CN112121061A - Construction and application of multifunctional hollow cerium nano-particles and hollow cerium nano-composite drug-loading system - Google Patents
Construction and application of multifunctional hollow cerium nano-particles and hollow cerium nano-composite drug-loading system Download PDFInfo
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Abstract
The invention name is as follows: the technical field of construction and application of multifunctional hollow cerium nano particles and hollow cerium nano compound drug-carrying systems is as follows: advanced nanocomposite and technical field summary content: the invention introduces the construction and application of a multifunctional hollow cerium nano-particle and a compound drug-loading system thereof. Because the cerium nanoparticles have excellent mimic enzyme activity, in order to improve the application of the cerium nanoparticles in tumor treatment, hollow cerium nanoparticles are developed as a drug delivery platform. The hollow cerium nano particles are prepared by a one-pot hydrothermal method, the synthetic raw materials are easy to obtain, the method is simple and rapid, the hollow degree of the hollow cerium nano particles can be accurately controlled, the method can be used for industrial production, and the product has strong bionic enzyme activity; the constructed hollow cerium nano-composite drug-carrying system has good stability, keeps the activity of bionic enzyme, improves the problems of water solubility and drug effect of the drug, responds to tumor microacid environment, selectively supplies oxygen and improves photodynamic curative effect.
Description
The technical field is as follows:
the invention relates to a preparation method and application of a nano material for clinically treating solid tumors, in particular to bionic hollow cerium nano particles synthesized based on a one-pot hydrothermal method, which are subjected to surface biological modification to construct a nano carrier to form a hollow cerium nano compound, and are loaded with therapeutic drugs to construct a drug loading system to realize visual tracking and exert a strong photodynamic tumor treatment effect. The synthesis method disclosed by the invention can realize accurate control of the hollow degree of the hollow cerium nano-particles, and the product has strong bionic enzyme activity; the constructed hollow cerium nano-composite drug-carrying system has good stability, keeps the activity of bionic enzyme, improves the problems of water solubility and drug effect of the drug, responds to tumor microacid environment, selectively supplies oxygen and improves photodynamic curative effect; the synthetic raw materials are easy to obtain, the method is simple and rapid, and mass production can be realized. Belongs to the field of advanced nano composite material and technology.
Background art:
breast cancer remains one of the major malignancies threatening human health. In order to achieve effective treatment, cancer treatment strategies using cerium nanoparticles have recently attracted considerable attention from researchers. As a classical inorganic nano material, cerium nano particles exist in a cerium redox state on the surface. Based on different valence state ratios, they have strong mimic enzyme activities, such as superoxide enzyme, catalase, and oxidative phosphatase, and are called "biomimetic enzyme" or "nanoenzyme". However, the use of cerium nanoparticles requires overcoming some obstacles: many active drugs and functional small molecules have poor adsorption capacity on carrier surfaces, such as the FDA-approved photosensitizer chlorin e 6; furthermore, even chemical covalent bonding is not conducive to loading and release of the drug, but may lead to reduced or even inactivation of the drug effect.
Fortunately, however, the development of hollow cerium nanoparticles based on the fundamental properties of cerium nanoparticles is effective as a solution to the above problemsAnd (4) selecting. Hollow cerium nanoparticle structures composed of nanoscale shell layers and internal voids are of great interest due to their characteristics of high specific surface area, large pore volume, low density, high bearing capacity, and the like. The nano shell layer of the hollow cerium nano particle has high permeability and low diffusion resistance. At present, the traditional synthesis methods of hollow nano materials mainly comprise a template auxiliary method, a self-template strategy, self-organization formation and the like, and although the preparation methods are more, the methods are complex and time-consuming to operate, require multi-step reaction and are difficult to master the hollow degree. Researchers have synthesized magnetic and plasma properties
Hollow ceria spheres; in addition, there is also a report on a strategy for preparing a highly efficient hollow ceria hollow catalyst. Although these studies indicate that the corresponding hollow structures can be successfully synthesized, their nano-scale effects and mimic enzyme activity are essentially lost. Therefore, it is desired to develop a simple synthetic method and to develop a mimic enzyme activity thereof. In recent years, due to the unique chemical and biological characteristics of the hollow cerium nanoparticles, the hollow cerium nanoparticles play a certain role in the biomedical fields such as antibiosis and glaucoma treatment. However, there have been few studies on the application of hollow cerium nanoparticles to the field of tumors. In addition, strategies to enhance oxygen-dependent photodynamic therapy using hollow cerium nanoparticles to selectively provide oxygen in response to tumor pH and hydrogen peroxide have not been discovered.
On the premise of ensuring the activity of functional enzymes, the further development of the hollow cerium nanoparticles in the biomedical field is always challenging due to the difficulty of surface biological modification. Inspired by chemical properties, adenosine triphosphate is an amphiphilic molecule with hydrophobic aromatic groups and negatively charged hydrophilic residues; the biocompatible adenosine triphosphate can be used as a solubilizer to improve the solubility of the nanomaterial. In addition, the prior literature reports that cerium nanoparticles can mimic oxidative phosphatase catalysis of dephosphorylation of adenosine triphosphate to exert biological effects. Then, based on our previous findings, the bisphosphonic acid group can effectively realize the modification of nano-cerium. Meanwhile, because of the structure of polyphosphate groups, adenosine triphosphate has a strong chelating effect with metal ions, such as cerium ions. Finally, the levels of adenosine triphosphate are significantly enhanced around the tumor microenvironment and various biological effects of cancer can be mediated by P2 purinergic receptors. In conclusion, the application of adenosine triphosphate to multifunctional hollow cerium nanoparticles is considered, and the potential application value of the adenosine triphosphate in tumor treatment is exerted.
Chlorin e6 is an FDA-approved photosensitizer for tumor photodynamic therapy, but it is a water-insoluble drug, thus limiting its widespread use to some extent. In order to solve the problem of water solubility, the water solubility of the cerium dioxide nanoparticles is improved better under the premise of not changing the molecular performance of the drug by loading the cerium dioxide nanoparticles into cavities of the hollow cerium dioxide nanoparticles by utilizing electrostatic interaction, and better pharmacological action and substantial clinical improvement are expected to be generated.
Here, we have newly proposed a simple and green method for synthesizing hollow cerium nanoparticles based on a one-pot hydrothermal method. Under the template of reactant cerium nitrate hexahydrate and glycol, nitric acid with acidity and oxidizability is introduced to adjust the hollowness and porosity of the nano material in an etching mode. Meanwhile, since the cerium nitrate hexahydrate is nitrate, the use of nitric acid avoids the generation of other impurities. The resulting hollow cerium nanoparticles are then modified with polyphosphate adenine nucleoside triphosphates, conferring biocompatibility and stability thereto. In addition, the adenine nucleoside triphosphate-hollow cerium nanocomposite with voids acts as an excellent nanocarrier, can deliver active drugs, and exhibits enzymatic activity that mimics the release of oxygen from hydrogen peroxide. Finally, the adenosine triphosphate-hollow cerium nano-composite drug-carrying system realizes that the anti-tumor effect is exerted only in a tumor microacid environment and high expression of hydrogen peroxide at a tumor part. The project establishes a simple and rapid method for synthesizing hollow cerium nano particles with accurately controllable hollow degree, the novel hollow cerium nano compound drug-loaded platform realizes accurate treatment on solid tumors, provides a novel scheme for early treatment of breast cancer patients, and has good application prospect in clinical research.
The invention content is as follows:
1. the invention aims to develop a simple, convenient and rapid preparation method of hollow cerium nano-particles with precisely controllable hollow degree, ensure the activity of multifunctional mimic enzyme, improve the biocompatibility and stability of the hollow cerium nano-particles, provide a new nano-drug delivery platform, and provide a new scheme for the clinical early treatment of breast cancer patients, and is characterized by comprising the following steps:
(1) preparing hollow cerium nano-particles with different hollowness degrees;
(2) preparing an adenosine triphosphate-hollow cerium nano composite;
(3) constructing a hollow cerium nano-composite drug-loading system;
(4) and (3) verifying the multifunction of the hollow cerium nano-particles and the hollow cerium nano-composite drug-carrying system.
2. The preparation process of the hollow cerium nano-particles with different hollowness degrees specifically comprises the following steps:
the hollow cerium nano particles with different hollow degrees are prepared by adopting a one-pot hydrothermal method, firstly, 1.085g of cerium nitrate hexahydrate solid is dissolved in 5mL of ultrapure water to prepare 0.5M cerium nitrate, and then 5 reactions are carried out in parallel, which are respectively named as reactions I, II, III, IV and V. Secondly, the mixed solution of 30mL of ethylene glycol and 1mL of 0.5M cerium nitrate is stirred for 5min at room temperature in a beaker, 2mL of ultrapure water, 0.5M, 3.5M, 7.5M and 15M ultrapure water nitrate solutions are respectively added in parallel until the reaction is performed for 5min, and the reaction is performed for (i), (ii), (iii), (iv) and (iv). Then transferring the reaction liquid into a reaction kettle, and placing the reaction kettle in a muffle furnace to react for 12 hours at 180 ℃. And finally, cooling to room temperature after the reaction is finished, respectively centrifugally washing the reaction solution for 10min by using a proper amount of absolute ethyl alcohol at 5000rpm, washing for three times, then fixing the volume to 10mL by using ultrapure water to obtain hollow cerium nano particles with different hollow degrees, and marking and storing the hollow cerium nano particles at 4 ℃ for later use.
3. The preparation process of the adenosine triphosphate-hollow cerium nano composite specifically comprises the following steps:
taking 1mL of cerium with the content of 0.95mg mL-13.5mL of 10mg mL of the hollow cerium nanoparticle stock solution of (1)-1And (3) stirring the adenosine triphosphate solution at room temperature for 24h, then dialyzing and purifying the solution for 24h by using ultrapure water, changing the ultrapure water at least once every 5 h by using a snake skin dialysis bag with the molecular weight cut-off of 10kD during dialysis, finally collecting the liquid in the dialysis bag to obtain the adenosine triphosphate-hollow cerium nano compound, and marking and storing the compound at 4 ℃ for further use.
4. The construction process of the hollow cerium nano-composite drug-carrying system specifically comprises the following steps:
firstly, 1.5mL of adenosine triphosphate-hollow cerium nano-composite solution is mixed with 80 μ L of 10mM chlorin e6 solution, the pH of the system is adjusted by 20 μ L of 1M Trs-HCl with the pH of 8.8, the mixture is stirred for 24h at room temperature, then the mixture is purified for 24h by ultrapure water dialysis, snake skin dialysis bags with the molecular weight cutoff of 10kD are used, the ultrapure water is changed at least once every 5 h, finally the liquid in the dialysis bags is collected, the purified hollow cerium nano-composite drug-loaded system is obtained, and the purified hollow cerium nano-composite drug-loaded system is marked and stored at 4 ℃ for further use.
5. The verification of the multifunction of the hollow cerium nano-particles and the hollow cerium nano-composite drug-loading system specifically comprises the following steps:
(1) oxygen generation capacity of hollow cerium nanoparticles: firstly, 1mL of cerium with the content of 0.95mg mL is respectively taken-1The stock solution of the hollow cerium nano-particles is slowly stirred at room temperature, the oxygen saturation change of the stock solution within 300s is monitored by a JPBJ-608 portable dissolved oxygen analyzer and REXDC1.1 data acquisition software, then 100 mu L of 10mM hydrogen peroxide is added, and the oxygen saturation change within 300s is monitored at the same time; monitoring the oxygen saturation change in 300s by using 1mL of ultrapure water as a blank;
(2) oxygen production capacity of the adenosine triphosphate-hollow cerium nanocomposite: firstly, taking 1mL of adenosine triphosphate-hollow cerium nano compound stock solution, slowly stirring at room temperature, respectively adding 2 mLPBS with pH5.7 or pH7.4, monitoring the oxygen saturation change of the hollow cerium nano compound stock solution within 300s through a JPBJ-608 portable dissolved oxygen analyzer and REXDC1.1 data acquisition software, then continuously adding 100 mu L of 10mM hydrogen peroxide, and simultaneously monitoring the oxygen saturation change of the hollow cerium nano compound stock solution within 300 s;
(3) oxygen production capacity of the hollow cerium nano-composite drug-loaded system: firstly, slowly stirring 1mL of hollow cerium nano-composite drug-carrying system stock solution at room temperature, monitoring the oxygen saturation change of the stock solution within 300s by a JPBJ-608 portable dissolved oxygen analyzer and REXDC1.1 data acquisition software, then continuously adding 2mL of PBS with pH5.7, monitoring the oxygen saturation change within 300s by the JPBJ-608 portable dissolved oxygen analyzer and REXDC1.1 data acquisition software, and finally continuously adding 100 mu L of 10mM hydrogen peroxide and monitoring the oxygen saturation change within 300 s; the oxygen saturation change in 300s was monitored in the same manner with 1mL of ultrapure water as a blank.
Compared with the prior art, the preparation method and the application of the multifunctional hollow cerium nano-particles and the hollow cerium nano-composite drug-loading system for treating breast cancer have the outstanding characteristics that:
(1) the hollow cerium nano-particles can be quickly, simply and conveniently synthesized by a one-step method, and the hollow degree of the hollow cerium nano-particles can be accurately regulated and controlled according to the concentration of nitric acid; meanwhile, a plurality of or a plurality of hollow cerium nano-particles can be prepared at one time, thereby being convenient for realizing commercialization and promoting the development of the hollow cerium nano-particles in accurate medicine.
(2) Biological modification of adenosine triphosphate fine-tunes pharmacological properties of the naked hollow cerium nanoparticles, such as stability and biocompatibility, even targeting; the constructed adenosine triphosphate-hollow cerium nano compound keeps the activity of bionic enzyme and can be used for loading clinical medicines.
(3) The hollow cerium nano-composite drug-carrying system constructed by the method can improve the water solubility of the drug, improve the drug effect and provide a new scheme for clinically treating early breast cancer.
Description of the drawings:
fig. 1 is a schematic diagram of the construction of the hollow cerium nanoparticles and the hollow cerium nanocomposite drug-loaded system of the present invention.
Fig. 2 is a transmission electron micrograph, a hydrated particle size map, and an X-ray diffraction pattern of hollow cerium nanoparticles of different hollowness degrees according to the present invention.
FIG. 3 is a scanning electron microscope, a transmission electron microscope and an element surface distribution diagram of hollow cerium nanoparticles prepared with a typical nitric acid concentration (7.5M) according to the present invention.
Fig. 4 is a schematic diagram of the preparation process and chemical characterization of the hollow cerium nanocomposite and the drug-loading system constructed by the present invention.
Fig. 5 shows the versatility of the cerium nanoparticles, hollow cerium nanocomposites and drug-loaded systems with different hollowness constructed in the present invention.
The specific implementation mode is as follows:
the invention is further illustrated below with reference to specific examples, which are intended to be illustrative only and not to limit the scope of the invention.
Example 1
Step 3, firstly, mixing 1.5mL of adenosine triphosphate-hollow cerium nano-composite stock solution with 80 μ L of 10mM chlorin e6 solution, adjusting the pH of the system with 20 μ L of 1M Trs-HCl with the pH of 8.8, stirring at room temperature for 24h, then performing dialysis purification for 24h through ultrapure water, replacing the ultrapure water once at least every 5 h by using a snake skin dialysis bag with the molecular weight cutoff of 10kD, finally collecting the liquid in the dialysis bag to obtain a purified hollow cerium nano-composite drug-loaded system (ATP-HCNPs @ Ce6), and marking and storing at 4 ℃ for further use. The preparation schematic diagram is shown in fig. 4a, and the successful construction of the hollow cerium nano-composite drug-carrying system is proved through an X photoelectron spectrum (fig. 4d) and an infrared spectrum (fig. 4 e).
Step 4, firstly, taking stock solution of 1mL of hollow cerium nanoparticles (the concentration of nitric acid is 0M, namely equal amount of ultrapure water) and slowly stirring at room temperature, monitoring the oxygen saturation change of the stock solution within 300s through a JPBJ-608 portable dissolved oxygen analyzer and REXDC1.1 data acquisition software, then adding 100 mu L of 10mM hydrogen peroxide, and simultaneously monitoring the oxygen saturation change within 300 s; the change in oxygen saturation within 300s was monitored in the same manner as the blank with 1mL of water as the solvent. When the nitric acid concentration is 0M, namely, the same amount of ultrapure water is used for substitution, the prepared hollow cerium nano-particles are solid spheres and also have certain oxygen production capacity (figure 5 a).
And 6, firstly, slowly stirring 1mL of adenosine triphosphate-hollow cerium nano-composite (ATP-HCNPs) stock solution at room temperature, respectively adding 2 mLPBS with pH5.7 or pH7.4, monitoring the oxygen saturation change within 300s by a JPBJ-608 portable dissolved oxygen analyzer and REXDC1.1 data acquisition software, and then continuously adding 100 mu L of 10mM hydrogen peroxide while monitoring the oxygen saturation change within 300 s. Modification of adenosine triphosphate does not hinder the oxygen production function of the hollow cerium nanoparticles; and compared with ph7.4, the oxygen production capacity of the adenosine triphosphate-hollow cerium nanocomposite only responds to ph5.7 and hydrogen peroxide simultaneously (fig. 5c), further indicating that the multifunctional hollow cerium nanocomposite is successfully constructed.
Step 7, firstly, taking 1mL stock solution of a hollow cerium nano-composite drug-loaded system (ATP-HCNPs @ Ce6), slowly stirring at room temperature, monitoring the oxygen saturation change of the stock solution within 300s through a JPBJ-608 portable dissolved oxygen analyzer and REXDC1.1 data acquisition software, then continuously adding 2 mLPBS with pH of 5.7, monitoring the oxygen saturation change within 300s through the JPBJ-608 portable dissolved oxygen analyzer and REXDC1.1 data acquisition software, and finally continuously adding 100 muL 10mM hydrogen peroxide and monitoring the oxygen saturation change within 300 s; the oxygen saturation change in 300s was monitored in the same manner with 1mL of ultrapure water as a blank. The oxygen production function of the hollow cerium nano-particles and the hollow cerium nano-composite is not hindered by the drug loading, the oxygen production capacity of the hollow cerium nano-composite drug-loaded system is in double response to pH5.7 and hydrogen peroxide (figure 5c), and the successful construction of the multifunctional hollow cerium nano-composite drug-loaded system is further shown, so that the multifunctional hollow cerium nano-composite drug-loaded system can be further applied to the photodynamic therapy of tumor-related diseases, particularly the early treatment of breast cancer patients.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (2)
1. The construction and application of the multifunctional hollow cerium nano-particles and the hollow cerium nano-composite drug-carrying system are characterized by comprising the following steps:
(1) preparation of hollow cerium nanoparticles of different hollowness degrees:
the hollow cerium nano particles with different hollow degrees are prepared by adopting a one-pot hydrothermal method, firstly, 1.085g of cerium nitrate hexahydrate solid is dissolved in 5mL of ultrapure water to prepare 0.5M cerium nitrate, and then 5 reactions are carried out in parallel, which are respectively named as reactions I, II, III, IV and V. Secondly, the mixed solution of 30mL of ethylene glycol and 1mL of 0.5M cerium nitrate is stirred for 5min at room temperature in a beaker, 2mL of ultrapure water, 0.5M, 3.5M, 7.5M and 15M ultrapure water nitrate solutions are respectively added in parallel until the reaction is performed for 5min, and the reaction is performed for (i), (ii), (iii), (iv) and (iv). Then transferring the reaction liquid into a reaction kettle, and placing the reaction kettle in a muffle furnace to react for 12 hours at 180 ℃. And finally, cooling to room temperature after the reaction is finished, respectively centrifugally washing the reaction solution for 10min by using a proper amount of absolute ethyl alcohol at 5000rpm, washing for three times, then fixing the volume to 10mL by using ultrapure water to obtain hollow cerium nano particles with different hollow degrees, and marking and storing the hollow cerium nano particles at 4 ℃ for later use.
(2) Preparing an adenosine triphosphate-hollow cerium nano composite:
taking 1mL of cerium with the content of 0.95mg mL-13.5mL of 10mg mL of the hollow cerium nanoparticle stock solution of (1)-1The adenosine triphosphate solution is stirred at room temperature for 24h, and then purified by dialysis with ultrapure water for 24h, using a snake skin dialysis bag with a molecular weight cut-off of 10kD, and replacing the ultrapure water every 5 h at leastAnd finally, collecting the liquid in the dialysis bag to obtain the adenosine triphosphate-hollow cerium nano-composite, and labeling and storing at 4 ℃ for further use.
(3) Constructing a hollow cerium nano-composite drug-loading system:
firstly, 1.5mL of adenosine triphosphate-hollow cerium nano-composite solution is mixed with 80 μ L of 10mM chlorin e6 solution, the pH of the system is adjusted by 20 μ L of 1M Trs-HCl with the pH of 8.8, the mixture is stirred for 24h at room temperature, then the mixture is purified for 24h by ultrapure water dialysis, snake skin dialysis bags with the molecular weight cutoff of 10kD are used, the ultrapure water is changed at least once every 5 h, finally the liquid in the dialysis bags is collected, the purified hollow cerium nano-composite drug-loaded system is obtained, and the purified hollow cerium nano-composite drug-loaded system is marked and stored at 4 ℃ for further use.
2. The hollow cerium nanoparticles, the adenosine triphosphate-hollow cerium nanocomposite and the hollow cerium nanocomposite drug-loaded system with different hollowness degrees according to claim 1, wherein the multifunctional property is verified, and the method comprises the following steps:
(1) oxygen production capacity of hollow cerium nanoparticles of different hollowness degrees: firstly, 1mL of cerium with the content of 0.95mg mL is respectively taken-1The stock solution of the hollow cerium nano-particles is slowly stirred at room temperature, the oxygen saturation change of the stock solution within 300s is monitored by a JPBJ-608 portable dissolved oxygen analyzer and REXDC1.1 data acquisition software, then 100 mu L of 10mM hydrogen peroxide is added, and the oxygen saturation change within 300s is monitored at the same time; monitoring the oxygen saturation change in 300s by using 1mL of ultrapure water as a blank;
(2) oxygen production capacity of the adenosine triphosphate-hollow cerium nanocomposite: firstly, taking 1mL of adenosine triphosphate-hollow cerium nano compound stock solution, slowly stirring at room temperature, respectively adding 2mL of PBS with pH5.7 or pH7.4, monitoring the oxygen saturation change of the hollow cerium nano compound stock solution within 300s through a JPBJ-608 portable dissolved oxygen analyzer and REXDC1.1 data acquisition software, then continuously adding 100 mu L of 10mM hydrogen peroxide, and simultaneously monitoring the oxygen saturation change of the hollow cerium nano compound stock solution within 300 s;
(3) oxygen production capacity of the hollow cerium nano-composite drug-loaded system: firstly, slowly stirring 1mL of hollow cerium nano-composite drug-carrying system stock solution at room temperature, monitoring the oxygen saturation change within 300s by a JPBJ-608 portable dissolved oxygen analyzer and REXDC1.1 data acquisition software, then continuously adding 2mL of PBS with pH of 5.7, monitoring the oxygen saturation change within 300s by the JPBJ-608 portable dissolved oxygen analyzer and REXDC1.1 data acquisition software, finally continuously adding 100 mu L of 10mM hydrogen peroxide, and monitoring the oxygen saturation change within 300s at the same time; the oxygen saturation change in 300s was monitored in the same manner with 1mL of ultrapure water as a blank.
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|---|---|---|---|
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