CN110638784A - Drug-loaded microsphere carrying oncolytic virus and preparation method thereof - Google Patents
Drug-loaded microsphere carrying oncolytic virus and preparation method thereof Download PDFInfo
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- CN110638784A CN110638784A CN201910926914.3A CN201910926914A CN110638784A CN 110638784 A CN110638784 A CN 110638784A CN 201910926914 A CN201910926914 A CN 201910926914A CN 110638784 A CN110638784 A CN 110638784A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- 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
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5052—Proteins, e.g. albumin
- A61K9/5057—Gelatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
- A61K35/768—Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a preparation method of drug-loaded microspheres loaded with oncolytic viruses, which comprises the following steps: (1) preparing an aqueous gelatin hydrogel solution; (2) preparing an oil phase solution; (3) using a microsphere precursor prepared by mixing a blue light radiation aqueous phase and an oil phase at a collection end to form idle-load microspheres through crosslinking; (4) carrying out post-treatment of oil stain removal and freeze drying on the crosslinked no-load microspheres in the step (3); (5) and (4) mixing the freeze-dried microspheres obtained in the step (4) with an oncolytic virus solution to obtain the drug-loaded microspheres loaded with the oncolytic virosomes. The invention has the advantages that the microsphere intervention oncolytic virus drug delivery is prepared by adopting materials such as biocompatible gelatin and the like. The local anoxic microenvironment created by the drug-loaded microspheres can reduce the immunogenicity of intravenous administration of oncolytic virus, improve the intratumoral replication rate of virus and enhance the anti-tumor capability of the drug.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a drug-loaded microsphere loaded with oncolytic virus and a preparation method thereof.
Background
Oncolytic Viruses (OV) refer to a class of native or recombinant Viruses that are capable of selectively killing tumor cells without damaging normal cells. An Oncolytic virus therapy (Oncolytic virotherapy) is a novel tumor targeted therapy, which is an anti-tumor preparation taking Oncolytic viruses with tumor selectivity and multiple killing ways as main components, can directly kill tumor cells to achieve the Oncolytic effect, releases tumor specific antigens in the process of tumor cell lysis, and activates the anti-tumor immune response of organisms. Currently, the commonly used oncolytic poxviruses for genetic engineering are mainly Lister strain, WR (WesternReverse) strain, Wyeth strain, Copenhagen strain and Techthyn strain.
The Pexa-Vec (PExastimogene dvacirrepvec) virus is an oncolytic vaccinia virus that has been extracted from Wyeth strain and genetically engineered to be replication competent. The Pexa-Vec virus contains 3 gene modifications: (1) deletion of Thymidine Kinase (TK) gene of poxvirus). When the poxvirus is propagated, TK forms a pool of nucleotides at high concentration to ensure the DNA replication of progeny. In normal cells, the nucleotide concentration is low, so TK is necessary for the poxvirus to proliferate in normal cells; whereas the nucleotide concentration in tumor cells is higher, the proliferation of poxviruses is independent of the presence of TK. Thus, a Pexa-Vec poxvirus with a deleted TK gene is able to replicate and proliferate preferentially in tumor cells containing sufficient nucleotides, but not in normal cells; (2) human Granulocyte-macrophage colony stimulating factor (GM-CSF) gene was inserted. GM-CSF can activate Antigen Presenting Cells (APCs) as an immunostimulating factor, mainly including DC and macrophages, and APC activates T cells by treating and presenting tumor antigen to achieve the effect of killing tumor; (3) the beta-galactosidase (lac-Z) gene was inserted for monitoring. In experiments with viral sensitivity to human tumors, researchers found that 56% of 29 tumor tissues including endometrial, ovarian, colorectal, and glioblastoma tumors and healthy control tissues exhibited Pexa-Vec sensitivity. Ovarian cancer tissue had the greatest sensitivity to Pexa-Vec (83%) compared to normal tissue with the lowest sensitivity to Pexa-Vec (13%), indicating that Pexa-Vec preferentially infects tumor cells. In addition, researchers have found that Pexa-Vec replicates in tumor-bearing nude mice 5-fold or more efficiently than normal tissues. Currently, various clinical trials for treating tumors using the Pexa-Vec virus are being conducted. In the research of the I/II clinical test of Pexa-Vec, the selective killing effect on various solid tumors (such as melanoma, liver cancer, colon cancer, kidney cancer and other tumors) is determined.
The current administration routes of the Pexa-Vec oncolytic virus are mainly intratumoral injection and intravenous injection. Intratumoral injection is mostly used for solid tumors or tumors with limited parts, and the intratumoral injection administration operation is complex, thus greatly limiting the clinical application scope of the medicine. The intravenous administration is expected to treat metastatic tumor or blood tumor, and has more clinical application prospect and commercial value. However, intravenous administration is easily diluted by circulating fluid (blood, etc.), and reduces the concentration of oncolytic virus reaching a target, thereby reducing the curative effect of tumor cell lysis. In addition, intravenous injection may easily result in the body producing neutralizing antibodies due to the immunogenicity of the virus itself, resulting in the oncolytic virus becoming ineffective or rapidly cleared. Thus, there is a need for a convenient and effective way of administering oncolytic viruses to reduce their immunogenicity and to enhance their anti-tumor effect.
Disclosure of Invention
In order to overcome the defects that the administration of oncolytic viruses such as Pexa-Vec and the like is complex and the treatment response is not sufficient by adopting modes such as intravenous injection, intratumoral injection and the like in the prior art, the invention provides the drug-loaded microsphere carrying the oncolytic viruses and the preparation method thereof, and the aim of realizing the positioning and targeting effect on a tumor part through interventional administration is fulfilled, so that the anti-tumor effect is enhanced, and the adjustment and the control of the drug release can also be realized.
In order to achieve the purpose, the technical scheme provided by the invention is that the preparation method of the drug-loaded microsphere loaded with the anti-tumor single antibody comprises the following steps:
(1) dissolving a gelatin material of methacrylated gelatin and a photoinitiator LAP in a phosphate buffer solution to obtain a gelatin hydrogel solution, and taking the gelatin hydrogel solution as a water phase for later use;
(2) preparing an oily solution containing a surfactant span 80, wherein the surfactant span 80 accounts for 2% by mass of the oily solution, standing the oily solution for 3-6 hours to remove bubbles, and using the oily solution as an oil phase for later use;
(3) respectively connecting the water phase prepared in the step (1) with the oil phase prepared in the step (2) with a micro-pump injector, wherein the mass of the oil phase is at least three times that of the water phase, setting the flow rate according to the particle size of the microspheres to be obtained, and irradiating a microsphere precursor prepared by mixing the water phase with the oil phase by using blue light at a collection end to form unloaded microspheres by crosslinking;
(4) carrying out post-treatment of oil stain removal and freeze drying on the crosslinked no-load microspheres in the step (3);
(5) mixing the freeze-dried microspheres obtained in the step (4) with an oncolytic virus solution to obtain an oncolytic virus-loaded microsphere solution; and washing the microsphere solution, and freeze-drying to obtain the drug-loaded microspheres loaded with the oncolytic virus.
The drug-loaded microspheres are micro-spherical or quasi-spherical particles formed by dissolving or dispersing drugs in a sphere-forming material. By means of biodegradability of a specific high polymer material and controllability of degradation events, the sustained and controlled release effect for a super-long time can be realized by adopting microsphere administration, the medicine is concentrated in a target area, peak valley phenomena of blood concentration can be avoided, toxic and side effects are reduced, the curative effect of the medicine is improved, the administration period is delayed, the administration compliance is improved, and the like. Gelatin is a product of partial denaturation or degradation of collagen in connective tissues or epidermal tissues of animals, a linear chain polymer is formed by crosslinking 18 amino acids and polypeptides, and the gelatin has good biocompatibility, biodegradability and bioabsorption; the adverse reaction of systemic immunity caused by immunotherapy can be avoided, and the drug-loaded microspheres prepared by the method can realize local administration, so that the local immune response regulation is realized, and the adverse reaction of systemic immune cytokine storm is reduced; the drug release can be adjusted and controlled through the property of the drug-loaded microspheres.
Further, the specific operation method in the step (1) comprises the steps of weighing 300mg of methacrylated gelatin and 30mg of photoinitiator LAP, adding the weighed methacrylated gelatin and 30mg of photoinitiator LAP into 6ml of phosphate buffer solution to obtain gelatin mixed solution, adding a pore-forming agent, wherein the pore-forming agent accounts for 1-20% of the gelatin mixed solution by mass percent, placing the gelatin mixed solution into a water bath kettle at 60 ℃, intermittently shaking the mixture until the mixture is completely dissolved to obtain hydrogel solution with the mass concentration of 5%, and storing the hydrogel solution in a dark place for later use.
Further, the oily solution in the step (2) is one or more of paraffin oil and mineral oil.
Further, the post-treatment method in the step (4) comprises the steps of cleaning the cross-linked idle-loaded microspheres with isopropanol to remove oil stains, cleaning with ultrapure water, preserving the microspheres with ultrapure water to obtain an idle-loaded ultrapure water microsphere suspension, and finally performing freeze drying on the microsphere suspension at-20 ℃ for 2 days to obtain the dried porous microspheres.
Further, the volume of the oncolytic virus solution in the step (5) is 1-2 times of that of the microspheres, and the microsphere solution loaded with the oncolytic virus is obtained after standing for 24 hours at the temperature of 4 ℃.
Further, the oncolytic virus in the step (5) is one or more than one of Lister virus, Western Reverse virus, Wyeth virus, Copenhagen virus, Techn virus, Pexa-Vec virus and T-VEC virus.
Further, in the step (5), the microsphere solution loaded with the oncolytic virus is washed by isopropanol and purified water, then is placed at the temperature of minus 20 ℃ for freezing, and is freeze-dried for 72 hours after freezing, so that the drug-loaded microspheres loaded with the oncolytic virus can be collected and obtained.
The invention claims the drug-loaded microspheres prepared by the preparation method and provided with the oncolytic virus, and the maximum load of a single virus in the microspheres is 1 x 10^9 ppm.
By adopting the technical scheme, the invention has the beneficial effects that: the invention adopts biocompatible materials such as gelatin and the like to prepare microspheres to intervene in oncolytic virus administration, and can realize safe and convenient administration. The local anoxic microenvironment created by the drug-loaded microspheres can reduce the immunogenicity of intravenous administration of oncolytic virus, improve the intratumoral replication rate of virus and enhance the anti-tumor capability of the drug. The particle size of the hydrogel porous microsphere ranges from several micrometers to several hundred micrometers, microspheres with different release capacities can be formed, and accurate release of oncolytic virus in positioning, quantification and timing is realized. .
Drawings
FIG. 1 is a scanning electron microscope image of unloaded microspheres prepared in the first embodiment of the present invention.
Fig. 2 is a scanning electron microscope picture of the drug-loaded microsphere prepared in the first embodiment of the invention.
Fig. 3 is a particle size distribution diagram of the drug-loaded microspheres prepared in the first embodiment of the invention.
Fig. 4 is a graph of the degradation rate of the drug-loaded microspheres prepared in the first embodiment of the invention.
Detailed Description
The present invention will be further described with reference to the following examples. The operation methods which are not specially described in the invention are all the prior art, the operation conditions which are not specially described are all normal temperature and normal pressure, and the reagents are all commercially available.
The first embodiment is as follows: the invention provides a preparation method of a drug-loaded microsphere loaded with an anti-tumor single antibody, which comprises the following steps:
(1) dissolving a gelatin material of methacrylated gelatin and a photoinitiator LAP in a phosphate buffer solution to obtain a gelatin hydrogel solution, and taking the gelatin hydrogel solution as a water phase for later use;
(2) preparing an oily solution containing a surfactant span 80, wherein the surfactant span 80 accounts for 2% by mass of the oily solution, standing the oily solution for 6 hours to remove bubbles, and using the oily solution as an oil phase for later use;
(3) respectively connecting the water phase prepared in the step (1) with the oil phase prepared in the step (2) with a micro-pump injector, wherein the mass of the oil phase is three times that of the water phase, setting the flow rate according to the particle size of the microspheres to be obtained, irradiating a microsphere precursor prepared by mixing the water phase with the oil phase at a collection end by using blue light for about 5s, and crosslinking the microsphere precursor to form unloaded microspheres;
(5) and (4) carrying out oil stain removal and freeze drying post-treatment on the cross-linked drug-loaded microspheres obtained in the step (4) to obtain the drug-loaded microspheres loaded with the anti-tumor single antibody.
The specific operation method of the step (1) comprises the steps of weighing 300mg of methacrylated gelatin and 30mg of photoinitiator LAP, adding the weighed methacrylated gelatin and 30mg of photoinitiator LAP into 6ml of phosphate buffer solution to obtain gelatin mixed solution, adding a pore-forming agent, placing the mixture in a water bath kettle at 60 ℃, intermittently shaking the mixture until the mixture is completely dissolved to obtain hydrogel solution with the mass concentration of 5%, and storing the hydrogel solution in a dark place for later use.
Further, the oily solution in the step (3) is paraffin oil.
And (4) cleaning the crosslinked unloaded microspheres for more than three times by using isopropanol to remove oil stains, cleaning the crosslinked unloaded microspheres for more than three times by using ultrapure water, preserving the microspheres by using the ultrapure water to obtain an unloaded ultrapure water microsphere suspension, and finally performing freeze drying on the microsphere suspension for 2 days at the temperature of-20 ℃ to obtain the dried porous microspheres.
And (3) standing the oncolytic virus solution in the step (5) for 24 hours at 4 ℃ for obtaining the oncolytic virus-loaded microsphere solution, wherein the volume of the oncolytic virus solution is 1 time of that of the microspheres.
The oncolytic virus in the step (5) is a Pexa-Vec virus.
And (5) washing the microsphere solution loaded with the oncolytic virus with isopropanol and purified water, freezing at-20 ℃, and freeze-drying for 72 hours to collect and obtain the drug-loaded microspheres loaded with the oncolytic virus.
Example two: the invention provides a preparation method of a drug-loaded microsphere loaded with an anti-tumor single antibody, which comprises the following steps:
(1) dissolving a gelatin material of methacrylated gelatin and a photoinitiator LAP in a phosphate buffer solution to obtain a gelatin hydrogel solution, and taking the gelatin hydrogel solution as a water phase for later use;
(2) preparing an oily solution containing a surfactant span 80, wherein the surfactant span 80 accounts for 2% by mass of the oily solution, standing the oily solution for 3 hours to remove bubbles, and using the oily solution as an oil phase for later use;
(3) respectively connecting the water phase prepared in the step (1) with the oil phase prepared in the step (2) with a micro-pump injector, wherein the mass of the oil phase is at least three times, for example, 5 times, of that of the water phase, setting the flow rate according to the particle size of the microspheres to be obtained, irradiating the microsphere precursor prepared by mixing the water phase and the oil phase at a collecting end by using blue light for about 5s to form unloaded microspheres by crosslinking;
(5) and (4) carrying out oil stain removal and freeze drying post-treatment on the cross-linked drug-loaded microspheres obtained in the step (4) to obtain the drug-loaded microspheres loaded with the anti-tumor single antibody.
The specific operation method in the step (1) comprises the steps of weighing 300mg of methacrylated gelatin and 30mg of photoinitiator LAP, adding the weighed methacrylated gelatin and 30mg of photoinitiator LAP into 6ml of phosphate buffer solution to obtain gelatin mixed solution, adding a pore-forming agent, placing the mixture in a water bath kettle at 60 ℃, intermittently shaking the mixture until the mixture is completely dissolved to obtain hydrogel solution with the mass concentration of 5%, and storing the hydrogel solution in a dark place for later use.
Further, the oily solution in the step (3) is mineral oil.
And (4) cleaning the crosslinked unloaded microspheres for more than three times by using isopropanol to remove oil stains, cleaning the crosslinked unloaded microspheres for more than three times by using ultrapure water, preserving the microspheres by using the ultrapure water to obtain an unloaded ultrapure water microsphere suspension, and finally performing freeze drying on the microsphere suspension for 2 days at the temperature of-20 ℃ to obtain the dried porous microspheres.
And (3) standing the oncolytic virus solution in the step (5) for 24 hours at 4 ℃ for obtaining the oncolytic virus-loaded microsphere solution, wherein the volume of the oncolytic virus solution is 2 times of that of the microspheres.
The oncolytic virus in the step (5) is Lister virus.
And (5) washing the microsphere solution loaded with the oncolytic virus with isopropanol and purified water, freezing at-20 ℃, and freeze-drying for 72 hours to collect and obtain the drug-loaded microspheres loaded with the oncolytic virus.
By adopting the method, the oncolytic virus can be loaded into the drug-loaded microspheres simultaneously, as shown in figure 2 (figure 1 is the prepared unloaded microspheres for making a comparison with the drug-loaded microspheres loaded with the oncolytic virus), and the property change of the drug-loaded microspheres caused by the loading of the oncolytic virus is avoided, for example, as shown in figures 3 and 4, the particle size distribution range of the drug-loaded microspheres obtained by the invention can be wide so as to be suitable for different requirements, and the drug-loaded microspheres also have the effect of slow release. The preparation method is also suitable for Lister virus, Western Reverse virus, Wyeth virus, Copenhagen virus, Tiantan virus strain and T-VEC virus, the preparation methods are the same, the obtained effect is the same, the particle size distribution is from dozens to hundreds of micrometers, the particle size distribution has the function of slow release degradation and is only repeated by characters, and therefore, in order to save space, the embodiments are not listed.
The most common administration methods of the prior art: the injection in tumor is mainly used for solid tumor or tumor with limited part, the injection administration operation in tumor is complex, and the clinical application scope of the medicine is greatly limited; and secondly, intravenous administration is carried out, and the intravenous administration is easy to be diluted by circulating liquid (blood and the like), so that the concentration of the oncolytic virus reaching a target point is reduced, and the curative effect of cracking tumor cells is reduced. In addition, intravenous injection may easily result in the body producing neutralizing antibodies due to the immunogenicity of the virus itself, resulting in the oncolytic virus becoming ineffective or rapidly cleared. Compared with the administration mode in the prior art, the preparation method can load the oncolytic virus into the drug-loaded microsphere, can target and position the oncolytic virus into tumor by introducing the microsphere, is convenient to administer, can embolize tumor blood vessels to cause tumor local hypoxia, necrosis and apoptosis, and can stimulate the release of tumor-related antigens; the self-immunity of the oncolytic virus is reduced, so that the anti-tumor effect is improved, the systemic immune adverse reaction caused by immunotherapy can be avoided due to local administration, and the adjustability and controllability of the drug release are realized by virtue of the self-property of the microspheres.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. A preparation method of drug-loaded microspheres loaded with oncolytic viruses is characterized by comprising the following steps:
(1) dissolving a gelatin material of methacrylated gelatin and a photoinitiator LAP in a phosphate buffer solution to obtain a gelatin hydrogel solution, and taking the gelatin hydrogel solution as a water phase for later use;
(2) preparing an oily solution containing a surfactant span 80, wherein the surfactant span 80 accounts for 2% by mass of the oily solution, standing the oily solution for 3-6 hours to remove bubbles, and using the oily solution as an oil phase for later use;
(3) respectively connecting the water phase prepared in the step (1) with the oil phase prepared in the step (2) with a micro-pump injector, wherein the mass of the oil phase is at least three times that of the water phase, setting the flow rate according to the particle size of the microspheres to be obtained, and irradiating a microsphere precursor prepared by mixing the water phase with the oil phase by using blue light at a collection end to form unloaded microspheres by crosslinking;
(4) carrying out post-treatment of oil stain removal and freeze drying on the crosslinked no-load microspheres in the step (3);
(5) mixing the freeze-dried microspheres obtained in the step (4) with an oncolytic virus solution to obtain an oncolytic virus-loaded microsphere solution; and washing the microsphere solution, and freeze-drying to obtain the drug-loaded microspheres loaded with the oncolytic virus.
2. The preparation method of the drug-loaded microspheres loaded with the oncolytic virus of claim 1, wherein the specific operation method of the step (1) comprises the steps of weighing 300mg of methacrylated gelatin and 30mg of photoinitiator LAP, adding the weighed methacrylated gelatin and the photoinitiator LAP into 6ml of phosphate buffer solution to obtain gelatin mixed solution, adding a pore-forming agent, wherein the pore-forming agent accounts for 1-20% by mass of the gelatin mixed solution, placing the gelatin mixed solution into a water bath kettle at 60 ℃, intermittently shaking the mixture until the mixture is completely dissolved to obtain a hydrogel solution with a mass concentration of 5%, and storing the hydrogel solution in a dark place for later use.
3. The method for preparing drug-loaded microspheres loaded with oncolytic virus of claim 1, wherein the oil solution in step (2) is one or more of paraffin oil and mineral oil.
4. The preparation method of the drug-loaded microspheres loaded with the oncolytic virus according to claim 1, wherein the post-treatment method in the step (4) comprises the steps of cleaning the cross-linked unloaded microspheres with isopropanol to remove oil stains, cleaning with ultrapure water, preserving the microspheres with ultrapure water to obtain an unloaded ultrapure water microsphere suspension, and finally freeze-drying the microsphere suspension at-20 ℃ for 2 days to obtain the dried porous microspheres.
5. The method for preparing the drug-loaded microspheres loaded with the oncolytic virus of claim 1, wherein in the step (5), the volume of the oncolytic virus solution is 1-2 times of the volume of the microspheres, and the microsphere solution loaded with the oncolytic virus is obtained by standing at 4 ℃ for 24 hours.
6. The method for preparing drug-loaded microspheres loaded with oncolytic viruses according to claim 1, wherein in the step (5), the oncolytic virus is one or more of Lister virus, Western Reverse virus, Wyeth virus, Copenhagen virus, Temple virus, Pexa-Vec virus and T-VEC virus.
7. The method for preparing drug-loaded microspheres loaded with oncolytic viruses according to claim 1, wherein the step (5) comprises washing the microsphere solution loaded with oncolytic viruses with isopropanol and purified water in sequence, freezing at-20 ℃, and freeze-drying for 72h to obtain the drug-loaded microspheres loaded with oncolytic viruses.
8. A drug-loaded microsphere loaded with an oncolytic virus, wherein the drug-loaded microsphere is prepared by the method of any one of claims 1-7.
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