CN115475243B - Stimulus-responsive nano liquid metal material and preparation method and application thereof - Google Patents
Stimulus-responsive nano liquid metal material and preparation method and application thereof Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/50—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
- A61K47/51—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 non-active ingredient being a modifying agent
- A61K47/56—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A61P35/00—Antineoplastic agents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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Abstract
The invention provides a stimulus-responsive nano liquid metal material and a preparation method and application thereof. The liquid metal material has excellent flexibility and metal characteristics, and shows remarkable characteristics superior to those of the traditional nano material in the field of tumor nano vaccines. On one hand, the stimulus-responsive nano liquid metal material can target and improve the temperature of a tumor part under the stimulation of an external field, induce apoptosis or directly kill tumor cells, and stimulate local inflammatory reaction to promote immune response; on the other hand, the stimulus-responsive nano liquid metal material can effectively adsorb tumor fragments, the flexibility of the stimulus-responsive nano liquid metal material is beneficial to cell uptake, and then the pH degradation characteristic is beneficial to lysosome escape and biodegradation, so that the targeting and activating antigen presenting capacity is enhanced.
Description
Technical Field
The invention belongs to the technical field of liquid metal materials, and particularly relates to a stimulus response type nano liquid metal material, a preparation method thereof and application thereof in forming nano in-situ tumor vaccine by combining thermal therapy.
Background
In recent years, as a novel tumor treatment method, tumor hyperthermia based on nano materials is receiving attention because of the advantages of small invasiveness, high efficiency, low adverse reaction, tumor metastasis inhibition and the like. The nanometer heat treatment utilizes the stimulus sensitive material to absorb and convert the external energy into heat treatment, thereby increasing the temperature of the tumor part, inducing apoptosis or directly killing tumor cells. However, thermal therapy alone still does not control tumor metastasis and recurrence. For this reason, it is desirable to control the growth of metastatic tumors by stimulating the host immune system to produce an anti-tumor immune response. The nanometer material mediated heat treatment and the immune treatment are combined, so that the treatment effect of the tumor can be further improved, and the recurrence and the metastasis are reduced. In the thermotherapy process, antigen presenting cells such as dendritic cells can capture a large amount of released tumor-associated antigens, which are processed and then presented to lymphocytes to induce lymphocyte proliferation and activation, thereby generating corresponding anti-tumor immunity.
The prior researches are mostly single-function high polymer materials or hard metal materials, the synthesis process of the materials is complex, and the high polymer materials are difficult to respond to external stimulus due to single function; while rigid metallic materials lacking flexibility are susceptible to side effects or complications, limiting their practical use. Therefore, there is an urgent need for a stimulus-responsive material that is simple and flexible in synthetic process and can be used as both a hyperthermia sensitizer and an immune activator.
Disclosure of Invention
In order to solve the dilemma of the traditional tumor therapy in clinic, the invention provides a stimulus response type nano liquid metal material, a preparation method thereof and application thereof in the formation of nano in-situ tumor vaccine by combining heat treatment. The stimulus-responsive nano liquid metal material comprises an inner core structure formed by liquid metal, an outer shell structure formed by liquid metal oxide and a surfactant containing an antigen adsorption functional group, wherein the surface of the surfactant is modified on the outer surface of the liquid metal oxide, the stimulus-responsive nano liquid metal material can be synthesized in one step through an ultrasonic method, the stimulus-responsive nano liquid metal material can realize the functions of adsorbing tumor fragments in vivo, activating antigen presenting cells in a targeted manner and the like, and then the application of the stimulus-responsive nano liquid metal material in the formation of nano in-situ tumor vaccine by combining thermal therapy and the formation of nano in-situ tumor vaccine by combining thermal therapy can be applied to tumor thermal therapy and immunotherapy.
The invention aims at realizing the following technical scheme:
a stimuli-responsive nano-liquid metal material having a core-shell structure comprising an outer shell and an inner core, wherein the material forming the inner core comprises a liquid metal and the material forming the outer shell comprises a liquid metal oxide and a surfactant comprising an antigen-adsorbing functional group.
According to the embodiment of the invention, the liquid metal oxide forms a liquid metal oxide layer and is coated on the outer surface of the liquid metal, and the outer surface of the liquid metal oxide layer is modified with a surfactant containing an antigen adsorption functional group.
According to an embodiment of the invention, the liquid metal oxide is spontaneously formed, coating the outer surface of the liquid metal and forming a liquid metal oxide layer.
According to an embodiment of the present invention, the mass ratio of the liquid metal and the liquid metal oxide to the surfactant having an antigen adsorption functional group is 10 (0.01 to 1), preferably 10 (0.1 to 0.5), i.e., 10 parts by mass of the liquid metal and the liquid metal oxide and 0.01 to 1 part by mass of the surfactant having an antigen adsorption functional group.
According to an embodiment of the invention, the thickness of the liquid metal oxide layer is 1-5 nm.
According to an embodiment of the invention, the liquid metal is selected from at least one of gallium, gallium indium alloy, gallium indium tin zinc alloy or gallium indium tin zinc bismuth alloy.
According to an embodiment of the present invention, the liquid metal oxide is a liquid metal oxide formed spontaneously from the above liquid metal, i.e. gallium oxide.
According to an embodiment of the present invention, the surfactant containing an antigen adsorption functional group is selected from maleimide derivatives, illustratively, at least one selected from phosphatidylethanolamine-polyethylene glycol-maleimide, maleimide-polyethylene glycol-maleimide, phospholipid-polyethylene glycol-maleimide.
Wherein the antigen adsorption functional group is maleimide.
Wherein the polyethylene glycol has a number average molecular weight of 500-5000.
According to an embodiment of the present invention, the hydrophobic group in the surfactant containing an antigen adsorption functional group is coated on the surface of the liquid metal oxide, and the functional group (maleimide) in the surfactant containing an antigen adsorption functional group adsorbs an antigen.
According to an embodiment of the invention, the maleimide is used for adsorbing antigens, for example proteins by means of S-C bond formation with the proteins.
According to an embodiment of the present invention, the particle size of the stimulus-responsive nano liquid metal material is 10 to 200nm, preferably 50 to 150nm.
According to an embodiment of the present invention, the particle size of the inner core in the stimulus-responsive nano liquid metal material is 5 to 190nm, preferably 40 to 140nm.
According to the embodiment of the invention, the thickness of the shell in the stimulus-responsive nano liquid metal material is 2-15 nm.
According to the embodiment of the invention, the surface active agent containing the antigen adsorption functional group is modified on the outer surface of the liquid metal oxide layer, so that functions of adsorbing tumor antigens in vivo, targeting and activating antigen presenting cells and the like can be realized.
According to the embodiment of the invention, the stimulus-responsive nano liquid metal material can respond to external stimulus, such as laser, alternating magnetic field and the like; the antigen adsorption functional group is capable of adsorbing tumor antigens such as nucleic acids, polysaccharides, proteins, polypeptides, and the like.
The invention also provides a preparation method of the stimulus-responsive nano liquid metal material, which comprises the following steps:
(1) The liquid metal is used as a raw material, placed in a surfactant solution containing an antigen adsorption functional group, and subjected to ultrasonic treatment to prepare the stimulus-responsive nano liquid metal material.
According to an embodiment of the invention, the method further comprises the steps of:
(2) Washing, dialyzing and freeze-drying the stimulus-responsive nano liquid metal material in the step (1) to remove the excessive surfactant.
According to an embodiment of the present invention, in the step (1), the mass ratio of the liquid metal to the surfactant having an antigen adsorption functional group is 10 (0.01 to 1), preferably 10 (0.1 to 0.5).
According to an embodiment of the present invention, in the step (1), the concentration of the surfactant solution containing an antigen adsorption functional group is 0.01 to 0.5mmol/L.
According to an embodiment of the present invention, in the step (1), the surfactant solution containing an antigen adsorption functional group is an aqueous solution of a surfactant containing an antigen adsorption functional group, an ethanol solution of a surfactant containing an antigen adsorption functional group, or a dichloromethane solution of a surfactant containing an antigen adsorption functional group.
According to an embodiment of the present invention, in the step (1), the power of the ultrasonic treatment is 165 to 440W, and the time of the ultrasonic treatment is 5 to 20 minutes.
According to an embodiment of the present invention, in step (2), the washing is washing with deionized water, and the purpose of the washing is to primarily remove the surfactant that is not coated on the surface of the liquid metal particles.
According to an embodiment of the invention, in step (2), the dialysis is carried out overnight in deionized water using a dialysis tube (8,000-14,000 da), the purpose of which is to thoroughly remove the surfactant that is not coated on the outer surface of the liquid metal particles.
According to an embodiment of the present invention, in the step (2), the freeze-drying temperature is-10 to-80 ℃, and the drying time is 12 to 48 hours.
The invention also provides application of the stimulus-responsive nano liquid metal material in forming nano in-situ tumor vaccine by heat treatment and combination.
The invention also provides a nano in-situ tumor vaccine which comprises the stimulus-responsive nano liquid metal material.
According to the embodiment of the invention, the stimulus-responsive nano liquid metal material is utilized to destroy tumor cells in situ under the stimulation of laser, and the antigen is presented and the immune system is activated after adsorbing tumor fragments, so that the immune response is realized.
According to the embodiment of the invention, the stimulus-responsive nano liquid metal material is used for digesting solid tumors at in-situ tumors and then releasing and adsorbing tumor antigens.
The invention has the beneficial effects that:
the stimulus-responsive nano liquid metal material provided by the invention can be combined with heat treatment to form nano in-situ tumor vaccine so as to realize the functions of adsorbing tumor fragments in vivo, activating antigen presenting cells in a targeted manner and the like. The liquid metal material has excellent flexibility and metal characteristics, and shows remarkable characteristics superior to those of the traditional nano material in the field of tumor nano vaccines. On one hand, the stimulus-responsive nano liquid metal material can target and improve the temperature of a tumor part under the stimulation of an external field, induce apoptosis or directly kill tumor cells, and stimulate local inflammatory reaction to promote immune response; on the other hand, the stimulus-responsive nano liquid metal material can effectively adsorb tumor fragments, the flexibility of the stimulus-responsive nano liquid metal material is beneficial to cell uptake, and then the pH degradation characteristic is beneficial to lysosome escape and biodegradation, so that the targeting and activating antigen presenting capacity is enhanced.
The invention provides and designs a stimulus response type nano liquid metal material for solving the dilemma of the traditional clinical tumor therapy, which can realize the functions of tumor targeted hyperthermia, in vivo tumor fragment adsorption, activation of antigen presenting cells, molecular imaging and the like, and provides a new idea for tumor immunotherapy induced by nano hyperthermia. The stimulus response type nano liquid metal material overcomes the defect of the traditional thermotherapy on the damage of far-end focus and free tumor cells, and is hopeful to induce the whole body immunotherapy while killing local focus.
Drawings
Fig. 1 is a schematic structural diagram of the stimulus-responsive nano-liquid metal material obtained in example 1.
Fig. 2 is a schematic flow chart of the application of the stimulus-responsive nano-liquid metal material obtained in example 1 in the formation of nano-in-situ tumor vaccine by heat treatment.
Fig. 3 is a photo-thermal performance test result of the stimulus-responsive nano liquid metal material obtained in example 1.
Fig. 4 is a photodynamic performance test result of the stimulus-responsive nano liquid metal material obtained in example 1.
FIG. 5 shows the particle size change of the stimulus-responsive nano-liquid metal material obtained in example 1 before and after adsorbing tumor cell antigens under laser stimulus.
FIG. 6 shows the potential change before and after adsorbing tumor cell antigens by the stimulus-responsive nano-liquid metal material obtained in example 1 under laser stimulus.
Detailed Description
The present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; the reagents, materials, etc. used in the examples described below are commercially available unless otherwise specified.
The sonication used in the examples below was done in a sonicator, manufactured by Emerson, model Branson SFX 550.
Example 1
Dissolving 0.005mmol of phospholipid-polyethylene glycol-maleimide (DSPE-PEG 2000-Mal, purchased from Shanghai Sanska Biotechnology Co., ltd.) in 100mL of ultrapure water to obtain a mixed solution with the concentration of 0.05mM, adding 100g of liquid metal gallium, carrying out ultrasonic treatment for 5 minutes under the condition of ultrasonic power of 385W, washing with deionized water, centrifuging to remove a lower crude product, dialyzing in deionized water by using a dialysis tube (8000-14,000 Da) overnight, and freeze-drying at-40 ℃ for 24 hours to obtain the stimulus-responsive nano liquid metal material. The schematic diagram of the stimulus-responsive nano liquid metal material obtained in this embodiment is shown in fig. 1, and as can be seen from fig. 1, the stimulus-responsive nano liquid metal material has a core-shell structure, the core-shell structure includes a shell and an inner core, wherein the material forming the inner core includes a liquid metal, the material forming the outer shell includes a liquid metal oxide and a surfactant containing an antigen adsorption functional group, the liquid metal oxide spontaneously forms and coats the outer surface of the liquid metal to form a liquid metal oxide layer, and the outer surface of the liquid metal oxide layer is coated with the surfactant containing the antigen adsorption functional group.
The stimulus-responsive nano liquid metal material can absorb laser energy to be converted into heat treatment under the stimulus of near infrared laser and can generate active oxygen, so that the solid tumor can be destroyed in situ; meanwhile, the antigen adsorption characteristic of the antigen can effectively adsorb tumor antigens released by cracking, and the smaller size and flexibility can promote the presentation and uptake of the tumor antigens to dendritic cells; in addition, the pH degradation characteristic of the liquid metal is beneficial to lysosome escape and biodegradation of the material, and tumor antigens can be effectively released in dendritic cells, so that targeting and antigen presentation activating capacity is enhanced, and immune response is promoted. For this purpose, it is possible to apply the material to hyperthermia in combination with the formation of nano-in-situ tumor vaccines, as shown in fig. 2.
To explore the photothermal properties of the material, an aqueous suspension of the nanoparticles (1.0 mg/mL) was chosen as the subject, and irradiated with 808nm laser (1.0/cm 2 1 minute on, 1 minute off), deionized water was used as a control group, and the test results are shown in fig. 3, which shows that the stimulus-responsive nano liquid metal material has excellent photo-thermal properties.
For in vitro detection of reactive oxygen species production, tumor cells were seeded into 12-well plates (10 5 cell/mL, 500. Mu.L/well) and at 37℃5vol% CO 2 Incubate 24 in carbon dioxide incubator at ambient. After removal of the medium and washing with PBS, the tumor cells were stained with 10mM 20-70-dichlorofluorescein diacetate (DCFH-DA, beijing Soy Biotechnology Co., ltd., china) for 25 minutes at 37 ℃. After re-washing, stained tumor cells were added and incubated for 15 minutes, and fluorescence was measured using an inverted fluorescence microscope (Axio ver A1, carl Zeiss Microscopy GmbH, germany). Experiments were performed with a blank control group (DMEM), a positive control group (0.1 mM of Rosup), a negative control group (1.0 mg/mL of stimulus-responsive nano liquid metal material), a nanoparticle + laser group (1.0 mg/mL of stimulus-responsive nano liquid metal material, 806 nm, 1.0W/cm) 2 Laser irradiation for 15 minutes), testThe results are shown in fig. 4, and the test results show that the stimulus-responsive nano liquid metal material has good photodynamic performance.
Antigen adsorption test by mixing the stimulus-responsive nano-liquid metal material with a tumor cell suspension, and irradiating with laser for 5 minutes (806 nm,1.0/cm 2 ) Then, the mixture was allowed to stand at 37℃for 30 minutes, and the particle size and the potential of the stimulus-responsive nano liquid metal material before and after adsorption of the antigen were measured by a nano particle size potentiometer (Zetasizer, markov, UK). The lung cancer cell antigen adsorption test shows that the stimulus response nano liquid metal material can effectively destroy tumor cells under the action of laser and adsorb released tumor antigens, the particle size change before and after the antigens is shown in figure 5, and the potential change before and after the antigens is shown in figure 6. In addition, quantitative tests on the quality of adsorbed tumor antigens were carried out by using the BCA test method, and the specific steps are as follows: 1.0mg/mL of stimulus-responsive nano liquid metal material and 1.0mg/mL of OVA (chicken soft albumin) solution are mixed according to a proportion (1:1), then ultrasonic treatment is carried out for 5 minutes (385W), standing is carried out for 20 minutes, then ultrasonic treatment is carried out for 5 minutes, then an ultrafiltration centrifuge tube (Millipore Co. Nominal molecular weight: 10000,4 ℃ C., centrifugation (8000 rpm,10 minutes) is used for filtering unadsorbed protein, and finally standard BCA test program is used for testing the content of adsorbed protein.
Example 2
This example differs from example 1 only in that ultrapure water in example 1 was replaced with dichloromethane.
Example 3
This example differs from example 1 only in that the phospholipid-polyethylene glycol-maleimide (DSPE-PEG 2000-Mal) in example 1 was replaced with phospholipid-polyethylene glycol-maleimide (DSPE-PEG 5000-Mal).
Example 4
This example differs from example 1 only in that the liquid gallium metal in example 1 was replaced by a liquid gallium indium eutectic alloy.
Example 5
This example differs from example 1 only in that the amount of phospholipid-polyethylene glycol-maleimide (DSPE-PEG 2000-Mal) added in example 1 was 0.1mmol, i.e., a mixed solution having a concentration of 0.1mM was obtained.
Example 6
This example differs from example 1 only in that the liquid gallium in example 1 was added in an amount of 500g, i.e., the liquid gallium content was 5g/mL.
Example 7
The present example differs from example 1 only in that the ultrasonic treatment condition in example 1 was that the ultrasonic power was 275W and the ultrasonic time was 10 minutes.
The properties of the stimulus-responsive nano-liquid metal materials prepared in examples 2 to 7 above were similar to those of example 1.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (11)
1. A nano liquid metal material, wherein the nano liquid metal material has a core-shell structure comprising an outer shell and an inner core, wherein the material forming the inner core comprises a liquid metal, and the material forming the outer shell comprises a liquid metal oxide and a surfactant containing an antigen adsorption functional group;
the liquid metal oxide forms a liquid metal oxide layer and is coated on the outer surface of the liquid metal, and the outer surface of the liquid metal oxide layer is modified with a surfactant containing an antigen adsorption functional group;
the liquid metal is selected from at least one of gallium, gallium indium alloy, gallium indium tin zinc alloy or gallium indium tin zinc bismuth alloy;
the surfactant containing an antigen adsorption functional group is selected from phospholipid-polyethylene glycol-maleimide.
2. The nano liquid metal material according to claim 1, wherein the mass ratio of the liquid metal and the liquid metal oxide to the surfactant containing the antigen adsorption functional group is 10 (0.01-1).
3. The nano-liquid metal material according to claim 1, wherein the thickness of the liquid metal oxide layer is 1-5 nm.
4. The nano-liquid metal material according to claim 1, wherein the surfactant containing an antigen adsorption functional group is selected from phosphatidylethanolamine-polyethylene glycol-maleimide.
5. The nano liquid metal material according to claim 1, wherein the particle size of the nano liquid metal material is 10-200 nm;
and/or the particle size of the inner core in the nano liquid metal material is 5-190 nm;
and/or the thickness of the shell in the nano liquid metal material is 2-15 nm.
6. A method of preparing a nano-liquid metal material as claimed in any one of claims 1 to 5, comprising the steps of:
(1) The nano liquid metal material is prepared by taking liquid metal as a raw material, placing the raw material into a surfactant solution containing an antigen adsorption functional group, and performing ultrasonic treatment.
7. The method of manufacturing according to claim 6, wherein the method further comprises the steps of:
(2) Washing, dialyzing and freeze-drying the nano liquid metal material in the step (1) to remove the excessive surfactant.
8. The method according to claim 6, wherein in the step (1), the mass ratio of the liquid metal to the surfactant having an antigen adsorption functional group is 10 (0.01 to 1);
and/or, in the step (1), the concentration of the surfactant solution containing the antigen adsorption functional group is 0.01-0.5 mmol/L;
and/or in the step (1), the power of the ultrasonic treatment is 165-440W, and the time of the ultrasonic treatment is 5-20 minutes.
9. A nano-in-situ tumor vaccine comprising the nano-liquid metal material of any one of claims 1-5.
10. The nano-in-situ tumor vaccine according to claim 9, wherein the nano-liquid metal material is used for in-situ destruction of tumor cells under laser stimulation, antigen presentation and immune system activation after adsorption of tumor fragments, and thus immune response is realized.
11. The nano-in-situ tumor vaccine according to claim 9, which is prepared by digesting solid tumor at in-situ tumor site with the nano-liquid metal material and then releasing and adsorbing tumor antigen.
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| WO2020250153A1 (en) * | 2019-06-11 | 2020-12-17 | Pharmaexceed S.R.L. | Nanoparticles for use in the redirection against the tumour of a non-tumour-specific immune response, based on a pre-existing immunity |
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| WO2020250153A1 (en) * | 2019-06-11 | 2020-12-17 | Pharmaexceed S.R.L. | Nanoparticles for use in the redirection against the tumour of a non-tumour-specific immune response, based on a pre-existing immunity |
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