CN113877055A - Radiation-sensitive wearable drug controlled release system - Google Patents
Radiation-sensitive wearable drug controlled release system Download PDFInfo
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- CN113877055A CN113877055A CN202110911314.7A CN202110911314A CN113877055A CN 113877055 A CN113877055 A CN 113877055A CN 202110911314 A CN202110911314 A CN 202110911314A CN 113877055 A CN113877055 A CN 113877055A
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Images
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Abstract
The invention discloses a radiation-sensitive wearable drug controlled-release system, which can be used for treating unpredictable radiation injury and is characterized in that the system is wearable, external ionizing radiation can be monitored in real time after the system is started, and when a body is radiated above a threshold value, a heating device can be quickly started, so that drug-loaded microneedles embedded in the skin can quickly release drugs, and the body can be protected in time.
Description
Technical Field
The invention relates to the field of medicine invention, in particular to a radiation-sensitive wearable medicine controlled release system and a preparation method thereof. The system can monitor ionizing radiation and quickly respond to release the medicine into the body.
Background
Radiation injury is acute, chronic or delayed body tissue damage caused by ionizing radiation. When ionizing radiation (such as X-rays, neutrons, protons, alpha particles, beta particles and gamma rays) acts on the organism, energy directly acts on biomolecules to cause the ionization and excitation of the biomolecules, so that protein chains, RNA or DNA chains are broken, enzymes are inactivated, and substances for maintaining the life functions of the organism are damaged. This effect of biomolecule damage directly caused by radiation is known as direct effect. The water content in human body is about 70%, and ionizing radiation can cause ionization and excitation of water molecules to generate a large amount of free radicals. The free radical is an unstable structure, has very active chemical properties, and is easy to interact with surrounding substances to destroy the normal structure of the biomolecule. This is an indirect effect of ionizing radiation. The ionizing radiation damage causes the change of the structure of biological molecules through direct and indirect effects, further causes the damage of the cellular level, the organ level to the whole body level by the damage of the molecular level, generates corresponding physiological metabolism disorder, and causes various symptoms and long-term effects and even death. Acute radiation sickness is a systemic disease caused by the body receiving a large dose (> 1Gy) of ionizing radiation within a short period of time. Acute radiation diseases are classified into three types, i.e., bone marrow type, intestinal type and brain type, according to the size of irradiation dose, the characteristics of pathology and clinical course. The acute radiation sickness of bone marrow type is an acute radiation sickness with typical staged course, which takes the damage of hematopoietic tissue of bone marrow as basic lesion and takes the main clinical manifestations of leucopenia, infection, hemorrhage, etc. Nuclear accidents, spatial radiation and tumor radiotherapy may all cause acute radiation sickness of the bone marrow type. The treatment of acute radiation sickness of bone marrow type has been highly regarded by various countries and is an important research content of radiation medicine and protection science.
The cell factor and polypeptide protein medicine can relieve the function failure of bone marrow caused by irradiation, stimulate the recovery of hematopoietic function, accelerate the proliferation and differentiation of hematopoietic stem cells and progenitor cells, and effectively treat acute radiation diseases, and comprises granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-12 (IL-12), bacterial flagellin derivative (CBLB502), recombinant human interleukin-11 (rhIL-11), recombinant human thrombopoietin (rhTPO) and the like. Cytokine and polypeptide protein drugs can be generally injected subcutaneously, and have poor patient compliance and many limiting conditions, and need medical care personnel to assist in drug administration. Many studies have demonstrated that cytokines can be used in large doses to effectively treat hematopoietic system damage, and that the earlier the dose is administered after exposure to radiation, the better the radioprotective effect. However, radiation damage caused by nuclear accidents or nuclear explosions is often sudden, people cannot make simultaneous or immediate response and administration, the traditional administration mode cannot be used for administration while being irradiated, and the optimal treatment opportunity is often missed.
Transdermal preparations are preparations that absorb drugs through the skin and exert their effects. The medicine can exert the drug effect on the local or the whole skin, and can avoid gastrointestinal side effects and first-pass effect caused by oral administration and discomfort and pain caused by injection administration. Because of the natural barrier action of the stratum corneum of the skin, transdermal drug delivery formulations have strict requirements on drug properties, are extremely limited in the dose of administration, are generally applicable to only a small number of small molecule drugs, and are up to 5 mg.
The micro-needle is a needle with the length of only 25-2000 mu m, can pierce the stratum corneum of the skin without touching the pain nerve, reduces the discomfort and pain of a patient, has good patient compliance, and can improve the skin penetration efficiency of the medicament. Wearable medical equipment is generally used for monitoring patient's sign, has important effect in fields such as health supervision, safety monitoring, curative effect evaluation, disease early discovery.
Disclosure of Invention
The invention discloses a radiation-sensitive wearable drug controlled-release system, which can be used for treating unpredictable radiation injury and is characterized in that the system is wearable, external ionizing radiation can be monitored in real time after the system is started, and when a body is radiated above a threshold value, a heating device can be quickly started, so that drug-loaded microneedles embedded in the skin can quickly release drugs, and the body can be protected in time.
The wearable drug controlled-release system sensitive to radiation is formed by combining different accessories, comprises a power supply, an ionizing radiation sensor, a controller, a flexible heater, a temperature sensor and drug-loading temperature-sensitive micro-needles, and can further comprise a connecting device and a shell according to the wearing requirements of different parts.
When the radiation dose reaches a set threshold value, the controller starts the flexible heater to heat, when the temperature reaches a set temperature, the temperature sensor plays a role, the heating is stopped, and the heat generated by heating melts the drug-carrying temperature-sensitive microneedle coating layer inserted into the skin to release the encapsulated drug into the body.
The power source is selected from the group consisting of alkaline batteries and lithium batteries, preferably alkaline batteries.
The ionizing radiation sensor is a device for detecting the radiation dose of the environment, can detect an external radiation signal and transmit the electric signal to the controller, and an internal semiconductor function device of the ionizing radiation sensor is selected from a geiger tube and a scintillator, preferably the scintillator.
The temperature sensor is a contact temperature sensor body temperature paster and can sense the body surface temperature in a contact way, so that an electric signal is transmitted to the controller.
The controller is a core device of a radiation controlled-release system, can receive electric signals transmitted by an ionizing radiation sensor and a temperature sensor, converts the electric signals into digital signals, and controls a heater to work to release medicines, and mainly comprises an STC12C2052 singlechip.
The flexible heater is a device for providing heat to control the drug-loaded temperature-sensitive micro-needle to release the drug, and comprises a flexible substrate layer and a heating layer. The flexible substrate material is selected from the group consisting of Polyimide (PI), polyethylene terephthalate (PET) and Polydimethylsiloxane (PDMS), preferably PET. The heating material of the flexible heater is selected from Ag nanowires, Ag nanoparticles, Cu nanowires, Cu nanoparticles, Al nanowires, Al nanoparticles, Fe nanowires, Fe nanoparticles, graphene, carbon nanotubes, carbon fibers, poly (3, 4-ethylenedioxythiophene)/polystyrene sulfonic acid (PEDOT/PSS polymer), preferably Ag nanowires, Ag nanoparticles, Cu nanowires and Cu nanoparticles. The conductive material of the flexible temperature sensor is Ag nanoparticles or PEDOT/PSS conductive polymer. The flexible temperature sensor is prepared by a dispensing method, an ink-jet printing method, a blade coating method, a spin coating method and a film transfer method, and the dispensing method, the ink-jet printing method and the blade coating method are preferred.
The drug-carrying temperature-sensitive microneedle is a core accessory of a radiation-sensitive wearable drug controlled-release system. The drug-carrying temperature-sensitive microneedle exists in a patch form, a plurality of microneedles with equal distances are arranged on the patch, and 1-10 microneedles, preferably 2-5 microneedles, can be arranged in a distance of 1 mm; at 1cm2The area of (A) can be 100-10000, preferably 400-2500 micro-needles. The shape of the microneedle is selected from conical, cylindrical and prismatic, preferably conical. The microneedle body height ranges from 100 μm to 2000 μm, preferably from 300 μm to 1000 μm. The diameter of the microneedle base is in the range of 50 to 500 μm, preferably 100 to 300 μm.
The drug-carrying temperature-sensitive micro-needle structure comprises a needle body and a coating layer. The needle matrix material is a biocompatible soluble material or a biocompatible soluble composition, and specifically comprises a polymer and a small molecule carbohydrate. The polymer is selected from dextran, chondroitin sulfate, polyvinyl alcohol, silk fibroin, sodium carboxymethyl cellulose, alginate, hyaluronate, polyvinylpyrrolidone, preferably from polyvinyl alcohol, sodium carboxymethyl cellulose, hyaluronate, polyvinylpyrrolidone, more preferably hyaluronate. The small molecule saccharide compound is selected from trehalose, maltose, sucrose, mannose, xylitol, lactose, galactose and glucose. The coating layer material is selected from tridecanoic acid, dodecanoic acid, tetradecylamine, hexadecylamine, and the mixture of the fatty acid and the fatty amine; these mixtures of fatty acids and fatty amines are selected from the group consisting of mixtures of tridecanoic and tetradecylamine, mixtures of dodecanoic and tetradecylamine, mixtures of tridecanoic and hexadecylamine, and mixtures of dodecanoic and hexadecylamine.
The preparation of the drug-loaded temperature-sensitive microneedle is divided into two stages: preparing a needle body and preparing a coating layer. The preparation of the needle body can adopt the preparation method of the soluble micro-needle in the public report, and only the medicine with proper shape, height of the needle body, diameter of the base and certain proportion can be obtained. Specifically, the needle body is prepared by the following steps: dissolving a certain amount of polymer and micromolecular carbohydrate in a medicinal solution, dropwise adding the solution into a microneedle mould, placing the microneedle mould in vacuum equipment to ensure that the solution completely enters a mould hole, drying the mould at room temperature until the mould is formed, continuously adding the polymer solution without the medicament into the mould, volatilizing the solvent, curing and forming the mould, and continuously operating until a complete microneedle body is obtained. The coating layer can be prepared by dipping coating process, atomizing adsorption coating process and spray coating process, preferably spray coating process. Specifically, the preparation steps of the coating layer are as follows: fixing the microneedle base on a plane, uniformly spraying an organic solvent solution for dissolving the coating layer material on the needle body by using spraying equipment until a complete coating layer is formed, and finally obtaining the drug-loaded temperature-sensitive microneedle.
The drug contained in the drug-loaded temperature-sensitive microneedle is a drug with an anti-radiation effect, preferably a cytokine or polypeptide protein drug, specifically a granulocyte colony stimulating factor (G-CSF), a granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-12 (IL-12), a bacterial flagellin derivative (CBLB502), recombinant human interleukin-11 (rhIL-11), recombinant human thrombopoietin (rhTPO), preferably a granulocyte colony stimulating factor, a granulocyte-macrophage colony stimulating factor, recombinant human thrombopoietin, and most preferably a granulocyte colony stimulating factor.
The drug-loaded temperature-sensitive microneedle has higher strength, can smoothly penetrate into the skin and is not easy to break. After the drug-carrying temperature-sensitive microneedle is inserted into the skin, the drug-carrying temperature-sensitive microneedle can be kept complete in the skin and can be kept stable for a long time, and under the condition of no heating, the coating layer is kept complete and the drug is not released into the body, but is melted after being heated, and the drug is rapidly released into the body along with the dissolution of the microneedle.
The connection means is selected from the group consisting of bluetooth technology and wireless connection technology, by means of which the ionizing radiation sensor may be connected to the controller, preferably bluetooth technology.
The material of the shell is selected from light-weight and corrosion-resistant materials, preferably photosensitive resin. The shell can be prepared by a 3D technology, and the controller can be protected to work stably.
The radiation-sensitive wearable drug controlled-release system is small in size, can be conveniently worn and fixed, can instantly respond to ionizing radiation above an external threshold value, starts heating, quickly releases drugs in a body, and enables the body to be protected to the maximum extent.
Drawings
Figure 1. granulocyte colony stimulating factor-loaded radiation-sensitive wearable drug controlled release system (GWS) assembly schematic diagram
Figure 2 is a GWS (GWS) assembly drawing of a radiation-sensitive wearable drug controlled release system carrying granulocyte colony stimulating factor
Figure 3 is a morphology diagram of a granulocyte colony stimulating factor-loaded microneedle (GMN) patch and a granulocyte colony stimulating factor-loaded temperature-sensitive microneedle (GTSMN) patch in the preparation process of a granulocyte colony stimulating factor-loaded radiation-sensitive wearable drug controlled release system (GWS). Electron micrographs of GMN (FIG. 3A) and GTSMN (FIG. 3B); GMN (fig. 3C) and GTSMN (fig. 3D) stereogram. The scale in the figure is 200 μm
FIG. 4 is a pressure and displacement curve diagram of a common microneedle (GMN) patch and a temperature sensitive microneedle (GTSMN) patch in the preparation process of a radiation sensitive wearable drug controlled release system (GWS) carrying granulocyte colony stimulating factor
Fig. 5 is a skin insertion section of a General Microneedle (GMN) patch and a temperature sensitive microneedle (GTSMN) patch in the preparation process of a granulocyte colony stimulating factor-loaded radiation-sensitive wearable drug controlled release system (GWS). The scale in the figure is 100. mu.m. Arrow indicates the hole formed by the insertion of microneedle
Figure 6 temperature profiles at various voltages for flexible heaters in granulocyte colony stimulating factor-loaded radiation-sensitive wearable drug controlled release system (GWS)
Figure 7 effect of flexible heater bending on electrical performance in granulocyte colony stimulating factor-loaded radiation-sensitive wearable drug controlled release system (GWS)
FIG. 8 shows the melting process of a rhodamine B-containing temperature-sensitive microneedle coating layer in a granulocyte colony stimulating factor-loaded radiation-sensitive wearable drug controlled release system (GWS) at different temperatures
Figure 9 release behavior of temperature sensitive microneedles (GTSMN) in granulocyte colony stimulating factor-loaded radiation sensitive wearable drug controlled release system (GWS) at different temperatures
Figure 10 in vitro release profile of temperature sensitive microneedles (GTSMN) in granulocyte colony stimulating factor-loaded radiation sensitive wearable drug controlled release system (GWS)
Figure 11 biosafety assessment of granulocyte colony stimulating factor-loaded radiation-sensitive wearable drug controlled release system (GWS). Skin state 12 hours after administration of healthy mice and GWS (A), body weight change 30 days after administration of healthy mice and GWS (B), HE pictures of healthy mice and GWS 0 and 3 days after administration
FIG. 12 is a graph of blood concentration time curves for temperature sensitive microneedle (GTSMN) loaded with granulocyte colony stimulating factor, radiation sensitive wearable drug controlled release system (GWS) loaded with granulocyte colony stimulating factor, radiation sensitive wearable drug controlled release system (4h/GWS) loaded with granulocyte colony stimulating factor after wearing for 4 hours, radiation sensitive wearable drug controlled release system (8h/GWS) loaded with granulocyte colony stimulating factor after wearing for 4 hours, and subcutaneous granulocyte colony stimulating factor (I.H.G-CSF)
Figure 13, (a) mouse dosing profile of a granulocyte colony stimulating factor-loaded radiation-sensitive wearable drug controlled release system (GWS); (B) time/dose rate versus time/flexible heater temperature; (C) white Blood Cell (WBC) time curves after each set of irradiation; (D) effect of various preparations containing granulocyte colony-stimulating factor on mouse granulocyte-macrophage colony (CFU-GM), and the effect of various preparations of G-CSF on mouse bone marrow nucleated cells. Bone marrow nucleated cytopathograms of Control (Control, E), GSTMN (F), I.H.G-CSF (G), 24h/I.H.G-CSF (H), GWS (I), 8h/GWS (J). The scale in the figure is 100 μm
Detailed Description
Example 1 radiation-sensitive wearable drug controlled release System carrying granulocyte colony stimulating factor
Dissolving the granulocyte colony stimulating factor in phosphate buffer solution with pH7.4 to obtain 4mg/ml granulocyte colony stimulating factor solution; adding sodium hyaluronate and trehalose to obtain drug-containing microneedle matrix solutions with concentrations of 10% (w/v) and 7% (w/v), respectively; dripping 0.2g of the microneedle matrix solution into a microneedle mould, placing in a vacuum drier at room temperature, sealing, reducing pressure, standing for 2 min, taking out, and cooling at room temperatureDrying and molding in a sterile clean cabinet; preparing a chloroform solution of polyvinylpyrrolidone K90 with the concentration of 15% (w/v), dropwise adding the chloroform solution into the mold, placing the mold in a vacuum drier at room temperature, hermetically reducing the pressure, placing the mold for 1 minute, taking out the mold, and placing the mold in a sterile clean cabinet at room temperature for drying and molding; preparing 1% (w/v) (2, 4, 6-trimethylbenzoyl) diphenyl phosphine oxide N-vinyl pyrrolidone solution, dripping the solution into the mold, and using the power of 600mW/cm with the emission wavelength of 365nm2Irradiating for 3 minutes by using an ultraviolet lamp to obtain the granulocyte colony stimulating factor-loaded microneedle; sticking a double-sided adhesive tape to the basal layer face of the granulocyte colony stimulating factor soluble microneedle, fixing a microneedle body in a culture dish, enabling the needlepoint to face outwards, using a normal hexane solution containing 1% (w/v) dodecanoic acid and 0.5% (w/v) hexadecylamine as a coating solution, placing the coating solution in an electrospray gun, enabling the distance between the electrospray gun and the microneedle to be about 15cm, carrying out 45-second spray coating on the microneedle in the vertical direction, and rapidly volatilizing a solvent at room temperature to obtain the granulocyte colony stimulating factor-loaded temperature-sensitive microneedle; printing ink by using an Ag nanoparticle solution and performing ink-jet printing on a PET (polyethylene terephthalate) film for 2 times by using a flexible electronic printer to obtain a 15mm double-layer serpentine pattern flexible heater, leading out electrodes at two ends by using a wire, packaging by using a PDMS (polydimethylsiloxane) film, and measuring the resistance of the flexible heater to be 20 omega by using a universal electric meter; the two electrodes of the flexible heater are connected with the single chip microcomputer; one surface of the heater covers the temperature sensor, and the other surface of the heater is fixed on the granulocyte colony stimulating factor temperature-sensitive micro-needle by using double-sided adhesive tape; 3 sections and 5 sections of alkaline batteries (1.5V/section) are used as power supplies and connected with the singlechip; assembling to obtain the radiation-sensitive wearable drug controlled-release system carrying the granulocyte colony-stimulating factor.
The assembly schematic diagram of the granulocyte colony stimulating factor-loaded radiation-sensitive wearable drug controlled release system (GWS) is shown in figure 1; the object is assembled as shown in figure 2.
The medicines in the preparation process can be replaced by granulocyte-macrophage colony stimulating factor, interleukin-12, bacterial flagellin derivatives, recombinant human interleukin-11 and recombinant human thrombopoietin, and a radiation-sensitive wearable medicine controlled-release system carrying the granulocyte-macrophage colony stimulating factor, a radiation-sensitive wearable medicine controlled-release system carrying the interleukin-12, a radiation-sensitive wearable medicine controlled-release system carrying the bacterial flagellin derivatives, a radiation-sensitive wearable medicine controlled-release system carrying the human interleukin-11 and a radiation-sensitive wearable medicine controlled-release system carrying the human thrombopoietin can be respectively obtained.
The Ag nanoparticle solution in the preparation process can be replaced by Fe nanoparticle solution and Cu nanoparticle solution to respectively obtain corresponding drug-loaded radiation-sensitive wearable drug controlled-release systems.
Experimental example 1 appearance of temperature-sensitive microneedle in radiation-sensitive wearable drug controlled-release system carrying granulocyte colony stimulating factor
Sample preparation: a granulocyte colony stimulating factor-loaded microneedle (GMN) patch and a granulocyte colony stimulating factor-loaded temperature-sensitive microneedle (GTSMN) prepared as in example 1.
The experimental method comprises the following steps:
1. scanning electron microscope
GMN and GTSMN were fixed with conductive tape, and the morphology of GMN and GTSMN was observed with a scanning electron microscope (SEM, JSM-6330F, Japan) at 5 kV.
2. Body-viewing mirror
Morphology observation of GMN and GTSMN was performed with a stereoscope (S6D, Leica, Germany) to characterize the coating integrity of temperature sensitive microneedles and measure the tip and height dimensions of the needles.
Results and discussion:
microneedle gaps in GTSMN were found to be surrounded by a coating (fig. 3A and 3B). The tip width and tip length of GMN are somewhat different from GTSMN. The GMN tip had a tip width of 23 μm and a tip length of 846 μm (FIG. 3C). The GTSMN had a tip width of 87 μm and a tip length of approximately 791 μm (FIG. 3D). Indicating that the GTSMN had sufficient length after coating, but the tip became wider.
Experimental example 2 mechanical properties of temperature sensitive microneedle in radiation sensitive wearable drug controlled release system carrying granulocyte colony stimulating factor
Sample preparation: a granulocyte colony stimulating factor-loaded microneedle (GMN) patch and a granulocyte colony stimulating factor-loaded temperature-sensitive microneedle (GTSMN) prepared as in example 1.
The experimental method comprises the following steps:
the mechanical properties of the microneedles were measured using a universal tensile tester (WDW type, denwangtarbei instruments equipment ltd). The back lining surfaces of the two microneedles are fixed in the center of a universal pull horizontal objective table through double faced adhesive tapes, the trigger force of a machine is set to be 0.05N, the maximum pressure is 50N, the compression rate is 0.5mm/min, and after the probe contacts the needle point of the microneedle, the change curve of the pressure along with the displacement is recorded for comparing the needle point rigidity of the two microneedles.
Results and discussion:
GMN has deformation displacement of 0.82mm under the action of pressure of 20N. The deformation displacement of the GTSMN array was 0.67mm also under a pressure of 20N (fig. 4). The results indicate that GTSMN can relieve extraneous stress and increase the mechanical strength of the microneedles compared to GMN. GTSMN, which possesses high mechanical strength, can provide a basis for skin insertion of microneedles.
Experimental example 3 skin insertion Performance of temperature-sensitive microneedle in radiation-sensitive wearable drug controlled-release System carrying granulocyte colony stimulating factor
Sample preparation: a granulocyte colony stimulating factor-loaded microneedle (GMN) patch and a granulocyte colony stimulating factor-loaded temperature-sensitive microneedle (GTSMN) prepared as in example 1.
The experimental method comprises the following steps:
the depth of insertion of the microneedles into the skin is critical to affect drug delivery and therapeutic efficacy. GMN is inserted into the skin to a depth of about 230 μm, and the skin is inserted to an aperture of 48 μm (FIG. 5A); GTSMN has a skin insertion depth of about 210 μm and a skin insertion aperture of 46 μm (fig. 5B), and the skin penetration of both microneedles is substantially consistent. The stratum corneum (10-20 μm thick) of the skin is the primary barrier limiting transdermal drug delivery, and both microneedles can penetrate the stratum corneum.
Experimental example 4 evaluation of thermal Properties of Flexible Heater in radiation-sensitive wearable drug controlled Release System carrying granulocyte colony stimulating factor
Sample preparation: a flexible heater was prepared as in example 1.
The experimental method comprises the following steps:
the temperature change curve of the flexible heater was measured at fixed voltages of 1.5V, 3V, and 4.5V by using a contact temperature sensor (HT9581, xinste instruments ltd, china).
Results and discussion:
the temperature in the flexible heater increased to 32 deg.C, 45 deg.C and 55 deg.C (FIG. 6) at 1.5V, 3V and 4.5V for 30s, respectively, indicating that the temperature of the flexible heater increased faster with higher voltage. After heating for 4 minutes, the heater temperature at each voltage was stable and as the voltage increased, the temperature reached by the flexible heater also increased. After 6 minutes, the heating is stopped, the flexible heater under each voltage is cooled back to the original temperature within 3 minutes, and the flexible heater is proved to be capable of rapidly cooling at room temperature, so that the danger of personal safety caused by operation failure can be avoided. The higher the voltage, the faster the temperature rise of the flexible heater, in order to make the granulocyte colony stimulating factor-loaded radiation-sensitive wearable controlled-release drug system quickly respond and quickly release the drug, a 4.5V power supply is preferably used as a power supply of the granulocyte colony stimulating factor-loaded radiation-sensitive wearable controlled-release drug system.
Experimental example 5 Electrical Performance stability of Flexible Heater in radiation sensitive wearable drug controlled Release System carrying granulocyte colony stimulating factor
Sample preparation: a flexible heater was prepared as in example 1.
The experimental method comprises the following steps:
two electrodes of the flexible heater are connected to the electrochemical workstation, and two ends of the flexible heater are fixed between the slideway and the pulley of the bending performance instrument. Starting an electrochemical work station (fixed voltage 700mV) and a bending performance tester, and measuring the current curve of the flexible heater under the continuous bending recovery state.
Results and discussion:
flexible heaters made with PET substrates have good variability and are easily contacted with microneedle substrates. In the experiment, the current of the flexible heater is still stable under 10000 times of bending (fig. 7), which shows that the flexible heater can still work normally and stably under the condition of variability. The flexible heater is suitable for wearing.
Experimental example 6 melting time of coating layer of temperature sensitive microneedle in radiation sensitive wearable drug controlled release system carrying granulocyte colony stimulating factor at different temperatures
Sample preparation: according to the preparation method of the embodiment 1, a proper amount of rhodamine B is added into the granulocyte colony stimulating factor solution to prepare the rhodamine B-containing granulocyte colony stimulating factor-loaded radiation-sensitive wearable drug controlled release system (GWS-R).
The experimental method comprises the following steps:
connecting the GWS-R with a computer, entering a special compiling program, setting the release triggering temperature of the GWS-R to be 37 ℃, 41 ℃ and 45 ℃ respectively, and setting the radiation triggering release to be 0Gy triggering release. And taking a picture to record the melting process of the temperature-sensitive microneedle coating layer at three temperatures and different time points.
Results and discussion:
when the drug release temperature is set to 37 ℃, the temperature-sensitive microneedle coating layer does not melt within 120 seconds(s) (fig. 8). When the drug release temperature is set to 41 ℃, the coating layer starts to melt at the 30 th s, but the melting speed is slow, and part of the coating layer is still not melted until 120 s. When the drug release temperature is set at 45 ℃, the coating layer starts to melt in the 10 th s and is basically melted in the 60 th s.
Experimental example 7 drug release behavior of radiation-sensitive wearable drug controlled release system carrying granulocyte colony stimulating factor at different temperatures
Sample preparation: a granulocyte colony stimulating factor-loaded radiation-sensitive wearable drug controlled release system (GWS) prepared as in example 1.
The experimental method comprises the following steps:
connecting the GWS to a computer, entering a special compiling program, respectively setting the release triggering temperature of the GWS to be 37 ℃, 41 ℃ and 45 ℃, setting the dose of the radiation triggering release to be 0Gy to trigger release, and setting the heating time to be 5 minutes. GWS was placed on a Franz diffusion cell, a microneedle body with physiological saline just over GWS was added, and magnetic stirring was performed at 300rpm at 32 ℃. At the predetermined time point, 1ml of the released solution was taken out through a 0.22 μm filter, supplemented with an equal amount of fresh physiological saline, subjected to content measurement using a G-CSF kit, and the cumulative drug release rate was calculated.
Results and discussion:
when the temperature for triggering release of GWS is 37 ℃, the release rate of the drug is only about 5% within 60 minutes (figure 9); when the temperature for triggering drug release is 41 ℃, the melting time of the coating layer is longer, about 4 percent and about 18 percent of drug release are respectively realized in 3 minutes and 15 minutes, and the drug release rate is about 74.8 percent in 60 minutes; at a trigger release temperature of 45℃, the coating layer melts rapidly, with about 16% drug released in 1 minute and a drug release rate of about 92.3% at 60 minutes.
Experimental example 8 transdermal behavior of radiation-sensitive wearable drug controlled-release System carrying granulocyte colony stimulating factor
Sample preparation: granulocyte colony stimulating factor-loaded microneedle (GMN) patch, granulocyte colony stimulating factor-loaded temperature sensitive microneedle (GTSMN) patch, granulocyte colony stimulating factor-loaded radiation-sensitive wearable drug controlled release system (GWS) prepared as in example 1.
The experimental method comprises the following steps:
connecting the GWS to a computer, entering a special compiling program, setting the GWS drug release triggering temperature to be 45 ℃, setting the heating time to be 5 minutes, and setting the radiation trigger to be 0Gy to trigger the drug release. The dorsal skin of the C57BL/N6 mice was removed, GMN, GTSMN, GWS were inserted onto the skin, respectively, and the skin was then fixed between the Franz donor and recipient wells with the stratum corneum facing the donor well, after which the two diffusion wells were carefully clamped. The effective diffusion area of the diffusion cell is 1.2cm210ml of physiological saline was added to the receiving tank, and stirred at 32 ℃ at 300rpm, and 1ml of the solution in the receiving tank was taken out at a predetermined time, passed through a 0.22 μm filter, and then supplemented with an equal amount of fresh physiological saline. And (4) carrying out content measurement by using a G-CSF kit, and calculating the cumulative drug permeation amount and the steady transdermal rate.
Results and discussion:
compared with GMN, GTSMN which is not heated within 2 hours hardly permeates skin (figure 10) because the coating layer of GTSMN can prevent the drug from contacting with moisture, the microneedle can not be dissolved and releases the drug after being inserted into the skin, and the temperature-sensitive microneedle has good skin implantation in the skinAnd (4) stability. The cumulative permeation of GMN (18.8+0.8 μ g) and GWS (15.8+0.8 μ g) was not significantly different after 2 hours of administration. Steady State transdermal Rate (J) of GMNss＝17.68+4.2μg·cm-2·h-1) Steady transdermal rate with GWS (J)ss＝16.15±2.8μg·cm-2·h-1) There was also no significant difference. This result demonstrates the temperature sensitive drug transdermal effect of the temperature sensitive microneedle in GWS, and the drug can be made transdermal rapidly by heating.
EXAMPLE 9 in vivo biosafety of radiation-sensitive wearable drug controlled-release System with granulocyte colony-stimulating factor
Sample preparation: a granulocyte colony stimulating factor-loaded radiation-sensitive wearable drug controlled release system (GWS) prepared as in example 1.
The experimental method comprises the following steps:
removing back hairs of 12 male C57BL/N6 mice, dividing the mice into a healthy group and a GWS group, weighing 9 mice in each group respectively; GWS was fixed to the back skin of mice with an adhesive tape, and after 12 hours, the GWS was separated from the back skin, and the skin changes of the mice before and after application of the GWS were observed. To further evaluate the systemic safety of GWS, one mouse was sacrificed throughout each group after the experiment, and the mice were observed for cardiac, hepatic, spleen, lung, and kidney tissue changes 1 day and 3 days after administration by HE staining technique. The body weight of the remaining mice was measured every 2 days, and the change in body weight of the mice after the administration was examined.
Results and discussion:
the skin at the site of administration did not show symptoms such as bleeding, swelling and inflammation, and burning compared to before administration (fig. 11A); the body weight of mice in the GWS group was not statistically different from that of mice in the healthy group within 28 days, indicating that the GWS safety was good (fig. 11B). Pathological sections showed that none of heart, liver, spleen, lung, and kidney tissues of GWS group had symptoms of inflammatory cells, bleeding, and the like, at 0 day and 3 days after administration (fig. 11C). This result further demonstrates that GWS has good biological safety.
Experimental example 10 pharmacokinetics of radiation sensitive wearable drug controlled release System carrying granulocyte colony stimulating factor
Sample preparation: the temperature-sensitive microneedle (GTSMN) patch carrying granulocyte colony stimulating factor, the radiation-sensitive wearable drug controlled release system (GWS) carrying granulocyte colony stimulating factor, and the recombinant human granulocyte stimulating factor injection (G-CSF, manufactured by beijing dilu pharmaceutical products, ltd) prepared in example 1 were used.
The experimental method comprises the following steps:
the C57BL/N6 male mice (body weight, 20. + -.1 g) were used as model animals, and the animals were divided into four groups: a G-CSF group (I.H.G-CSF in the figure), a GTSMN group (GTSMN in the figure), a GWS group releasing medicine at 0 hour (GWS in the figure), a GWS group releasing medicine after 4 hours (4h/GWS in the figure) and a GWS working group releasing medicine after 8 hours (8h/GWS in the figure). G-CSF injection with a concentration of 100. mu.g/ml was prepared, 0.15ml was subcutaneously injected into the tail of 40 male mice, respectively, blood was taken from the tail vein at a predetermined time point (15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours), and the content was measured with a G-CSF kit in 5 mice at one time point. The GTSMN group and the 0-hour medicine release GWS group are operated as above, the medicines are respectively replaced by GTSMN and GWS, the microneedle patch is pasted on the back skin of the mouse, and the GWS is fixed on the back of the mouse by using an adhesive tape, wherein the later is set to have the irradiation dose rate of 0cGy/min to trigger the medicine release, and the number of the other animals in each group, the sampling time and the measuring method are as above. The drug release GWS group after 4 hours (4h/GWS) and the drug release GWS working group after 8 hours (8h/GWS) were the same as above, and samples were taken at predetermined 7 time points after 4 hours and 8 hours of administration, respectively.
Results and discussion:
the plasma concentration of GTSMN group was always at a low and stable plasma concentration value within 24 hours (fig. 12), indicating that the drug was not delivered to the mice when GTSMN was administered alone without heating, and that GTSMN had good stability in the skin. The 0-hour drug release GWS group can provide the in vivo drug absorption tendency similar to the subcutaneous injection group. T for the 0-hour drug release GWS group as compared with the group injected subcutaneously with G-CSF max1 hour, which is only 0.5 hour longer than the subcutaneous injection group. The result shows that the temperature sensitive microneedle of the GWS has good temperature sensitivity in the skin, and can quickly deliver the drug into the body of an animal after being heated. A similar study of 4 hours later release of the GWS composition and 8 hours later release of the GWS composition was also providedDrug absorption profile of the G-CSF group was injected subcutaneously. This result demonstrates that, when GWS is applied to the skin, it can trigger and stably release the drug into the body according to radiation at any time. Because the therapeutic principle of radiation-induced damage to the hematopoietic system is early treatment, subcutaneous injection of large doses of G-CSF within 0.5 hours after irradiation has proven to be the clinically best current dosing regimen, but this time is often exceeded when patients are transported from the irradiation site to the hospital. The GWS can be quickly released in vivo along with irradiation, thereby being very beneficial to the treatment of hematopoietic system injury caused by irradiation.
Experimental example 10 radiation monitoring and antiradiation of radiation-sensitive wearable drug controlled-release System carrying granulocyte colony-stimulating factor
Sample preparation: the temperature-sensitive microneedle (GTSMN) patch carrying granulocyte colony stimulating factor, the radiation-sensitive wearable drug controlled release system (GWS) carrying granulocyte colony stimulating factor, and the recombinant human granulocyte stimulating factor injection (G-CSF, manufactured by beijing dilu pharmaceutical products, ltd) prepared in example 1 were used.
The experimental method comprises the following steps:
1. radiation monitoring experiment
The method comprises the steps of connecting an external USB (universal serial bus) line with a computer outside a cobalt source, starting a GWS application program, setting a trigger dosage rate to be 20cGy/min, setting a trigger drug release temperature to be 45 ℃, setting heating time to be 300 seconds (figure 13A), starting a real-time picture to monitor the internal dosage rate of the cobalt source and the temperature of a flexible heater, fixing the GWS on the back of a mouse by using an adhesive tape, and sending the mouse to the cobalt source for irradiation (figure 13A).
2. Group administration to animals
With SPF grade C57BL/N6 male mice (20 +/-1G), animals were divided into 6 groups (14 animals per group), and the model Control group (Control in the figure), GTSMN group (GTSMN in the figure), subcutaneous G-CSF group (I.H.G-CSF in the figure, administered at 750. mu.g/kg), subcutaneous G-CSF group after 24 hours (24 h/I.H.G-CSF in the figure, administered at 750. mu.g/kg), GWS group releasing drug at 0 hour (GWS in the figure), and GWS group releasing drug after 8 hours (8h/GWS in the figure) were sequentially included. All mice received one total body irradiation of 6.5Gy with 60Co radiation at a dose rate of 57.6 cGy/min. Each group of mice was injected with 1.5ml of 4% (w/v) chloral hydrate solution through the abdominal cavity before irradiation, and the mice were fixed on a wooden board with an adhesive tape for waiting for irradiation.
3. Determination of peripheral hemograms
Each group of mice was bled 20. mu.l by excising tails on day 7 after irradiation, and 2ml of a hemocyte analysis diluent was injected to detect peripheral blood leukocytes (WBC) with a fully automatic hemocyte analyzer.
4. Culture of hematopoietic progenitor cells
After 7 days of irradiation, each group of mice is killed by 3 mice respectively, the mice are soaked and disinfected by sobering, the hind thighbones of the mice are taken out on a superclean bench, the two ends of the hind thighbones are cut off, marrow nucleated cells are flushed out by a 1640 culture medium and pass through a 70-micron cell screen to prepare single cell suspension, and the marrow nucleated cells are separated by single cell separation liquid, and the specific process is as follows:
(1) taking a proper centrifuge tube, adding a separation solution with the same amount as the single-cell bone marrow suspension, carefully sucking the single-cell bone marrow suspension by using a suction tube, adding the single-cell bone marrow suspension on the liquid surface of the separation solution, and centrifuging for 20 minutes at 450 Xg;
(2) after centrifugation, the centrifuge tube is divided into four layers from top to bottom; the first layer is a dilution liquid layer, the second layer is an annular milky single karyocyte layer, the third layer is a transparent separation liquid layer, and the fourth layer is a red blood cell layer;
(3) carefully sucking the second annular milky white mononuclear cell layer into another 15ml centrifugal tube by using a suction tube, adding 10ml cleaning solution into the centrifugal tube, uniformly mixing the cells, and centrifuging at 250 Xg for 10 minutes to obtain bone marrow nucleated cell suspension;
(4) regulation of bone marrow nucleated cell concentration to 5X 10 using MethoCult GF M3434 hematopoietic Stem/group cell colony culture fluid4The cells/ml are inoculated on a 24-well plate, 1ml of each well is inoculated at 37 ℃ and 5% CO2Cultured in the incubator of (1), and after 4 days, CFU-GM was counted.
5. Examination of bone marrow nucleated cells
After 7 days of irradiation, 1 mouse was sacrificed for each group, hind-limb femurs were removed, and bone marrow HE sections were prepared as follows. Hind femurs were kept in formalin solution, treated with decalcified solution and 12.5% neutral ethylenediaminetetraacetic acid (EDTA) solution for 1 month, samples were dehydrated in 70%, 80%, 96% ethanol sequentially at 2 hour intervals, then embedded in paraffin, cut perpendicular to the long bone axis to the depth of the bone, serial sections 5 μm thick were stained with HE, and the tissue sections were observed under a microscope.
Results and discussion:
1. radiation monitoring function of GWS
After a mouse wearing GWS is placed in a cobalt source room to prepare for work (about 740 seconds of timing), the cobalt source is lifted from a well, the real-time monitoring system displays that the ray intensity can reach a sensor threshold value (20cGy/min) instantly and starts the heating system rapidly, after the cobalt source is completely lifted (808 seconds of timing), the real-time monitoring system displays that the dose rate reaches a preset value (57.6cGy/min), after 1 second (809 seconds of timing), the flexible heater reaches a preset drug release temperature (45 ℃), after the temperature is kept for 300 seconds, the flexible heater stops working, and the temperature is rapidly reduced to the initial temperature (figure 13B).
The results demonstrate that GWS can accurately monitor environmental radiation dose and quickly respond to control flexible heater operation.
2. WBC changes within 30 days
The number of leukocytes in each group was significantly reduced after irradiation (fig. 13C), indicating that irradiation did damage peripheral blood cells in mice. Compared with the model Control group (Control in the figure), the group injected subcutaneously G-CSF (I.H.G-CSF in the figure), the group released-drug GWS at 0 hour (GWS in the figure) and the group released-drug GWS at 8 hours (8h/GWS in the figure) have significant recovery, while the group injected subcutaneously G-CSF (24 h/I.H.G-CSF in the figure) in the GTSMN group (GTSMN in the figure) and the group injected subcutaneously at 24 hours (24 h/I.H.G-CSF in the figure) have no significant difference compared with the model Control group (Control in the figure).
3. Restoration of hematopoietic progenitor cells
Progenitor cells are progenitor cells with proliferative capacity, including CFU-GM, CFU-MK, CFU-E CFU-GEMM. G-CSF promotes the proliferation and differentiation of CFU-GM, so that the hematopoietic system can quickly and effectively respond to the emergency (such as blood loss, hemolysis or infection) to generate a large amount of mature neutrophils to meet the demand of human body.
The number of CFU-GM in the GTSMN group and the G-CSF group injected subcutaneously after 24 hours has no significant difference with the model control group (figure 13D), while the G-CSF group injected subcutaneously, the GWS group released at 0 hour and the GWS group released at 8 hours have significant recovery compared with the model control group.
4. Bone marrow nucleated cells
Myelosuppression is one of the most prominent disorders of radiation damage. Only a few bone marrow nucleated cells were seen in the GTSMN group, the 24-hour post-subcutaneous G-CSF group, and the model control group (fig. 13E, 13F, 13G), while a large number of bone marrow nucleated cells were seen in the subcutaneous G-CSF group, the 0-hour drug-release GWS group, and the 8-hour post-drug-release GWS group (fig. 13H, 13I, 13J).
The experiments show that the GWS as a wearable intelligent drug delivery system can respond to radiation, automatically deliver drugs and protect instantaneously, and provides the maximum protection and treatment for unpredictable radiation injury.
Claims (10)
1. A radiation sensitive wearable controlled drug release system.
2. The radiation-sensitive wearable controlled-release drug system of claim 1, which is formed by combining different accessories, comprises a power supply, an ionizing radiation sensor, a controller, a flexible heater, a temperature sensor, a drug-loaded temperature-sensitive micro-needle, and can further comprise a connecting device and a shell according to wearing requirements of different parts.
3. The radiation sensitive wearable controlled drug release system of claim 2, wherein the flexible heater is a device for providing heat control to the drug-loaded temperature sensitive microneedle to release the drug, comprising a flexible substrate layer, a heating layer.
4. The radiation-sensitive wearable controlled-release drug system of claim 2, wherein the drug-loaded temperature-sensitive microneedle is in the form of a patch, and a plurality of microneedles with equal distance are arranged on the patch, and 1-10 microneedles can be arranged within 1 mm; at 1cm2There may be 100 to 10000 microneedles in the area of (a).
5. The radiation-sensitive wearable controlled drug release system of claim 4, wherein the shape of the microneedle is selected from the group consisting of conical, cylindrical, prismatic.
6. The radiation sensitive wearable controlled drug release system of claim 4, wherein the microneedle body height ranges from 100 μm to 2000 μm.
7. The controlled release system of a radiation-sensitive wearable drug as claimed in claim 2, wherein the drug-loaded temperature-sensitive microneedle structure comprises a needle body and a coating layer.
8. The controlled release wearable drug system of claim 7, wherein the needle matrix material is a biocompatible soluble material or a biocompatible soluble composition, in particular comprising a polymer and a small molecule carbohydrate; the coating layer material is selected from the group consisting of tridecylic acid, lauric acid, tetradecylamine, hexadecylenic amine, a mixture of tridecylic acid and tetradecylamine, a mixture of lauric acid and tetradecylamine, a mixture of tridecylic acid and hexadecylenic amine, and a mixture of lauric acid and hexadecylenic amine.
9. A radiation-sensitive wearable controlled drug release system according to claim 2, wherein the drug contained in the drug-loaded temperature-sensitive microneedle is a drug having an anti-radiation effect, preferably selected from the group consisting of cytokines, polypeptide protein drugs, and in particular from the group consisting of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-12 (IL-12), bacterial flagellin derivatives (CBLB502), recombinant human interleukin-11 (rhIL-11), and recombinant human thrombopoietin (rhTPO).
10. The controlled release system of claim 1, which is a granulocyte colony stimulating factor-loaded controlled release system, and is prepared by the following steps: dissolving the granulocyte colony stimulating factor in phosphate buffer solution with pH7.4 to obtain 4mg/ml granulocyte colony stimulating factor solution; adding sodium hyaluronate and trehalose to obtain drug-containing microneedle matrix solution with concentration of 10% (w/v) and 7% (w/v), respectivelyLiquid; 0.2g of the microneedle matrix solution containing the medicine is dripped into a microneedle mould, placed in a vacuum drier at room temperature, sealed and decompressed, placed for 2 minutes and then taken out, and placed in a sterile clean cabinet at room temperature for drying and forming; preparing a chloroform solution of polyvinylpyrrolidone K90 with the concentration of 15% (w/v), dropwise adding the chloroform solution into the mold, placing the mold in a vacuum drier at room temperature, sealing and decompressing, placing the mold for 1 minute, taking out the mold, and placing the mold in a sterile clean cabinet at room temperature for drying and molding; preparing 1% (w/v) (2, 4, 6-trimethylbenzoyl) diphenyl phosphine oxide N-vinyl pyrrolidone solution, dripping the solution into the mold, and using the power of 600mW/cm with the emission wavelength of 365nm2Irradiating for 3 minutes by using an ultraviolet lamp to obtain the granulocyte colony stimulating factor-loaded microneedle; sticking a double-sided adhesive tape to the basal layer face of the granulocyte colony stimulating factor soluble microneedle, fixing a microneedle body in a culture dish, enabling the needlepoint to face outwards, using a normal hexane solution containing 1% (w/v) dodecanoic acid and 0.5% (w/v) hexadecylamine as a coating solution, placing the coating solution in an electrospray gun, enabling the distance between the electrospray gun and the microneedle to be about 15cm, carrying out 45-second spray coating on the microneedle in the vertical direction, and quickly volatilizing a solvent at room temperature to obtain the granulocyte colony stimulating factor temperature-sensitive microneedle; printing ink by using an Ag nanoparticle solution and performing ink-jet printing on a PET (polyethylene terephthalate) film for 2 times by using a flexible electronic printer to obtain a 15mm double-layer serpentine pattern flexible heater, leading out electrodes at two ends by using a wire, packaging by using a PDMS (polydimethylsiloxane) film, and measuring the resistance of the flexible heater to be 20 omega by using a universal electric meter; the two electrodes of the flexible heater are connected with the single chip microcomputer; one surface of the heater covers the temperature sensor, and the other surface of the heater is fixed on the granulocyte colony stimulating factor temperature-sensitive micro-needle by using double-sided adhesive tape; 3 No. 5 alkaline batteries (1.5V/node) are used as power supplies and are connected with the singlechip; assembling to obtain the radiation-sensitive wearable drug controlled-release system carrying the granulocyte colony-stimulating factor.
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