CN116271187A - Bimodal developing temperature-sensitive Pickering emulsion interventional embolic material, and preparation method and application thereof - Google Patents
Bimodal developing temperature-sensitive Pickering emulsion interventional embolic material, and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of embolism, and discloses a bimodal developing temperature-sensitive Pickering emulsion interventional embolic material, a preparation method and application thereof. The preparation method comprises the following steps: dissolving temperature-sensitive nano gel freeze-dried powder with different qualities into ultrapure water to obtain gel water dispersion; mixing an oily developer with a fluorocarbon to obtain an oil phase mixture; and mixing the gel aqueous dispersion with the oil phase mixture, and carrying out intermittent emulsification under ice bath conditions to obtain the bimodal development temperature-sensitive Pickering emulsion. According to the invention, the oily developer and the fluorocarbon compound are compounded, and the bimodal development temperature-sensitive Pickering emulsion constructed by adopting the temperature-sensitive nanogel as the aqueous dispersion is used as the embolic material, so that on one hand, clear development under X rays is realized, and real-time monitoring of the embolic material is realized; on the other hand, the addition of the fluorocarbon ultrasonic developer ensures that Pickering emulsion has unique advantages, so that the stability of the embolic agent is improved while long-term development is satisfied.
Description
Technical Field
The invention relates to the technical field of embolism, in particular to a temperature-sensitive Pickering emulsion interventional embolic material capable of being subjected to both X-ray development and long-acting ultrasonic development and bimodal development, and a preparation method and application thereof.
Background
Hepatocellular carcinoma (liver cancer for short) has become a serious disease in China, which seriously endangers human health due to factors such as high malignancy, rapid growth, easy recurrence and the like. The treatment of liver cancer mainly comprises surgical excision, radiotherapy, chemotherapy and interventional therapy, and the catheter arterial embolism chemotherapy (TransArtrialChemoEmbolization, TACE) in the interventional therapy is one of the main means for treating middle and late liver cancer at present. The selection of embolic agents is a key element in the success or failure of TACE. The current embolic agent mainly faces two major difficulties, namely contradiction between mobility and embolic property of the embolic agent, for example, iodized oil can be rapidly dispersed into tiny tumor arteries due to good mobility, and tumor blood supply is blocked in a short time, but long-term embolism of the tumor arteries is difficult to realize due to scouring of blood and rapid in-vivo clearance.
Secondly, the embolic material commonly used in clinic has no self-development characteristic, and can not be used for monitoring the development of postoperative long-term liver cancer. The poly-N-isopropyl acrylamide temperature-sensitive nano gel has low viscosity in a sol state, can be converted into a non-flowable gel state from good flow state at human body temperature, has good fluidity and embolism, and overcomes the contradiction between fluidity and embolism, but the embolism agent does not have a developing function and needs to be mixed with an iodine-containing contrast agent for development, and the iodine agent has shorter half-life in blood, so that the monitoring of the embolism agent and long-term follow-up after embolism in the embolism process are not facilitated. The Pickering emulsion has good fluidity before embolism, embolic property after embolism and long-acting development performance after operation, and is hopeful to realize diagnosis and treatment integration.
Disclosure of Invention
The invention provides a bimodal development temperature-sensitive Pickering emulsion interventional embolic material, a preparation method and application thereof, which can be used for X-ray development and long-acting ultrasonic development to coordinate the development capability and embolic effect of temperature-sensitive embolic agent.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the first aspect of the invention provides a preparation method of a bimodal developing temperature-sensitive Pickering emulsion interventional embolic material, which comprises the following steps:
s1, providing a water phase, wherein the water phase is gel aqueous dispersion liquid obtained by mixing temperature-sensitive nano gel freeze-dried powder with ultrapure water;
s2, providing an oil phase, wherein the oil phase is formed by mixing an ultrasonic developing solution and an oily developing solution according to the mass ratio of (9-1): (1-9) mixed composite developer, wherein an oily developer and an ultrasonic developer are dispersed in an oil phase;
s3, mixing the water phase and the oil phase according to the mass ratio of (9-1): (1-9) mixing, and placing the mixture in an ice water bath condition for intermittent emulsification to obtain the bimodal temperature-sensitive Pickering emulsion embolic material.
Preferably, in step S1, the temperature-sensitive nanogel lyophilized powder adopts poly N-isopropyl acrylamide nanogel with a three-dimensional network structure and good temperature responsiveness.
Preferably, in step S1, the weight of the thermosensitive nanogel in each 10ml of the aqueous gel dispersion is 0.2-1 g.
Preferably, in step S2, the ultrasound developing solution uses fluorocarbon and/or air or oxygen bubbles coated with a membrane stabilizer such as protein, polysaccharide, lipid, etc.
More preferably, in step S2, the ultrasonic developing solution is fluorocarbon.
Preferably, in step S2, the oil-based developer is an oil-based developer such as iodized oil and/or vegetable oil for injection.
More preferably, in step S2, the oil-based developer is iodized oil.
More preferably, in step S2, the mass ratio of the oil-based developer to the ultrasonic developer in the oil phase is (5-9): (1-5).
Preferably, in the step S3, the water phase and the oil phase are mixed according to the mass ratio (5-9): (1-5) mixing.
Preferably, in step S3, the batch emulsification process is as follows:
under the ice water bath condition, the high-speed shearing emulsification is carried out at 8500-9600 rpm, each time of shearing emulsification is carried out for 20-40 s, each time of standing is stopped for 20-40 s, the repeated steps are carried out for 3-6 times, and the total shearing emulsification time is 100-150 s.
The second aspect of the invention provides a bimodal developing temperature-sensitive Pickering emulsion interventional embolic material prepared by the method, wherein the emulsion droplet size distribution range is 150-250 nm.
The third aspect of the invention provides an application of the bimodal development temperature-sensitive Pickering emulsion interventional embolic material in preparing medicines for treating liver cancer.
Compared with the prior art, the invention has the following technical effects:
the invention creatively compounds the oily developer and the fluorocarbon compound, adopts the temperature-sensitive nanogel as the bimodal development temperature-sensitive Pickering emulsion embolic agent constructed by the aqueous dispersion, and realizes clear development under X rays and real-time monitoring of embolic materials on one hand; on the other hand, the addition of the fluorocarbon ultrasonic developer provides the Pickering emulsion with the unique advantages that: the fluorocarbon compound does not generate bubbles at room temperature (25 ℃) in vitro, ultrasonic micro bubbles are generated when entering the body (37 ℃), meanwhile, sol-gel phase transition behavior is generated by gel at 37 ℃, flowing sol is converted into a solidified gel state, the micro bubbles are wrapped by iodized oil drops and are locked in gel solids at the same time, so that the gel is not easy to break, and the stability of the embolic agent is improved while long-term development is satisfied.
In addition, the invention ensures that the emulsification process is carried out below the low critical transition temperature (LCST) by carrying out intermittent emulsification under ice bath conditions, and avoids emulsion breaking and layering caused by phase change of temperature-sensitive nanogel due to overhigh shearing temperature rise, thereby preparing emulsion with stable performance.
In addition, the preparation method has simple process and strong adjustability, can fully dissolve and disperse chemotherapeutic drugs with different solubilities, and has broad-spectrum drug loading property; meanwhile, the emulsion obtained by the preparation method provided by the invention has temperature sensitivity, is liquid at normal temperature, is converted into solid after injection, can effectively solve the contradiction between fluidity and embolism faced by the existing embolic agent, realizes development in embolism and after embolism by adding iodized oil, realizes long-term development of postoperative ultrasound by adding fluorocarbon compounds, and therefore has wide application prospect.
Drawings
FIG. 1 is a process flow diagram of a method of making the present invention;
FIG. 2 is a phase diagram of aqueous dispersions of PNA of different concentrations prepared according to the present invention;
FIG. 3 shows the stability results of aqueous dispersions of fluorocarbon compounds of varying concentrations prepared according to the present invention;
FIG. 4 is an in vitro ultrasonic development chart of Pickering emulsions with different mixture ratios and W/O ratios provided by the invention;
FIG. 5 shows the B ultrasonic detection of the kidney on the embolic side of a normal rabbit provided by the invention;
FIG. 6 shows CT scan results of 1w, 2w and 3w after kidney embolism of a normal rabbit provided by the invention;
FIG. 7 shows emulsion droplet morphology of different concentration PNA nanogel stabilized Pickering emulsions provided by the invention;
FIG. 8 is a micro-morphology of emulsion droplets of Pickering emulsions in different oil phase ratios provided by an embodiment of the present invention;
fig. 9 shows the B-ultrasonic development results (tumor area in circle) during the tumor growth trend study of VX2 liver cancer experimental rabbits according to the embodiment of the invention;
fig. 10 is a graph showing the growth rate of tumor growth in the course of the experimental rabbit with VX2 liver cancer according to the example of the present invention.
Detailed Description
Firstly, the invention provides a preparation method of a bimodal development temperature-sensitive Pickering emulsion interventional embolic material which can be developed by X-rays and can be developed by long-term ultrasound, so as to coordinate the development capability and the embolic effect of the temperature-sensitive embolic agent. The core scheme is that gel freeze-dried powder with different quality is dissolved in ultrapure water to obtain gel aqueous dispersion; mixing an oily developer with a fluorocarbon to obtain an oil phase mixture; and mixing the gel aqueous dispersion with the oil phase mixture, and carrying out intermittent emulsification under ice bath conditions to obtain the bimodal development temperature-sensitive Pickering emulsion.
Specifically, as shown in fig. 1, the preparation method of the bimodal developing temperature-sensitive Pickering emulsion interventional embolic material mainly comprises the following steps:
s1, preparation of an aqueous phase: providing temperature-sensitive nano gel freeze-dried powder, and adopting a magnetic rotor stirring method to mix the temperature-sensitive nano gel freeze-dried powder with ultra-pure water to obtain gel aqueous dispersion, wherein the prepared gel aqueous dispersion is a water phase;
s2, preparing an oil phase: the ultrasonic developing solution and the oily developing solution are mixed according to the mass ratio of (9-1): (1-9) mixing by adopting a magnetic rotor stirring method, wherein the prepared composite developing solution is an oil phase, and an oily developing agent and an ultrasonic developing agent are dispersed in the oil phase;
s3, mixing the water phase prepared in the step S1 and the oil phase prepared in the step S2 according to the mass ratio (9-1): (1-9) fully mixing, and then placing the mixture in ice water bath conditions for intermittent emulsification to obtain the bimodal temperature-sensitive Pickering emulsion embolic material capable of being subjected to X-ray development and long-acting ultrasonic development;
s4, observing the structure, stability and in-vitro and in-vivo developability of the prepared nanogel and Pickering emulsion.
The bimodal thermosensitive Pickering emulsion embolic material prepared by the method has the advantages that thermosensitive nanogel (PNA) can be well aggregated and adsorbed around emulsion drops to play a role in stabilizing emulsion, the Pickering emulsion has higher stability and more uniform emulsion drop particle size distribution, has good fluidity before gelation, and can be well gelled at 35 ℃; the in-vivo and in-vitro ultrasonic observation has better long-acting developability.
It should be understood that the steps S1, S2, S3 are not limited to the order of the steps of the method according to the embodiment of the present invention, and the order of the steps may be flexibly adjusted according to the actual production conditions, for example, S1 may be implemented after the step S2 is completed.
In the embodiment of the invention, in the step S1, the temperature-sensitive nanogel freeze-dried powder adopts poly-N-isopropyl acrylamide nanogel with a three-dimensional network structure and good temperature responsiveness. The temperature-sensitive nano gel freeze-dried powder is polymerized by a comonomer and a cross-linking agent.
The sources of the temperature-sensitive nanogel, the comonomer and the cross-linking agent are not particularly limited, and commercially available products well known to those skilled in the art can be adopted, and the products obtained by the preparation can also be prepared by adopting conventional technical means in the art.
As a preferred embodiment thereof, methacrylic acid is used as the comonomer, and N, N-methylenebisacrylamide (hereinafter referred to as MBA) is used as the crosslinking agent. The poly-N-isopropyl acrylamide nanogel crosslinked by MBA is prepared by the following process:
adding N-isopropyl acrylamide, MBA, an emulsifier and an initiator into a three-neck flask with a reflux condenser, heating and dissolving the mixture by using ultrapure water under magnetic stirring, heating a reaction system to 70 ℃, adding methacrylic acid after reacting for 30min, continuing to react for 4 hours to obtain a white turbid suspension, dialyzing and purifying the suspension in the ultrapure water, and then freeze-drying the suspension, wherein the freeze-dried powder is PNA.
In the embodiment of the invention, in step S1, the mixing of the temperature-sensitive nano gel lyophilized powder and the ultrapure water is a conventional operation in the art, so that the lyophilized powder can be completely swelled in the ultrapure water, and the temperature-sensitive nano gel lyophilized powder can be dispersed in the ultrapure water by adopting a magnetic rotor stirring method.
In the step S1, the weight of the temperature-sensitive nano gel contained in each 10ml of the water phase is 0.2-1 g. Preferably, the weight of the temperature-sensitive nanogel in each 10ml of the aqueous phase is 0.6-0.8 g.
In the embodiment of the present invention, in step S2, there is no particular limitation on the mixing manner, and the mixing of the oily developer and the ultrasonic developer is performed by using magnetic rotor stirring or manual stirring, which are well known to those skilled in the art, in order to uniformly disperse.
In step S2, the ultrasonic developing solution uses fluorocarbon and/or air or oxygen bubbles coated with membrane stabilizers such as proteins, polysaccharides, lipids, and the like. The oily developer adopts the same type of oily developer such as iodized oil and/or vegetable oil for injection.
As a preferred embodiment thereof, the ultrasonic developing solution preferably employs a fluorocarbon. The oil-based developer is preferably iodized oil. The iodized oil in the oil phase part can be used as a developer and a carrier for wrapping the fluorocarbon, and small bubbles generated by temperature change of the fluorocarbon are locked in the iodized oil while development is satisfied, so that long-term ultrasonic development is realized.
In addition, the aqueous phase is mixed with an ultrasonic developing aqueous dispersion, and the ratio of the ultrasonic developing agent is 10 to 90%, more preferably 10 to 50%, per milliliter of the ultrasonic developing aqueous dispersion. In this way, the amount of the ultrasonic developer with the proper proportion is screened according to the stability of the mixture, so that the negative influence caused by the excessive or the insufficient amount of the ultrasonic developer is avoided. When the ratio of the ultrasonic developer is smaller than the above ratio, the ultrasonic developing ability of the embolic agent cannot be effectively improved, and when the ratio of the ultrasonic developer is larger than the above ratio, the overall embolic effect of the embolic agent is reduced.
In the embodiment of the invention, the oily developer and the ultrasonic developer are mixed to obtain an oil phase, and the mass ratio of the oily developer to the ultrasonic developer in each milliliter of the oil phase is (9-1): (1-9); preferably, the mass ratio of the oily developer to the ultrasonic developer in each milliliter of the oil phase is (5-9): (1-5); more optionally, the mass ratio of oily developer to ultrasonic developer in each milliliter of oil phase is 7:3.
in the mass ratio of the oil developer to the ultrasonic developer, the X-ray developing capability and the ultrasonic developing capability are good, and the oil developer stably wraps the ultrasonic developing small bubbles at 37 ℃ so as to ensure long-term development of the ultrasonic.
In the embodiment of the invention, in the step S3, the water phase and the oil phase are mixed to obtain the bimodal development temperature-sensitive Pickering emulsion, wherein the mass ratio of the water phase to the oil phase in each milliliter of the emulsion is (1-9): (1-9). Preferably, the mass ratio of the aqueous phase to the oil phase in each milliliter of the emulsion is (5-9): (1-5). More preferably, the mass ratio of the aqueous phase to the oil phase per ml of emulsion is 7:3. the screening process was verified by in vitro stability of different mixtures, W/O ratio, ultrasound developability within 14 days, and in vivo animal experiments.
In addition, in the step S3, the water phase and the oil phase are mixed and are subjected to intermittent emulsification, so that the bimodal temperature-sensitive Pickering emulsion embolic agent is obtained. The manner in which the aqueous phase and the oil phase are mixed is not particularly limited in the present invention, and the mixing of the oily developer and the ultrasonic developer is well known to those skilled in the art. If magnetic rotor stirring or manual stirring is adopted, the purpose is to disperse uniformly.
Specifically, in step S3, the batch emulsification process is as follows: high-speed shearing and emulsifying at 7000-8000 rpm under ice water bath condition, each time of shearing and emulsifying for 20-40 s, each time of stopping and standing for 20-40 s, repeating for 3-6 times, and the total shearing and emulsifying time is 100-150 s. Preferably, the high-speed shearing emulsification is carried out at 9000rpm under ice water bath conditions, each shearing emulsification is carried out for 30s, each standing is stopped for 30s, the repeated steps are carried out for 4 times, and the total shearing emulsification time is 120s.
The oil phase and the water phase are intermittently emulsified under the ice bath condition, so that the emulsification process is ensured to be carried out below a low critical transition temperature (LCST), and emulsion breaking and layering caused by phase change of the temperature-sensitive nanogel due to overhigh shearing temperature are avoided, thereby preparing the emulsion with stable performance.
The main technical scheme of the preparation method is that temperature-sensitive nano gel freeze-dried powder is mixed with ultrapure water to obtain nano gel aqueous dispersion (aqueous phase), and the aqueous phase and an ultrasonic developer are mixed and screened according to different proportion to obtain the ultrasonic developer with proper proportion; then mixing the ultrasonic developer with oil developers with different proportions, and screening to obtain a stable oil phase; finally, emulsifying the water phase and the oil phase according to different proportions to obtain the bimodal development temperature-sensitive Pickering emulsion.
Compared with the prior art, the dual-mode development temperature-sensitive Pickering emulsion embolic agent is compounded by adopting iodized oil and fluorocarbon, and the temperature-sensitive nanogel is used as an aqueous dispersion to construct the dual-mode development temperature-sensitive Pickering emulsion embolic agent, so that clear development under X rays and real-time monitoring of embolic materials are realized. On the other hand, the addition of the fluorocarbon ultrasonic developer provides the Pickering emulsion with the unique advantages that: the fluorocarbon compound does not generate bubbles at room temperature (25 ℃) in vitro, ultrasonic micro bubbles are generated when entering the body (37 ℃), meanwhile, sol-gel phase transition behavior is generated by gel at 37 ℃, flowing sol is converted into a solidified gel state, the micro bubbles are wrapped by iodized oil drops and are locked in gel solids at the same time, so that the gel is not easy to break, and the stability of the embolic agent is improved while long-term development is satisfied.
The embodiment of the invention also provides a bimodal development temperature-sensitive Pickering emulsion interventional embolic material which is prepared by adopting the method, and the embolic material can be developed by X-rays and long-acting ultrasound.
The bimodal developing temperature-sensitive Pickering emulsion interventional embolic material prepared by the method has higher stability and temperature responsiveness, the emulsion droplet particle size is uniform, and the emulsion droplet particle size distribution range is 150-250 nm.
Finally, the embodiment of the invention also provides application of the bimodal development temperature-sensitive Pickering emulsion interventional embolic material in preparing medicines for treating liver cancer.
When in use, the bimodal development temperature-sensitive Pickering emulsion interventional embolic material is injected into the blood vessel of the liver cancer part through TACE, and then the purpose of treating the liver cancer is achieved through the occurrence of gelation, so that the development capability and the embolic effect of the temperature-sensitive embolic agent are effectively coordinated.
The Pickering emulsion obtained by oil-water emulsification mixing is inserted into the embolic material, and is uniformly mixed with the developer which can be developed under X-rays and can be developed by ultrasonic enhancement, the bimodal development capability of the embolic agent is ensured by adjusting the proportion of the oil phase mixture, and the stability and durability of the embolism are ensured by adjusting the proportion (water-oil ratio) of the aqueous dispersion and the oil phase mixture.
The third aspect of the invention provides an application of the bimodal development temperature-sensitive Pickering emulsion interventional embolic material in preparing medicines for treating liver cancer.
When in use, the Pickering emulsion interventional embolic material prepared by the invention is delivered to the tumor vascular site through TACE operation, gelation occurs under the body temperature environment (37 ℃), and the embolic effect of the temperature-sensitive embolic agent is effectively ensured; the ultrasonic small bubbles in the emulsion are wrapped by the oil phase and locked in the gel network, so that the ultrasonic small bubbles are not easy to be washed or broken by blood flow, not only can long-term postoperative review be met, but also long-term enhanced development after operation is realized.
In summary, the preparation method provided by the embodiment of the invention has simple operation process and strong adjustability, can fully dissolve and disperse chemotherapeutic drugs with different solubilities, has broad-spectrum drug loading property, and meanwhile, the emulsion interventional embolic material prepared by the method is liquid at normal temperature and turns into solid after injection due to temperature sensitivity, so that the contradiction between fluidity and embolism faced by the existing embolic agent can be effectively solved. The iodized oil is added to realize development in and after embolism, and the fluorocarbon compound is added to realize long-term development of ultrasonic after operation, so that the method has wide application prospect.
Stability investigation
To examine the effect of PNA nanogel concentration on Pickering emulsion stability, the phase transition of aqueous PNA dispersions of different concentrations at 25-40℃was observed, as shown in FIG. 2.
It was observed that the stable W/O was 7 with aqueous dispersions of 6% and 8% PNA: 3, as shown in fig. 7.
The effect of different oil phases on the micro-morphology of emulsion droplets in Pickering emulsion was examined, and the emulsion droplet morphology was observed with a laser confocal microscope at 488nm and 546nm wavelength excitation light, as shown in FIG. 8.
To investigate the in vitro developability at different ultrasound developers, mixtures, W/O ratios, the stable different mixtures, emulsions, aqueous dispersions of W/O ratios of 8% pna nanogel aqueous dispersions were characterized using an ultrasound contrast apparatus, as shown in fig. 3 and 4.
To explore in vivo embolization and long-term development after Pickering breast embolism, experimental rabbits were subjected to kidney embolism, CT scan and ultrasonic detection were performed at different time points before and after embolism, and embolization and long-term ultrasonic development at different time points were observed, as shown in FIGS. 5 and 6.
And in order to explore the application of Pickering emulsion in liver cancer embolism, tumor vascular embolism is carried out on VX2 liver cancer tumor rabbits, CT scanning and ultrasonic detection are carried out at different time points before and after embolism, embolism and long-acting ultrasonic development at different time points are observed, tumor volume and tumor growth rate are measured and calculated at the same time, and fig. 9 is a tumor ultrasonic development chart (tumor area in a circle); FIG. 10 is a growth graph of tumor growth rate.
The present invention will be described in detail and in detail by way of the following examples, which are not intended to limit the scope of the invention, for better understanding of the invention.
Example 1 preparation method of temperature-sensitive nanogel PNA and observation of stability and phase transition temperature
(1) The preparation method of the temperature-sensitive nano gel PNA comprises the following steps: 1.7-g N-isopropylacrylamide, 0.03g of N, N-methylenebisacrylamide, 0.05g of octadecyl trimethyl ammonium chloride and 0.08g of 2, 2-azobis (2-methylpropionamide) dihydrochloride are added into a 250ml three-neck flask provided with a reflux condenser and a conduit device, 150ml of ultrapure water is heated and dissolved under magnetic stirring, the reaction system is heated to 70 ℃ and then kept for 30 minutes, 215 microlitres of methacrylic acid is added, the reaction is continued for 4 hours at 70 ℃ to obtain a white turbid suspension, the suspension is dialyzed and purified in the ultrapure water and freeze-dried, and PNA freeze-dried powder is collected, so that is-obtained.
(2) 0.6g and 0.8g of PNA lyophilized powder were dissolved in 10ml of ultra pure water, respectively, and mixed under stirring under a magnetic rotor for 24 hours to prepare aqueous dispersions (aqueous phase) of 6% and 8% PNA.
(3) The aqueous PNA dispersions prepared in the above steps were placed in 5ml vials and the stability and phase change of the aqueous PNA dispersions were observed at 25-40℃as shown in the box of FIG. 2.
Example 2 screening and stability observations of oil phase partial ultrasound developer
(1) The preparation method of the temperature-sensitive nanogel PNA is the same as that of the step (1) in the embodiment 1, and the process is not described; and mixing the temperature-sensitive nano gel PNA with ultrapure water to prepare gel aqueous dispersion liquid serving as an aqueous phase.
(2) 8% of the aqueous gel dispersion liquid and 10%, 30% and 50% of fluorocarbon ultrasonic developer by mass of the total mass of the mixed solution are mixed, and the total volume of the mixed solution is 1ml.
(3) The aqueous dispersion of the above procedure was withdrawn and placed in a plastic dropper, and its stability was observed at normal temperature (25 ℃ C.) as shown in FIG. 3 at the box.
Example 3 preparation of bimodal development temperature-sensitive Pickering emulsion interventional embolic material and in-vitro development observation, the specific method comprises the following steps:
(1) The preparation method of the temperature-sensitive nanogel PNA is the same as that of the step (1) in the embodiment 1, and the process is not described; and mixing the temperature-sensitive nano gel PNA with ultrapure water to prepare gel aqueous dispersion liquid serving as an aqueous phase.
(2) According to the mass ratio of the iodized oil to the fluorocarbon in the oil phase of 7:3, placing the iodized oil and the fluorocarbon compound into a 5mL small bottle, and stirring and uniformly mixing the mixture until the total volume is 1mL to prepare an oil phase.
(3) Mixing the water phase and the oil phase, wherein the water-oil ratio is preferably 7:3, carrying out intermittent emulsification 9000rpm high-shear emulsification under ice bath conditions, wherein each time of shear emulsification is 30s, each time of standing for 30s, repeating for 4 times, and the total shear emulsification time is 120s, thereby obtaining the Pickering emulsion interventional embolic material capable of being developed and embolized.
(4) The Pickering emulsion interventional embolic material obtained in the above step is extracted, placed in plastic drip irrigation, immersed in water bath at 37 ℃ for 5min at constant temperature, and subjected to in-vitro developability characterization by using an ultrasonic probe after gelation, as shown at the block of FIG. 4.
Example 4 in vivo developability observation of bimodal development temperature-sensitive Pickering emulsion interventional embolic material the specific method comprises the following steps:
(1) The preparation method of the temperature-sensitive nanogel PNA and Pickering emulsion interventional embolic material is the same as that of example 1 and example 3, and the process is not described.
(2) Taking the W/O ratio of 7:3, delivering the emulsion to normal rabbit kidneys by arterial chemoembolization (TACE) as an experimental group; the post-embolism 0d, 1d, 3d, 1w, 2w and 3w were subjected to ultrasound developability review of the post-embolism kidneys in the B-ultrasound mode, respectively, while the post-embolism 1w, 2w and 3w were subjected to CT scan review, as shown in fig. 5, 6.
Example 5 investigation of the Effect of different concentrations of PNA on Pickering emulsion stability
(1) The preparation method of the temperature-sensitive nanogel PNA is the same as that of the step (1) in example 1, and the process is not described.
(2) According to example 1, 0.6g and 0.8g of PNA lyophilized powder, respectively, were dissolved in 10ml of ultra pure water to prepare 6% and 8% aqueous PNA dispersions, respectively, to prepare 6% aqueous PNA dispersion and 8% aqueous PNA dispersion, respectively, and the stabilized oil phase ratio was 7:3,W/O is 7:3.
(3) The stability of emulsions 1d, 3d and 7d was observed by light microscopy at 20X as shown in figure 7.
Example 6 investigation of the Effect of different oil phases on the micro-morphology of emulsion droplets in Pickering emulsions
(1) PNA nanogels were prepared as described in step (1) of example 1, and this process is not described.
(2) 0.8g of PNA lyophilized powder was dissolved in 10ml of ultra pure water to prepare an 8% aqueous dispersion of PNA, and iodized oil was added to the oil phase: the fluorocarbon is preferably 7:3 are respectively put into 5mL vials with the total mass of 3mL, and are stirred and mixed uniformly to prepare the oil phase.
(3) A W/O ratio of 7 was prepared as in steps (2) and three of example 2: 3 (coumarin 6-labeled oil phase, rhB-labeled nanogel), and the microcosmic appearance of Pickering droplets was observed using a laser confocal microscope at 488nm and 546nm wavelength excitation light, as shown in FIG. 8.
Example 7 investigation of the application of Pickering emulsion in the treatment of liver cancer
(1) The stable W/O of the 8% PNA gel dispersion prepared according to the procedure of examples 1, 2 was 7:3.
(2) Constructing a VX2 liver cancer experimental rabbit model, delivering the emulsion to a blood supply artery of a tumor vessel Through Arterial Chemoembolization (TACE), performing ultrasonic imaging review on the tumor in a pre-embolization mode-1 d, a post-embolization mode-1 w, performing CT scanning review on the experimental rabbit tumor in a pre-embolization mode-1 w, performing CT scanning image reconstruction on the experimental rabbit tumor, calculating the tumor size after reconstruction through CT scanning images, and calculating the tumor growth rate according to the formula V=A×B2xpi/6 and TumorGrowthRate% = (Vt-V0) V0 x 100 (A is the maximum diameter of the maximum section of the tumor, B is the transverse diameter, V0 and Vt are the tumor volumes of 1w and 2w before and after TAE respectively). As shown in fig. 9 and 10.
Comparative example 1
An aqueous dispersion of PNA was prepared using the preparation method provided in example 1. The comparative example 1 differs from example 1 in that: 0.2g and 0.4g of PNA lyophilized powder were dissolved in 10ml of ultra-pure water to prepare 2% and 4% PNA aqueous dispersion, and the stability and phase change of the aqueous gel dispersion were observed under the same conditions, as shown in FIG. 2.
Comparative example 2
An ultrasonically developed aqueous dispersion was obtained using the preparation method provided in example 2. This comparative example 2 differs from example 2 in that: the concentration of fluorocarbon in the ultrasonic developing aqueous dispersion was 70% and 90%, and the other conditions were unchanged, and in vitro stability was observed, as shown in fig. 3.
Comparative example 3
The preparation method provided in the example 3 is adopted to prepare the bimodal development temperature-sensitive Pickering emulsion embolic material. This comparative example 3 differs from example 3 in that: iodized oil in oil phase: fluorocarbon was used in an amount of 5: 5. 7:3. 9:1, mixing the water phase and the oil phase, preparing each group of W/O ratios according to the table 1, and observing the in vitro development condition under the same conditions, wherein the in vitro development condition is shown in fig. 4.
TABLE 1
The preparation method and the operation method provided in example 4 are adopted. This comparative example 4 differs from example 4 in that: in the normal rabbit kidney embolism experiment, iodized oil is used as an embolic agent, and the other conditions are unchanged as shown in fig. 5 and 6.
Comparative example 5
The preparation method provided in example 5 is adopted to prepare the temperature-sensitive embolic agent. This comparative example 5 differs from example 5 in that the W/O stabilized with aqueous dispersion of 6% PNA is 7:3, the remaining conditions were unchanged, as shown in fig. 7.
Comparative example 6
The temperature-sensitive embolic agent prepared by the preparation method provided in the example 6. This comparative example 6 differs from example 6 in that the iodized oil in the oil phase: the fluorocarbon compound is prepared according to the following proportion of 5: 5. 9:1, the remainder being unchanged, as shown in figure 8.
Comparative example 7
The investigation method provided in example 7 was used. The comparative example 7 is different from example 7 in that the VX2 hepatoma rabbit was embolized with only physiological saline for injection.
Test verification
As shown in FIG. 2, the aqueous PNA dispersions of example 1 and comparative example 1 were observed for stability and phase change at 25 to 40℃respectively, and the aqueous PNA dispersions of four different concentrations were changed from a liquid state to a solid state by flowing at 32℃and were degraded in stability by precipitation of water at 2% and 4% concentrations by increasing the temperature.
When stability observations were made on aqueous dispersions of fluorocarbon compounds of different concentrations as provided in example 2 and comparative example 2, it can be seen that the poor stability of 70% and 90% aqueous dispersions at 25 ℃ resulted in significant delamination, as shown in fig. 3.
The emulsions of different W/O ratios prepared under the three different mixture conditions provided in example 3 and comparative example 3 were subjected to long-term ultrasonic development observation for 14 days, and it can be seen that the W/O ratio was 7: the ultrasound developability of the emulsion of group 3 was significantly better over the other groups for 14 days, as shown in fig. 4.
As can be seen from example 4 and comparative example 4, the developability and embolization effect of the Pickering emulsion group (experimental group) in 21d in the in vivo experiment were significantly higher than those of the iodized oil group (control group), as shown in fig. 5 and 6.
The Pickering emulsions of different concentrations provided in example 5 and comparative example 5 were observed by light microscopy, and the emulsion stability of 8% of example 5 as an aqueous dispersion was significantly higher than that of comparative example 5 as a 6% aqueous dispersion, as shown in FIG. 7.
The emulsions of example 6 and comparative example 6 were subjected to confocal laser observation at different oil phase mixture ratios, and in example 6, the ratio of the emulsions was 7:3 Pickering emulsion droplets as oil phase have small particle size and good particle size distribution, and in comparative example 6, the emulsion droplets have a particle size distribution of 5:5 after emulsification of Pickering emulsion as oil phase, air bubbles were leaked out, stability was poor, and 9:1 Pickering emulsion droplets as oil phase had a low uniformity of particle size distribution and large emulsion droplets appeared, illustrated at 7:3 has good stability as oil phase as shown in figure 8.
The embolization of the emulsions provided in example 7 and comparative example 7, compared with the normal saline group, showed significantly lower tumor growth rate in the Pickering emulsion group, indicating that the Pickering emulsion had better growth inhibition, as shown in FIGS. 9 and 10.
The above description of the specific embodiments of the present invention has been given by way of example only, and the present invention is not limited to the above described specific embodiments. Any equivalent modifications and substitutions for the present invention will occur to those skilled in the art, and are also within the scope of the present invention. Accordingly, equivalent changes and modifications are intended to be included within the scope of the present invention without departing from the spirit and scope thereof.
Claims (10)
1. The preparation method of the bimodal development temperature-sensitive Pickering emulsion interventional embolic material is characterized by comprising the following steps of:
s1, providing a water phase, wherein the water phase is gel aqueous dispersion liquid obtained by mixing temperature-sensitive nano gel freeze-dried powder with ultrapure water;
s2, providing an oil phase, wherein the oil phase is formed by mixing an ultrasonic developing solution and an oily developing solution according to the mass ratio of (9-1): (1-9) mixed composite developer;
s3, mixing the water phase and the oil phase according to the mass ratio of (9-1): (1-9) mixing, and placing the mixture in an ice water bath condition for intermittent emulsification to obtain the bimodal temperature-sensitive Pickering emulsion embolic material.
2. The preparation method of claim 1, wherein in step S1, the temperature-sensitive nanogel lyophilized powder adopts poly-N-isopropyl acrylamide nanogel with a three-dimensional network structure and good temperature responsiveness.
3. The method according to claim 1, wherein in step S1, the weight of the thermosensitive nanogel is 0.2 to 1g per 10ml of the aqueous gel dispersion.
4. The method according to claim 1, wherein in step S2, the ultrasonic developing solution is a fluorocarbon and/or air or oxygen bubbles coated with a membrane stabilizer such as protein, polysaccharide, lipid, etc.
5. The method according to claim 1, wherein in step S2, the oily developer is an oily developer such as iodized oil and/or vegetable oil for injection.
6. The method according to claim 5, wherein in step S2, the mass ratio of the oil-based developer to the ultrasonic developer in the oil phase is (5 to 9): (1-5).
7. The preparation method according to claim 1, wherein in step S3, the mass ratio of the aqueous phase to the oil phase is (5-9): (1-5).
8. The method according to claim 1, wherein in step S3, the batch emulsification process is:
under the ice water bath condition, the high-speed shearing emulsification is carried out at 8500-9600 rpm, each time of shearing emulsification is carried out for 20-40 s, each time of standing is stopped for 20-40 s, the repeated steps are carried out for 3-6 times, and the total shearing emulsification time is 100-150 s.
9. A bimodal development temperature-sensitive Pickering emulsion interventional embolic material prepared by the method of any one of claims 1 to 8, wherein the emulsion droplet size distribution range is 150-250 nm.
10. Use of the bimodal development temperature-sensitive Pickering emulsion interventional embolic material as claimed in claim 9 in the preparation of a medicament for treating liver cancer.
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