process is simple, the operation is convenient, complex and expensive equipment is not needed, and the industrial production is easy to realize.
It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.
Claims (5)
1. A nano diagnostic agent, comprising: albumin, and porphyromonas sodium bound on the surface of the albumin, wherein the molar ratio of the porphyromonas sodium to the albumin is 5:1-3: 1; the particle size of the nano diagnosis and treatment agent is 100-120 nm; further comprising paclitaxel bound to the hydrophobic center of the albumin; the molar ratio of the paclitaxel to the albumin is 8:1-6: 1.
2. The method for preparing a nano diagnostic and therapeutic agent as defined in claim 1, comprising the steps of:
mixing beta-mercaptoethanol, albumin and a solvent, then adding paclitaxel and stirring to obtain a mixed solution, and dialyzing the mixed solution in water to obtain albumin-paclitaxel nanoparticles;
stirring and mixing the sodium porphyranthin and the albumin-paclitaxel nano particles to obtain the nano diagnosis and treatment agent.
3. The method for preparing a nano diagnostic and therapeutic agent according to claim 2, wherein the dialysis time is 12-24 hours.
4. The method for preparing a nano diagnostic and therapeutic agent according to claim 2, wherein the time for mixing the sodium porphyrinates and the albumin-paclitaxel nanoparticles with stirring is 2-6 hours.
5. The use of the nano diagnostic agent of claim 1 in the preparation of a preparation for treating tumors.
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