CN113230269B - Radiotherapy protective agent and preparation method and application thereof - Google Patents
Radiotherapy protective agent and preparation method and application thereof Download PDFInfo
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- CN113230269B CN113230269B CN202110525315.8A CN202110525315A CN113230269B CN 113230269 B CN113230269 B CN 113230269B CN 202110525315 A CN202110525315 A CN 202110525315A CN 113230269 B CN113230269 B CN 113230269B
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- gelatin
- protective agent
- hydrogen sulfide
- mixed solution
- radiotherapy
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Abstract
The invention discloses a radiotherapy protective agent, a preparation method and an application thereof, belongs to the technical field of radiotherapy protection, and solves the problem of poor protection effect of gastrointestinal radiotherapy protective agent by oral administration in the prior art. The preparation method of the radiotherapeutic protective agent comprises the following steps: mixing gelatin-based hydrogel and a hydrogen sulfide donor GYY4137 at room temperature, and stirring to obtain a gelatin @ hydrogen sulfide donor compound, wherein the gelatin-based hydrogel is obtained by regulating the pH value of gelatin nanoparticles synthesized by a cross-linking method, and the hydrogen sulfide donor GYY4137 is coated by the gelatin-based hydrogel through electrostatic acting force and physical adsorption. The acid-sensitive sustained-release oral radiotherapy protective agent prepared by the invention can reduce physical damage to the gastrointestinal tract during radiotherapy, and provides a new idea and a new method for protecting patients after clinical radiotherapy.
Description
Technical Field
The invention relates to the technical field of radiotherapy protection, in particular to an oral gas slow-release radiotherapy protective agent and a preparation method and application thereof.
Background
Malignant tumor is a frequently encountered disease and a common disease, and seriously threatens human health. In our country, the cancer situation is particularly severe. At present, tumor treatment means are increasing, and the clinical tumor treatment means mainly comprise surgery, radiotherapy and chemotherapy. Especially, the wide adaptation disease and high cure rate of radiotherapy make the radiotherapy have an important position in tumor treatment. The therapeutic principle of radiotherapy (abbreviated as radiotherapy) is that high-energy ion rays (such as X rays and gamma rays) directly interact with cellular DNA to cause DNA damage, or indirectly react with water molecules to generate free radical species (such as superoxide radical, singlet oxygen, hydrogen peroxide, hydroxyl free radical and the like) to destroy DNA or other cellular components, and induce apoptosis and necrosis. However, radiation therapy inevitably damages healthy cells while killing tumor cells. Various side effects after radiation therapy, such as hypoxia, vomiting, nausea, abdominal pain and diarrhea, can greatly reduce the quality of life of cancer patients. Therefore, in clinical radiotherapy, the tumor is treated by using a radiosensitizer to sensitize hypoxic cells of tumor tissues to the sensitivity of rays, or by using the radiosensitizer and radiotherapy together to replace expensive fast neutrons, hyperbaric oxygen, pi-neutron beams and the like. The radioactive gastroenteritis is a main complication of radiotherapy of gynecological malignant tumors and male prostate malignant tumors and is also a common complication of pelvic radiotherapy. In particular, the enterocyte is degenerated and desquamated under the action of rays, the intestinal mucosa becomes thin, the blood capillary expands, the intestinal mucosa is congested and edematous, and clinical manifestations such as abdominal pain, diarrhea, anal pendant expansion, tenesmus, mucous stool or bloody stool appear. Therefore, it is imperative to develop new radioprotective agents (hereinafter abbreviated as radioprotective agents) for the alleviation and even treatment of radiation-induced damage to the intestinal tract. The majority of radiotherapy protective agents are mainly used for protecting normal cells, and the radiotherapy protective agents comprise sulfhydryl compounds, antioxidants, plant extracts, immunomodulators and other medicines. Only a few nano-drugs can be used for the targeted radiotherapy of tumors and then the protection of normal cells, so that the selective protection of normal cells is realized, but the nano-drugs are still in the basic research stage. The U.S. food and drug administration has approved two specific drugs, amifostine and palifomine, for protection of normal cells and tissues after radiation therapy, but these two drugs are only aimed at reducing the side effects during radiotherapy for head and neck cancer and oral cancer. Moreover, these two intravenous drugs do not meet the requirement for oral administration as a gastrointestinal radioprotector. Oral administration is the best method of treating gastrointestinal disorders because it is considered the simplest and fastest method for the drug to reach the gastrointestinal tract and come into direct contact with the target site. Therefore, there is a great need to develop new radioprotective agents for the protection of gastrointestinal radiotherapy by oral administration.
Hydrogen sulfide (H)2S) is the third endogenous gas signaling molecule found following Nitric Oxide (NO) and carbon monoxide (CO). The mammal cardiovascular tissue expresses cystathionine gamma lyase and 3-mercaptopyruvate transsulfurase, and endogenously generates H2And S. Endogenous or appropriate concentrations of exogenous H2S openable ATP sensitive K+Channel, block L-form Ca2+The channel regulates and controls signal transduction molecules such as protein kinase C, extracellular regulated protein kinase, phosphoinositide-3 kinase/protein kinase B and the like, and further plays an important protective role through pathophysiological mechanisms such as anti-inflammation, anti-apoptosis, anti-oxidative stress, angiogenesis promotion and the like when the heart is stimulated by ischemia, anoxia and the like. H2S is a novel protective substance for antagonizing heart injury. As a neuroprotective agent, it also has antioxidant, anti-inflammatory, and anti-apoptotic effects under pathological conditions; and, show potential therapeutic value in several diseases of the central nervous system, including alzheimer's disease, parkinson's disease, ischemic stroke and traumatic brain injury. In addition to this, H2S has a protective role in the pathogenesis of atherosclerosis through a variety of pathways. Sirtuin-1(SIRT1) is a histone deacetylase, which is an essential mediating longevity gene and has anti-atherosclerosis effect by regulating acetylation of some functional proteins. Endogenous cystathionine gamma lyase/H2S sulfurizes SIRT1 directly, enhances the combination of SIRT1 and zinc ions, then promotes acetylation activity and increases SIRT1 stability, thereby reducing the formation of atherosclerotic plaques.
Studies have also shown that a range of concentrations of H are present during the treatment of inflammatory diseases of the gastrointestinal tract2S not only reduces inflammation but also accelerates healing of the gastrointestinal tract such as ulcers or hemorrhagic gastroenteritis, while suppressing H2Production of S in the gastrointestinal tract may result in a slowing of healing of the inflamed tissue or even an exacerbation of inflammation. So far, there have been many H2S slow-release donor for providing exogenous H2S can achieve the functions of anti-inflammation, anti-apoptosis or anti-oxidative stress and the like and treat various diseases. For example: since 2013, antibody Therapeutics Inc. (an "antibody") has been known as H2S sustained release NSAIDs are useful in the treatment of a variety of inflammatory diseases. Wherein ATB-346 is used as H2S sustained release drugs have been used in clinical phase II studies for the treatment of arthritis and analgesics. Thus, currently H2S is mainly used for treating inflammatory diseases such as cardiovascular and cerebrovascular diseases, and has not been researched in the field of radiotherapy protection, and particularly has not been reported as a slow-release gas radiotherapy protective agent.
Disclosure of Invention
In view of the above analysis, the present invention aims to provide a radiotherapeutic protective agent, a preparation method and an application thereof, which can solve at least one of the following technical problems: (1) the radiation therapy protective agent which is orally taken and intravenously administrated has poor protection and treatment effects on gastrointestinal inflammation caused by radiation therapy; (2) in the prior art, many H2S donors, e.g. Na2S, NaHS Release of H2S has a fast and uncontrollable speed, so that H is easily caused2S poisoning or other side effects. H2S is used as a gas signal molecule with dose dependence in organisms, and the pH value response type controllable slow release of a specific donor in the organisms is not researched in the radiotherapy protection field.
The purpose of the invention is mainly realized by the following technical scheme:
in one aspect, the invention provides a preparation method of a radiotherapeutic protective agent, which comprises the following steps: mixing gelatin-based hydrogel and a hydrogen sulfide donor GYY4137 at room temperature, and stirring to obtain a gelatin @ hydrogen sulfide donor compound, wherein the gelatin @ hydrogen sulfide donor compound is a pH value sensitive slow-release radiotherapy protective agent.
Further, the gelatin-based hydrogel is obtained by regulating the pH value of gelatin nanoparticles synthesized by a cross-linking method, and the gelatin-based hydrogel wraps a hydrogen sulfide donor GYY4137 by electrostatic acting force and physical adsorption.
Further, the preparation method of the radiotherapeutic protective agent comprises the following steps:
step S1, synthesizing gelatin nano particles by a crosslinking method, and obtaining gelatin-based hydrogel by adjusting and controlling the pH value;
the step S1 includes:
s101, heating and dissolving gelatin powder in deionized water to obtain a first mixed solution;
s102, filtering the first mixed solution, adding a glutaraldehyde solution, and stirring at normal temperature for 5-10 min to obtain a second mixed solution;
s103, adding a methanol/water mixed solution into the second mixed solution, and continuously stirring for 0.8-1.5 h to obtain a third mixed solution;
s104, adding concentrated hydrochloric acid into the third mixed solution, and continuously stirring for 4.4-5.5 hours to obtain a fourth mixed solution;
s105, adding acetone into the fourth mixed solution, sealing and standing for 11-15 h, removing redundant liquid to obtain gelatin precipitate, and washing the gelatin precipitate with deionized water for multiple times; then, adding 5-10 mL of deionized water, stirring the gelatin for precipitation to obtain sticky gelatin nanoparticles, and centrifugally collecting and washing the gelatin nanoparticles; then adjusting the pH value to 7.0-7.4, and converting the gelatin nano particles into gelatin-based hydrogel;
step S2, mixing the gelatin-based hydrogel and a hydrogen sulfide donor GYY4137 at room temperature, and stirring for 1-3 hours to form a gelatin @ hydrogen sulfide donor compound; then, the mixture was collected by centrifugation and washed to obtain a gelatin @ hydrogen sulfide donor complex.
Further, in the step S101, the heating and dissolving temperature is 45-55 ℃, the stirring speed is 90-110 rpm, and the stirring time is 0.8-1.5 h.
Further, in S101, the mass-to-volume ratio of the gelatin powder to the deionized water is: 0.5-1.5 g, 100 mL.
Further, in the step S103, the volume ratio of methanol to water in the methanol/water mixed solution is 45: 5.
Further, in step S1, the volume ratio of the deionized water, the glutaraldehyde solution, the methanol/water mixed solution, and the concentrated hydrochloric acid is: 100:4:50:0.4.
Further, in the step S2, the mass-to-volume ratio of the hydrogen sulfide donor GYY4137 to the gelatin-based hydrogel is 0.5-2 mg:1 mL.
On the other hand, the invention provides a radiotherapeutic protective agent, which is prepared by adopting the preparation method.
On the other hand, the invention provides the application of the radiotherapy protective agent, and the radiotherapy protective agent is used as an oral radiotherapy protective agent to protect gastrointestinal tract inflammation and hemorrhagic gastroenteritis after radiotherapy.
Compared with the prior art, the invention can realize at least one of the following beneficial effects:
(1) the gelatin @ hydrogen sulfide donor compound (Gel @ GYY) is obtained by a simple two-step synthesis method, gelatin nanoparticles are synthesized by a cross-linking method, then a pH value is regulated to obtain a gelatin-based hydrogel, the gelatin-based hydrogel is of a network structure and large in specific surface area, and the hydrogen sulfide donor GYY4137 is wrapped by electrostatic acting force and physical adsorption to obtain the gelatin @ hydrogen sulfide donor compound (Gel @ GYY). Gel is biodegradable and has good safety. Gel @ GYY is used as a pH value sensitive response degradation type material and can be used as oral H2S gas slow-release type radiotherapeutic protective agent. The gelatin-based hydrogel Gel in Gel @ GYY can be degraded into gelatin without toxic or side effect in the stomach of an organism, is easy to absorb, reaches the intestinal tract, and is gradually metabolized from the body after staying in the body for about 10 hours; meanwhile, the gelatin-based hydrogel is used as a carrier, has certain adhesiveness in gastrointestinal tracts, and more importantly, the stomach is strong in acidity and can slowly release Gel @ GYY sensitive to acidic pH, so that the utilization rate of GYY4137 is improved, and H is prolonged2The retention time of the S donor GYY4137 in the gastrointestinal tract ensures that GYY4137 can sufficiently release H2S；H2S not only can protect the damage of high-energy X-rays to the gastrointestinal tract during radiotherapy, but also can reduce inflammation caused by radiotherapy; particularly, due to the good diffusivity of the gas, the Gel @ GYY can uniformly protect the whole gastrointestinal tract organ,then, H2S is metabolized out of the body in the form of sulfate, has no toxic or side effect, and has high biological safety.
(2) The Gel @ GYY prepared by the invention has good free radical ROS scavenging effect; gel @ GYY can also remove DPPH free radicals and ABTS free radicals, can effectively reduce DNA damage after X-ray radiation, can inhibit the reduction of MMP (matrix metal oxide) so as to inhibit apoptosis of cells, plays a role in protecting normal cells, can be used as an oral acidic pH value-sensitive gas slow-release type degradable radiotherapy protective agent to reduce the damage of gastrointestinal tracts during radiotherapy, can protect gastrointestinal tract inflammation and hemorrhagic gastroenteritis after radiotherapy, and provides a new idea and a new method for protecting clinical radiotherapy.
(3) The preparation method is simple and easy to implement, does not need a complex operation process, and is green, environment-friendly, high in yield and wide in application range.
In the invention, the above technical schemes can be combined with each other to realize more preferable combination schemes. Additional features and advantages of the invention will be set forth in the description which follows, or may be learned by practice of the invention. The objectives and other advantages of the invention will be realized and attained by the structure particularly pointed out in the written description and drawings.
Drawings
The drawings are only for purposes of illustrating particular embodiments and are not to be construed as limiting the invention, wherein like reference numerals are used to indicate like parts throughout.
In FIG. 1, a is a scanning electron micrograph of Gel of the present invention; b is a transmission electron micrograph of GNPs of the present invention;
FIG. 2 is a Zeta potential diagram for Gel, GYY4137 and Gel @ GYY of the present invention;
FIG. 3 is a Fourier infrared FT-IR spectrum of Gel and Gel @ GYY of the present invention;
FIG. 4 is a graph showing the results of the cytotoxicity test of the CCK-8 method of the present invention after incubating Gel and Gel @ GYY with rat small intestine crypt epithelial cell IEC-6 for 24 hours;
FIG. 5 is a graph of the free radical scavenging ability of Gel @ GYY of the present invention; wherein a is the scavenging capacity of Gel @ GYY with different concentrations on DPPH free radicals; b is the scavenging capacity of Gel @ GYY with different concentrations on ABTS free radicals;
FIG. 6 is a schematic diagram showing the results of experiments of scavenging active oxygen in rat small intestine crypt epithelial cells measured by DCFH-DA fluorescence probe experiments under different treatment conditions;
FIG. 7 is a diagram showing the results of an experiment for detecting DNA damage by staining small intestine epithelial cells with gamma-H2 AX under different treatment conditions;
FIG. 8 is a graph showing experimental results of changes in Mitochondrial Membrane Potential (MMP) of small intestine epithelial cells under different treatment conditions;
FIG. 9 is a graph showing the results of cytochrome c release test;
FIG. 10 shows the measurement of H in Gel @ GYY under neutral conditions and under acidic conditions by the DTNB method2A schematic of the amount of S released; wherein a is H released from 176 μ M GYY at pH 7.42S ultraviolet absorption spectrograms at different time points; b is a 176 μ M loading of GYY at pH 7.4 to liberate H2The amount of S; c is a 176 μ M loading of GYY at pH 4.0 to release H2(S) ultraviolet absorption at different time points; d is a 176 μ M loading of GYY at pH 4.0 to release H2The amount of S.
Detailed Description
The preferred embodiments of the present invention will now be described in detail with reference to the accompanying drawings, which form a part hereof, and which together with the embodiments of the invention serve to explain the principles of the invention and not to limit its scope.
Currently, few studies have been made of radioprotective agents that are orally administered for the protection against gastrointestinal radiation. The inventor finds that: based on H2S physiological functions of anti-inflammation, anti-apoptosis and anti-oxidative stress, and a certain H is expected to be selected2The S donor slow release agent is used as one of the components of the radiotherapeutic protective agent and is used for relieving ulcer or hemorrhagic gastrointestinal tract diseases caused by radiotherapy. But most are H2S donors, e.g. Na2The physicochemical properties of S and NaHS are difficult to control and release H immediately after oral administration2S, is not able to effectively enrich and release H in the gastrointestinal tract2And S. And sheetH of one2The S donor sustained-release agent can be rapidly metabolized from the body without a specific carrier, and the sufficient retention time of the S donor sustained-release agent in the gastrointestinal tract cannot be ensured, so that the proper H must be selected2S donor and preparation method thereof for preparing carrier band-carried slow-release type H with specific carrier2S-donor radiotherapeutic protective agent.
The inventor finds that: based on the good biocompatibility, the good biodegradable characteristic and the hemostatic function of the gelatin-based hydrogel, the natural high-molecular gelatin-based hydrogel is selected as a carrier, and H is adsorbed by electrostatic and physical adsorption encapsulation effects (the porous structure of the gelatin-based hydrogel is positively charged, and GYY4137 is negatively charged)2S slow release donor GYY4137(pH sensitive), a stable gelatin @ hydrogen sulfide donor complex (i.e., a gelatin and hydrogen sulfide donor complex) was synthesized.
The gelatin-based hydrogel is synthesized by a crosslinking method and the pH value is regulated, so that the gelatin-based hydrogel is simple, green and environment-friendly, and a large amount of gelatin-based hydrogel with good biocompatibility can be synthesized at one time. The gelatin-based hydrogel then encapsulates the hydrogen sulfide donor, GYY4137, by electrostatic forces and physical adsorption. H in a certain concentration range2S can resist oxidative stress and simultaneously reduce free radicals generated during radiotherapy, including hydroxyl free radicals, superoxide anions, hydrogen peroxide and the like. And, H having an anti-inflammatory function in a certain concentration range2S can reduce gastrointestinal inflammation and hemorrhage caused by radiotherapy. The invention constructs a gastrointestinal tract nano radiotherapy protective agent gelatin @ hydrogen sulfide donor compound, the protective agent can reach the gastrointestinal tract after being orally taken, and the gelatin is degraded and H is released in the acidic stomach2S, the injury of the gastrointestinal tract during radiotherapy can be reduced, and a new idea and a new method are provided for clinical radiotherapy protection.
The invention provides a preparation method of a radiotherapy protective agent, which comprises the following steps: the gelatin-based hydrogel and the hydrogen sulfide donor GYY4137 were mixed at room temperature and stirred to obtain a gelatin @ hydrogen sulfide donor complex.
Specifically, the preparation method of the radiotherapeutic protective agent comprises the following steps:
step S1, synthesizing gelatin nano particles by a crosslinking method, and obtaining gelatin-based hydrogel by adjusting and controlling the pH value; specifically, step S1 includes:
s101, heating and dissolving gelatin powder in deionized water to obtain a first mixed solution;
s102, filtering the first mixed solution, adding a glutaraldehyde solution, and stirring at normal temperature for 5-10 min to obtain a second mixed solution;
s103, adding a methanol/water mixed solution into the second mixed solution, and continuously stirring for 0.8-1.5 h to obtain a third mixed solution;
s104, adding concentrated hydrochloric acid into the third mixed solution, and continuously stirring for 4.4-5.5 hours to obtain a fourth mixed solution;
s105, adding acetone into the fourth mixed solution, sealing and standing for 11-15 h, removing redundant liquid to obtain gelatin precipitate, and washing the gelatin precipitate with deionized water for multiple times; then, adding 5-10 mL of deionized water, stirring the gelatin for precipitation to obtain sticky gelatin nanoparticles, and centrifugally collecting and washing the Gelatin Nanoparticles (GNPs); then adjusting the pH value to 7.0-7.4, and converting the gelatin nano particles into gelatin-based hydrogel (abbreviated as Gel);
step S2, mixing the gelatin-based hydrogel and a hydrogen sulfide donor GYY4137 at room temperature, and stirring for 1-3 hours to form a gelatin @ hydrogen sulfide donor compound; then, the mixture was collected by centrifugation and washed with water twice to obtain a gelatin @ hydrogen sulfide donor complex (abbreviated as Gel @ GYY).
Specifically, in the step S101, in order to ensure that the gelatin particles are sufficiently dissolved, the gelatin particles are heated and stirred in the process of dissolving in deionized water, and the heating temperature is controlled to be 45-55 ℃, preferably 50 ℃; the stirring speed is 90-110 rpm, preferably 100 rpm; the stirring time is 0.8-1.5 h, preferably 1 h.
Specifically, in S101, the mass-to-volume ratio of the gelatin powder to the deionized water is: 0.5-1.5 g, 100 mL.
Specifically, in the step S102, the mass percentage of the glutaraldehyde solution is 50%, and the volume ratio of the first mixed solution to the glutaraldehyde solution is 100: 3-6; preferably, the volume ratio of the first mixed solution to the glutaraldehyde solution is 100: 4.
Specifically, in S102, the stirring speed is 950 to 1100rpm, preferably 1000 rpm.
Specifically, in S103, the volume ratio of methanol to water in the methanol/water mixture is 45: 5.
Specifically, in S104, the mass concentration of concentrated hydrochloric acid was 37%.
Specifically, in S105, the number of times of washing the gelatin precipitate with deionized water is 3 to 8, and preferably, the number of times of washing the gelatin precipitate with deionized water is 5.
Specifically, in S105, the conditions for centrifugally collecting the obtained gelatin nanoparticles are that the centrifugal rotation speed is 10000-13000 rpm, preferably 12000 rpm.
Specifically, in S105, the diameter of the gelatin nanoparticles may be controlled to be within a range of 10 to 30 nm.
Specifically, in S105, the gelatin-based hydrogel has a network-like folded structure, thereby facilitating subsequent coating and loading of GYY 4137.
Specifically, in the above S105, in order to prevent the gelatin-based hydrogel from deteriorating, the obtained gelatin-based hydrogel was stored in a refrigerator at 4 ℃.
Specifically, in step S1, the volume ratio of the deionized water, the glutaraldehyde solution, the methanol/water mixed solution, and the concentrated hydrochloric acid is: 100:4:50:0.4.
Specifically, in step S1, acetone is a precipitant, and the amount of acetone added is too much, which wastes raw materials; the addition of too little acetone resulted in poor precipitation. Therefore, in the present invention, the mass-to-volume ratio of the gelatin particles in S101 to the acetone in S105 is controlled as follows: 0.5g, 500-700 mL.
Specifically, in step S2, the concentration of the gelatin-based hydrogel is 1 g/mL-1。
Specifically, in the step S2, the mass-to-volume ratio of the hydrogen sulfide donor GYY4137 to the gelatin-based hydrogel is 0.5 to 2mg:1 mL; preferably, the mass-to-volume ratio of the hydrogen sulfide donor GYY4137 to the gelatin-based hydrogel is 1mg:1 mL.
Specifically, in the step S2, the rotation speed of stirring the gelatin-based hydrogel and the hydrogen sulfide donor GYY4137 at room temperature is 900 to 1100 rpm; preferably, the rotation speed is 1000 rpm.
Specifically, in the step S2, the condition for obtaining the gelatin @ hydrogen sulfide donor compound by centrifugation is that the centrifugation rotation speed is 10000-13000 rpm, preferably 12000 rpm.
Specifically, the gelatin @ hydrogen sulfide donor compound prepared by the preparation method of the radiotherapy protective agent is an acidic pH value sensitive slow-release type radiotherapy protective agent in a biological system, and the gelatin @ hydrogen sulfide donor compound is H under an acidic condition2The S release amount is far higher than that under a neutral condition, the release time is long, the gas can be slowly released, and the radiotherapeutic protective agent is sensitive to an acidic pH value. The gelatin @ hydrogen sulfide donor compound can reach the gastrointestinal tract after being orally taken, and can degrade gelatin and release H in acidic stomach2S, the injury of the gastrointestinal tract during radiotherapy can be reduced, and the gelatin @ hydrogen sulfide donor compound can be used as an oral radiotherapy protective agent for protecting gastrointestinal tract inflammation and hemorrhagic gastroenteritis after radiotherapy, so that a new idea and a new method are provided for clinical radiotherapy protection.
Compared with the prior art, the invention uses Gel @ GYY obtained by a simple two-step synthesis method as H sensitive to pH value2The S gas controlled-release biodegradable material can be degraded into gelatin without toxic and side effects in the stomach of an organism, is easy to absorb, reaches the intestinal tract, and is gradually metabolized from the body after staying in the body for about 10 hours; meanwhile, the gelatin-based hydrogel is used as a carrier, has certain adhesion in gastrointestinal tracts, and prolongs the H content2The retention time of the S donor GYY4137 in the gastrointestinal tract ensures that GYY4137 can sufficiently release H2S；H2S not only can protect the damage of high-energy X-rays to the gastrointestinal tract during radiotherapy, but also can reduce inflammation caused by radiotherapy; in particular, Gel @ GYY provides uniform protection of the entire gastrointestinal tract due to good gas diffusivity, followed by H2S is metabolized out of the body in the form of sulfate, has no toxic or side effect, and has high biological safety.
The Gel @ GYY prepared by the invention has good free radical scavenging effect; gel @ GYY can also remove DPPH free radicals and ABTS free radicals, can effectively reduce DNA damage after X-ray radiation, can be used as a radiotherapy protective agent to reduce damage to gastrointestinal tracts during radiotherapy, and provides a new idea and a new method for clinical radiotherapy protection.
The preparation method is simple and easy to implement, does not need a complex operation process, and is simple, green, environment-friendly, high in yield and wide in application range.
Example 1
The embodiment provides a radiotherapeutic protective agent, which is prepared by the following steps:
(1) cross-linking method for synthesizing gelatin nano-particles and gelatin-based hydrogel
Dissolving 0.5g of gelatin powder in 100mL of deionized water, and dissolving for 1h at 50 ℃ and 100 rpm; filtering the solution, adding 4mL of 50% (wt) glutaraldehyde solution, and stirring at room temperature and 1000rpm for 5 min; then 50mL of methanol (45mL) was added: stirring the mixture of water (5mL) and 9:1 (volume ratio) for 1 h; then, 400 μ L of concentrated hydrochloric acid with the mass concentration of 37% is added, and stirring is continued for 5 h; adding 500mL of acetone into the final mixed solution, sealing and standing for 12 h; removing the redundant liquid to obtain gelatin precipitate, and washing the gelatin precipitate with deionized water for multiple times; and then adding 5-10 mL of deionized water, stirring the gelatin for precipitation to obtain sticky gelatin nanoparticles, centrifugally collecting and washing the gelatin nanoparticles, adjusting the pH value to 7.2, converting the gelatin nanoparticles into gelatin-based hydrogel (abbreviated as Gel), and storing the gelatin-based hydrogel in a refrigerator at 4 ℃.
(2) Electrostatic and physical adsorption of gelatin-based hydrogel to H2S donor
GYY4137 was selected as the hydrogen sulfide donor, and 1mL of the solution was added to a concentration of 1g mL-1Mixing the gelatin-based hydrogel with 1mg of GyY4137 at room temperature at 1000rpm, stirring for 2h to form 1mg/ml gelatin @ hydrogen sulfide donor complex; finally, it was collected by centrifugation at 12000rpm, washed to give a gelatin @ hydrogen sulfide donor complex (abbreviated as Gel @ GYY), and stored at 4 ℃.
Specifically, the detection results of Gel, GNPs, Gel @ GYY are as follows:
test example 1
Scanning electron microscope and transmission electron microscope observations.
As shown in FIG. 1, a is a scanning electron micrograph of Gel of example 1 of the present invention; b is a transmission electron micrograph of the GNPs, and as can be seen from the micrograph b, the diameter of the GNPs nanoparticles is about 20nm and the nanoparticles are uniformly distributed; as can be seen from the graph a, after the gelatin nanoparticles are converted into the gelatin-based hydrogel, the gelatin-based hydrogel has a net-shaped folding structure and a large specific surface area, so that the subsequent coating and loading of GYY4137 are facilitated.
Test example 2
Gel, GYY4137 and Gel @ GYY.
FIG. 2 is a Zeta potential diagram of Gel, GYY4137 and Gel @ GYY of example 1 of the present invention, and it can be seen from FIG. 2 that the Gel aqueous solution is positively charged and has a Zeta potential of +20.16 mV; and GYY4137 and Gel @ GYY are negatively charged, and the Zeta potentials are-23.5 mV and-8.3 mV respectively, which indicates that GYY4137 is successfully wrapped by Gel.
Test example 3
Fourier infrared FT-IR spectra of Gel and Gel @ GYY.
FIG. 3 is a Fourier infrared FT-IR spectrum of Gel and Gel @ GYY of example 1 of the present invention, which is 1100cm as evidenced by the spectrum of FIG. 3-1Primary amine R-NH being GYY41372C-N stretch of (953 cm)-1Is a phosphoric acid ester of GYY4137 (RO)3) P-O-C symmetric stretch of P ═ O, so GYY4137 is present in the resulting Gel @ GYY structure.
Test example 4
And (3) determining cytotoxicity experiments of Gel and Gel @ GYY after the Gel and the rat small intestine crypt epithelial cell IEC-6 are incubated for 24 hours by a CCK-8 method.
FIG. 4 is a diagram of the result of a cytotoxicity experiment of 24 hours after incubating Gel and Gel @ GYY of example 1 of the present invention and rat small intestine crypt epithelial cell IEC-6 measured by a CCK-8 method, and the diagram proves that the cell survival rate is still higher than 95% when the concentration of Gel and Gel @ GYY reaches 40mg/mL, which meets the requirements of biological safety experiments and can be safely used.
Test example 5
Gel @ GYY has radical scavenging ability.
FIG. 5 is the radical scavenging ability of Gel @ GYY of example 1 of the present invention; a is Gel @ GYY with different concentrationsThe scavenging ability to DPPH free radicals is obviously improved along with the increase of the concentration of Gel @ GYY; and b is the scavenging capacity of Gel @ GYY with different concentrations on ABTS free radicals, and the scavenging capacity on the ABTS free radicals is obviously improved along with the increase of the concentration of the Gel @ GYY. This is sufficient to demonstrate that a dose of Gel @ GYY releases H2The S has the effect of eliminating free radicals.
Test example 6
And (3) measuring the active oxygen scavenging experiment of the rat small intestine crypt epithelial cells by using a DCFH-DA fluorescent probe experiment under different treatment conditions.
FIG. 6 is a schematic diagram of the results of experiments of scavenging Reactive Oxygen Species (ROS) in rat small intestine crypt epithelial cells measured by DCFH-DA fluorescence probe experiments under different treatment conditions in example 1 of the present invention, and it can be seen from the experiments that after X-ray irradiation, a large amount of ROS are generated in small intestine epithelial cells, and after 50 μ g/mL of Gel @ GYY is added to the X-ray + Gel @ GYY effect group, the ROS scavenging effect is significant, and the green fluorescence is significantly reduced, which proves that Gel @ GYY has a good ROS scavenging effect.
Test example 7
Schematic diagram of the experimental result of the damage of the small intestine epithelial cells for detecting DNA by using a gamma-H2 AX staining method under different treatment conditions.
FIG. 7 is a graph showing the results of the experiments for detecting DNA damage by staining small intestine epithelial cells with gamma-H2 AX under different treatment conditions in example 1 of the present invention. Wherein, Control is normal rat small intestine crypt epithelial cell IEC-6, and no treatment is carried out, and double-strand break (red) in small intestine epithelial cell nucleus can be observed in an X-ray irradiation group. The DNA damage of the X-ray + Gel @ GYY incubation group is obviously reduced (the red color is obviously reduced), which shows that the Gel @ GYY can effectively reduce the DNA damage after X-ray radiation.
Test example 8
Experiments on changes in Mitochondrial Membrane Potential (MMP) of small intestinal epithelial cells under different treatment conditions.
FIG. 8 is a graph showing the results of experiments on changes in Mitochondrial Membrane Potential (MMP) of small intestine epithelial cells under different treatment conditions in example 1 of the present invention. Mitochondrial membrane potential changes after induction of apoptosis, leading to changes in membrane permeability, and a decrease in mitochondrial membrane potential is a marker event in the early stages of apoptosis. JC-1 is a mitochondrial membrane potential fluorescent probe, in a normal mitochondria, JC-1 is gathered in a mitochondrial matrix to form a polymer, and the polymer emits strong red fluorescence (Ex-585 nm and Em-590 nm); unhealthy mitochondria can only exist as monomers in the cytoplasm due to the decrease or loss of membrane potential, and produce green fluorescence. In experimental results, JC-1 is taken as a mitochondrial membrane potential fluorescent probe, MMP in an X-ray irradiation group is obviously lower than that in a control group (control), which indicates that a large amount of MMP is lost under X-ray irradiation, and MMP in a Gel @ GYY (X-ray + Gel @ GYY) group incubated before X-ray irradiation is almost the same as that in the control group, which indicates that the Gel @ GYY can inhibit the reduction of MMP, thereby inhibiting the apoptosis of cells and playing a role in protecting normal cells. The scale bar of the figure is 25 microns.
Test example 9
Cytochrome c release assay.
FIG. 9 is a schematic diagram showing the results of cytochrome c release test in example 1 of the present invention, in which the decrease of matrix metalloproteinase causes mitochondrial dysfunction in epithelial cells of small intestine, so that cytochrome c is released to activate apoptosis pathway, and the release of cytochrome c is observed by the co-localization analysis of mitochondria and cytochrome c. As can be seen from the figure, the control group, mitochondria (red fluorescence) and cytochrome c (green fluorescence) almost overlapped, whereas cytochrome c of the X-ray group was released from mitochondria, but incubation of the Gel @ GYY group (X-ray + Gel @ GYY) before X-ray irradiation could well inhibit cytochrome c release from mitochondria.
Test example 10
Determination of H in Gel @ GYY under neutral and acidic conditions by DTNB method2The amount of S released.
FIG. 10 shows the measurement of H in Gel @ GYY under neutral conditions and under acidic conditions by the DTNB method in example 1 of the present invention2The result of the release amount of S is shown schematically, DTNB can react with sulfhydryl in hydrogen sulfide to generate disulfide bond, so that a characteristic absorption peak appears at 420 nm; wherein a) is H released from GYY at a loading of 176 μ M at pH 7.42UV absorption of S at different time pointsA spectrogram; b) release of H at 176 μ M loading of GYY at pH 7.42The amount of S; c) release of H at 176 μ M loading of GYY at pH 4.02(S) ultraviolet absorption at different time points; d) release of H at 176 μ M loading of GYY at pH 4.02The amount of S. Thus, the gelatin @ hydrogen sulfide donor complex of the present invention has an H value under acidic conditions2The S release amount is far higher than that of H under neutral condition and acidic condition2The release amount of S is 8 times of that of S under a neutral condition, and the S is released continuously for a long time within one week. Gel @ GYY can not only perform H2Slow release of S gas, and an acidic pH-sensitive radiotherapeutic protective agent, its H2The released concentration of S gas is also within the range of concentrations required for radical scavenging and anti-inflammatory functions.
The test shows that the Gel @ GYY prepared by the invention has good free radical scavenging effect; gel @ GYY can also remove DPPH free radicals and ABTS free radicals, can effectively reduce DNA damage after X-ray radiation, can inhibit the reduction of MMP (matrix metal oxide) so as to inhibit apoptosis of cells and play a role in protecting normal cells, is a radiotherapy protective agent sensitive to an acidic pH value, can be used as an oral radiotherapy protective agent for protecting gastrointestinal tract inflammation and hemorrhagic gastroenteritis after radiotherapy, and provides a new idea and a new method for protecting clinical radiotherapy.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention.
Claims (9)
1. A preparation method of a radiotherapeutic protective agent is characterized by comprising the following steps: mixing gelatin-based hydrogel and a hydrogen sulfide donor GYY4137 at room temperature, and stirring to obtain a gelatin @ hydrogen sulfide donor compound, wherein the gelatin @ hydrogen sulfide donor compound is a pH value sensitive slow-release radiotherapy protective agent;
the preparation method of the radiotherapeutic protective agent comprises the following steps:
step S1, synthesizing gelatin nano particles by a crosslinking method, and obtaining gelatin-based hydrogel by adjusting and controlling the pH value;
the step S1 includes:
s101, heating and dissolving gelatin powder in deionized water to obtain a first mixed solution;
s102, filtering the first mixed solution, adding a glutaraldehyde solution, and stirring at normal temperature for 5-10 min to obtain a second mixed solution;
s103, adding a methanol/water mixed solution into the second mixed solution, and continuously stirring for 0.8-1.5 h to obtain a third mixed solution;
s104, adding concentrated hydrochloric acid into the third mixed solution, and continuously stirring for 4.4-5.5 hours to obtain a fourth mixed solution;
s105, adding acetone into the fourth mixed solution, sealing and standing for 11-15 h, removing redundant liquid to obtain gelatin precipitate, and washing the gelatin precipitate with deionized water for multiple times; then, adding 5-10 mL of deionized water, stirring the gelatin for precipitation to obtain sticky gelatin nanoparticles, and centrifugally collecting and washing the gelatin nanoparticles; and then adjusting the pH value to 7.0-7.4, and converting the gelatin nano particles into gelatin-based hydrogel.
2. The method for preparing a radiotherapeutic protective agent according to claim 1, wherein the gelatin-based hydrogel is obtained by adjusting the pH value of gelatin nanoparticles synthesized by a cross-linking method, and the gelatin-based hydrogel wraps a hydrogen sulfide donor GYY4137 by electrostatic force and physical adsorption.
3. The method for preparing a radiotherapeutic protective agent according to claim 2, further comprising:
step S2, mixing the gelatin-based hydrogel and a hydrogen sulfide donor GYY4137 at room temperature, and stirring for 1-3 hours to form a gelatin @ hydrogen sulfide donor compound; then, the mixture was collected by centrifugation and washed with water twice to obtain a gelatin @ hydrogen sulfide donor complex.
4. The method for preparing a radiotherapeutic protective agent according to claim 3, wherein in S101, the temperature for heating and dissolving is 45-55 ℃, the stirring speed is 90-110 rpm, and the stirring time is 0.8-1.5 h.
5. The method for preparing a radiotherapeutic protective agent according to claim 3, wherein in the step S101, the mass-to-volume ratio of the gelatin powder to the deionized water is as follows: 0.5-1.5 g, 100 mL.
6. The method for preparing a radiotherapeutic protective agent according to claim 3, wherein in the step S103, the volume ratio of methanol to water in the methanol/water mixed solution is 45: 5.
7. The method for preparing a radiotherapeutic protective agent according to claim 3, wherein in step S1, the volume ratio of the deionized water, the glutaraldehyde solution, the methanol/water mixed solution, and the concentrated hydrochloric acid is: 100:4:50:0.4.
8. The method for preparing a radiotherapeutic protective agent according to claim 3, wherein in the step S2, the mass-to-volume ratio of GYY4137 to the gelatin-based hydrogel is 0.5-2 mg:1 mL.
9. A radioprotective agent comprising the radioprotective agent of any one of claims 1-8 prepared by the method.
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| Title |
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| A Fast Hydrogen Sulfide-Releasing Donor Increases the Tumor Response to Radiotherapy;Geraldine De Preter，et al.;《Molecular Cancer Therapeutics》;20151218;第15卷(第1期);第154-161页 * |
| A review of hydrogen sulfide (H2S) donors: Chemistry and potential therapeutic applications;Chadwick R. Powell，et al.;《Biochemical Pharmacology》;20171123;第149卷;第110-123页 * |
| Radioprotective role of H2S/CSE pathway in Chang liver cells;Yan Pan ，et al.;《Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis》;20120907;第738-739卷;第12-18页 * |
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