CN109498808B - Method for controllably synthesizing CuS @ EPO nano material through electrostatic assembly - Google Patents

Method for controllably synthesizing CuS @ EPO nano material through electrostatic assembly Download PDF

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CN109498808B
CN109498808B CN201811194984.6A CN201811194984A CN109498808B CN 109498808 B CN109498808 B CN 109498808B CN 201811194984 A CN201811194984 A CN 201811194984A CN 109498808 B CN109498808 B CN 109498808B
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endoperoxide
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刘见永
王治伟
丁豪
马金良
贾潇
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Abstract

The invention provides a method for controllably synthesizing a CuS @ EPO nano material through electrostatic assembly, and relates to the technical field of inorganic nano functional materials. The invention comprises the following steps: (1) mixing sodium citrate, copper chloride dihydrate and sodium sulfide nonahydrate, and reacting at 89-95 ℃ for 20-35 min to obtain nano CuS; (2) mixing 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, adding carboxylated pyridone endoperoxide, carrying out activation reaction, adding polyacrylamide hydrochloride, uniformly mixing, and centrifuging to obtain the polyacrylamide hydrochloride modified by the pyridone endoperoxide; (3) mixing the pyridinone endoperoxide modified polyacrylamide hydrochloride and the nano CuS to obtain the pyridinone endoperoxide modified CuS @ EPO nano material. The invention has no photo-thermal effect caused by infrared light, the nano-drug can still carry out PDT treatment, and the photo-thermal reagent CuS enriched in the tumor part can carry out PTT and accelerate the release of singlet oxygen.

Description

Method for controllably synthesizing CuS @ EPO nano material through electrostatic assembly
Technical Field
The invention relates to the technical field of inorganic nano functional materials, in particular to a method for controllably synthesizing a CuS @ EPO nano material through electrostatic assembly.
Background
Photodynamic therapy is a therapeutic approach for the non-invasive treatment of various neoplastic diseases. The treatment process includes photosensitizers, oxygen and light to create a photodynamic treatment process and produce singlet oxygen at the tumor site. Singlet oxygen is considered a cytotoxic substance that can interact with nucleic acids, proteins, DNA and deprive them of biological activity in the photodynamic therapy treatment of cancer. However, the toxic side effect is small, and the non-drug resistance seems to be very promising but has great defects. The efficacy of photodynamic therapy for solid tumors is limited to a large extent by a number of problems. Most of the photodynamic dyes can only be activated by visible light or ultraviolet light, and are easy to generate photobleaching under the condition of continuous laser irradiation. And the reduction of the ability of generating singlet oxygen at most tumor parts due to hypoxia is a great obstacle, and triggers a series of cellular defense mechanisms to reduce the treatment efficiency. In view of the shortcomings of conventional Photodynamic (PDT), a synergistic treatment modality combines PDT with other therapeutic approaches, such as photothermal therapy (PTT), which may be the preferred modality for overcoming the limitations of single PDT. Photothermal agents such as gold, chalcogenides, and graphene oxide can be loaded with photosensitizers for enrichment at tumor tissue sites via the EPR effect. The maximum absorption wave band is in the infrared region, and continuous illumination can be carried out on deep tumor tissues due to the strong penetrability of near infrared light and the high stability of the photothermal reagent. However, due to the mismatch of the absorption bands of the photothermal agent and the photosensitizer, the combined treatment modality for PDT/PTT typically requires two different wavelengths of excitation light, greatly extending the treatment time.
Due to the tunable thermal stability of endoperoxides, internal oxides such as naphthalene, anthracene and pyridine may be the best choice to enhance conventional PDT modalities. On the basis, a novel combined treatment mode of loading endoperoxide on a photo-thermal carrier, and guiding PDT/PTT by photo-thermal (PT) and photo-acoustic (PA) co-imaging is provided. Endoperoxides supported on photothermal agents showed significant PTT effects, but PDT treatment effects were not significant, photothermal-photodynamic (PTT/PDT) co-treatment could not be achieved, and no singlet oxygen was detected in the dark. The singlet oxygen can not be released in the dark, the function of killing cancer cells can not be realized, the temperature required by the naphthalene or anthracene endoperoxide derivative to release the singlet oxygen is too high, the naphthalene or anthracene endoperoxide derivative can not be really used under the condition of living bodies, and the photodynamic treatment effect is poor.
Disclosure of Invention
In view of the above, the invention provides a method for controllably synthesizing CuS @ EPO nanomaterials through electrostatic assembly, under the condition of no light irradiation, the nano-drug CuS @ EPO NPs absorbed by tumor cells can still slowly release singlet oxygen in the cells, and photo-thermal-photodynamic combined treatment can be carried out under the condition of light irradiation. The photothermal reagent enriched at the tumor part can perform PTT and accelerate the release of ROS, enhance the treatment effect and realize the synergistic treatment of PTT/PDT on the tumor part.
The invention relates to a method for controllably synthesizing a CuS @ EPO nano material through electrostatic assembly, which comprises the following steps:
(1) placing sodium citrate and copper chloride dihydrate in a round-bottom flask containing deionized water, magnetically stirring at room temperature for 15 min, gradually dropwise adding sodium sulfide nonahydrate aqueous solution into the solution, reacting at 89-95 deg.C for 20-35 min to obtain aqueous solution containing nano CuS, cooling, centrifuging, washing, and storing at below 25 deg.C; the mol ratio of the sodium citrate, the copper chloride dihydrate and the sodium sulfide nonahydrate is 1: 0.9-1.2: 0.9-1.2, the grain diameter of the nano CuS is 10-30nm, and the concentration of the copper chloride dihydrate is less than 2 mol/L;
(2) mixing 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, adding a carboxylated pyridone endoperoxide aqueous solution synthesized in advance, stirring at 0-2 ℃ for 1-1.3h, and carrying out an activation reaction; then adding the polyallylamine hydrochloride after the desalting and acidifying treatment, continuously stirring for 6 hours at room temperature, uniformly mixing, and centrifuging through an ultrafiltration tube to obtain the polyallylamine hydrochloride EPO-PAH modified by the pyridone endoperoxide; wherein, the mol mass ratio of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide, carboxylated pyridone endoperoxide activation and polyacrylamide hydrochloride is 1.9-2.2: 1.9-2.2:1:1;
(3) the pyridinone endoperoxide modified polyacrylamide hydrochloride EPO-PAH obtained in the step (2),
And (2) mixing the nano CuS in the step (1) according to the molar ratio of 2-4:1, and stirring for 24 hours to obtain the pyridone endoperoxide modified CuS @ EPO nano material.
The size of the nano material can be controlled by selecting sodium citrate as a surfactant, and a layer of carboxyl functional group is coated on the surface of the nano CuS, so that the surface of the nano CuS particle is negatively charged, the surface of the EPO-PAH particle is positively charged, and the positive and negative charges are mutually attracted, so that the EPO-PAH particle is adsorbed on the surface of the nano CuS particle to form the CuS @ EPO nano material. The CuS needs to be stored at a lower temperature when being generated, the more suitable temperature is about 4 ℃, because the CuS can be settled at a higher temperature, and the lower temperature has a reason to ensure that the nano CuS particles are stably suspended in the aqueous solution.
The prepared CuS @ EPO nano material has the following effect detection modes as a diagnostic reagent and a therapeutic reagent: the Kunming Mouse (KM) is injected with a solution containing CuS @ EPO nanomaterial in tail vein, and after 24 h of drug enrichment, photo-thermal and photodynamic combined treatment can be initiated through infrared light judgment, and whether photodynamic treatment can be continued under the condition of no light.
The pyridone endoperoxides are more suitable for photodynamic therapy at human body temperature. The biocompatible photothermal reagent copper sulfide nano material has obvious absorption in a near infrared region (wavelength =700-1100 nm), and is finally enriched in a tumor part due to an enhanced osmotic retention Effect (EPR) after pyridone endoperoxide modification. Under the irradiation of 980 nm light, the higher temperature of the surface of the copper sulfide nano material can promote the peroxide in the pyridone to release singlet oxygen, and the synergistic treatment of PDT/PTT is realized. In addition, the nano-drug CuS @ EPO NPs taken up by tumor cells can still slowly release singlet oxygen in the cells in the absence of light irradiation. The photodynamic process can be continued in the dark, and the photothermal and photodynamic combined treatment is carried out under the illumination condition.
Under the condition of no light irradiation, the nano-drug CuS @ EPO NPs absorbed by tumor cells can still slowly release singlet oxygen in the cells, and photo-thermal-photodynamic combined treatment can be carried out under the condition of light irradiation. The nano-drug can still carry out PDT treatment without the photothermal effect caused by infrared light, overcomes the dependence of the traditional light excitation treatment mode on a light source, and reduces the damage of the light source to the skin. The photo-thermal reagent CuS enriched in the tumor part can carry out PTT and accelerate the release of singlet oxygen, enhances the treatment effect and realizes the cooperative treatment of PTT/PDT on the tumor part.
Drawings
FIG. 1 is an XRD diagram of a CuS @ EPO nanomaterial prepared according to a first embodiment of the present invention;
FIG. 2 shows the photothermal effect and the photothermal conversion of the CuS @ EPO nanomaterial prepared in the first embodiment of the present invention;
FIG. 3 shows the oxygen release capacity of the CuS @ EPO nanomaterial prepared in the first embodiment of the present invention under the illumination condition;
FIG. 4 is an MTT method cell phototoxicity and dark toxicity experiment of the CuS @ EPO nanomaterial prepared in the first embodiment of the present invention;
FIG. 5 is a KM mouse in vivo tumor inhibition rate experiment of the CuS @ EPO nanomaterial prepared in the first embodiment of the invention.
Detailed Description
In order to make the present invention more comprehensible, the technical solutions of the present invention are further described below with reference to specific embodiments, but the present invention is not limited thereto.
Example one
A method for controllably synthesizing a CuS @ EPO nano material through electrostatic assembly comprises the following steps:
(1) placing sodium citrate and copper chloride dihydrate in a round-bottom flask filled with deionized water, magnetically stirring at room temperature for 15 min, gradually dropwise adding sodium sulfide nonahydrate aqueous solution into the solution, reacting at 89 ℃ for 20 min to obtain an aqueous solution containing nano CuS, cooling, centrifuging, washing, and storing at 4 ℃; the molar weight of sodium citrate, copper chloride dihydrate and sodium sulfide nonahydrate is 5mol, 4.5mol and 4.5mol, the particle size of the nano CuS is about 20nm, and the concentration of the copper chloride dihydrate is 1 mol/L;
(2) mixing 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, adding a carboxylated pyridone endoperoxide aqueous solution synthesized in advance, stirring at 0 ℃ for 1h, and carrying out an activation reaction; then adding the polyallylamine hydrochloride after the desalting and acidifying treatment, continuously stirring for 6 hours at room temperature, uniformly mixing, and centrifuging through an ultrafiltration tube to obtain the polyallylamine hydrochloride EPO-PAH modified by the pyridone endoperoxide; wherein, the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, the N-hydroxysuccinimide, the carboxylated pyridone endoperoxide activation and the polyallylamine hydrochloride have the molar mass of 9.5mol, 5mol and 5mol;
(3) the pyridinone endoperoxide modified polyacrylamide hydrochloride EPO-PAH obtained in the step (2),
Stirring and mixing the nano CuS in the step (1) for 24 hours according to the molar mass of 10mol and 5mol to obtain the pyridone endoperoxide modified CuS @ EPO nano material.
FIG. 1 is an XRD pattern of CuS @ EPO NPs prepared in the first example. The resulting product was demonstrated against a standard card of copper sulfide (JCPDS: 06-0464) and a broader characteristic peak was observed, further illustrating the broadening of the characteristic peak due to the size effect of the nanomaterials.
FIG. 2 shows the photothermal effect and photothermal conversion of the CuS @ EPO NPs prepared in the first example. To explore the photothermal effect of copper sulfide as a photothermal agent, we recorded the temperature rise of copper sulfide with a series of concentration gradients as a function of illumination time. The 980 nm infrared light is selected as the exciting light of the light source, the change of the temperature of the solvent is recorded by a photo-thermal camera in a 2 mL test system, and the temperature reduction condition of the solvent under the condition of no light is recorded and is used as the basis for the subsequent calculation of the photo-thermal conversion rate. As can be seen, the copper sulfide nano-material can observe obvious temperature rise phenomenon (28 ℃), while the control group aqueous solution has only slight change (7 ℃).
FIG. 3 is a graph of the oxygen-releasing capacity of the first CuS @ EPO NPs prepared in example under light conditions. Wherein, 9, 10-Dimethylanthracene (DMA) is selected as a singlet oxygen trapping agent, and is combined with singlet oxygen in a solvent to destroy the conjugated structure of the singlet oxygen trapping agent, so that the fluorescence intensity is reduced. The nanometer materials CuS @ PAH NPs and CuS @ EPO NPs without pyridone endoperoxide modification are simultaneously irradiated by infrared light, and the generation of singlet oxygen is proved by detecting the change of DMA fluorescence intensity. The fluorescence intensity of the CuS @ EPO NPs group is gradually reduced along with the prolonging of the illumination time, while the fluorescence intensity of the CuS @ PAH NPs of the control group has no obvious change.
FIG. 4 shows MTT method cytotoxicity light toxicity and dark toxicity experiments of the first CuS @ EPO NPs prepared in example. As can be seen, in vitro experiments, the PDT/PTT combination therapy has a significant synergistic effect compared to the single treatment modality. Moreover, the single photodynamic therapy effect is better than the photothermal therapy, and nearly 80% of cancer cell apoptosis is observed.
FIG. 5 is a KM mouse in vivo tumor inhibition assay of CuS @ EPO NPs prepared in example one, according to the volume calculation formula: v = a b2The treelet tumor volume change was calculated (a: tumor length, b: tumor width). As can be seen, in vivo experiments, the PDT/PTT combination therapy has a significant synergistic effect compared to the single treatment modality. However, the effect of photothermal therapy is significantly better than that of single photodynamic therapy because some singlet oxygen is released in advance during the in vivo circulation of the nano-drug.
Example two
A method for controllably synthesizing a CuS @ EPO nano material through electrostatic assembly comprises the following steps:
(1) placing sodium citrate and copper chloride dihydrate in a round-bottom flask filled with deionized water, magnetically stirring at room temperature for 15 min, gradually dropwise adding sodium sulfide nonahydrate aqueous solution into the solution, reacting at 95 ℃ for 20 min to obtain an aqueous solution containing nano CuS, cooling, centrifuging, washing, and storing at 6 ℃; the molar mass of the sodium citrate, the copper chloride dihydrate and the sodium sulfide nonahydrate is 5mol and 6 mol: 6mol, the grain diameter of the nano CuS is about 30nm, and the concentration of the copper chloride dihydrate is 1.2 mol/L;
(2) mixing 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, adding a carboxylated pyridone endoperoxide aqueous solution synthesized in advance, stirring at the temperature of 2 ℃ for 1.3 hours, and carrying out an activation reaction; then adding the polyallylamine hydrochloride after the desalting and acidifying treatment, continuously stirring for 6 hours at room temperature, uniformly mixing, and centrifuging through an ultrafiltration tube to obtain the polyallylamine hydrochloride EPO-PAH modified by the pyridone endoperoxide; wherein, the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, the N-hydroxysuccinimide, the carboxylated pyridone endoperoxide activation and the polyacrylamide hydrochloride have the molar mass of 11mol, 5mol and 5mol;
(3) the pyridinone endoperoxide modified polyacrylamide hydrochloride EPO-PAH obtained in the step (2),
Stirring and mixing the nano CuS in the step (1) for 24 hours according to the molar mass of 20mol and 5mol to obtain the pyridone endoperoxide modified CuS @ EPO nano material.
EXAMPLE III
A method for controllably synthesizing a CuS @ EPO nano material through electrostatic assembly comprises the following steps:
(1) placing sodium citrate and copper chloride dihydrate in a round-bottom flask filled with deionized water, magnetically stirring at room temperature for 15 min, gradually dropwise adding sodium sulfide nonahydrate aqueous solution into the solution, reacting at 90 ℃ for 20 min to obtain an aqueous solution containing nano CuS, cooling, centrifuging, washing, and storing at 10 ℃; the molar mass of the sodium citrate, the cupric chloride dihydrate and the sodium sulfide nonahydrate is 5mol, 5mol and 5mol, the particle size of the nano CuS is about 20nm, and the concentration of the cupric chloride dihydrate is 2 mol/L;
(2) mixing 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, adding a carboxylated pyridone endoperoxide aqueous solution synthesized in advance, stirring at the temperature of 1 ℃ for 1.2 hours, and carrying out an activation reaction; then adding the polyallylamine hydrochloride after the desalting and acidifying treatment, continuously stirring for 6 hours at room temperature, uniformly mixing, and centrifuging through an ultrafiltration tube to obtain the polyallylamine hydrochloride EPO-PAH modified by the pyridone endoperoxide; wherein, the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, the N-hydroxysuccinimide, the carboxylated pyridone endoperoxide activation and the polyacrylamide hydrochloride have the molar mass of 10mol, 5mol and 5mol;
(3) the pyridinone endoperoxide modified polyacrylamide hydrochloride EPO-PAH obtained in the step (2),
Stirring and mixing the nano CuS in the step (1) for 24 hours according to the molar mass of 15mol and 5mol to obtain the CuS @ EPO nano material modified by pyridone endoperoxide.
The experimental results of the CuS @ EPO nanomaterials prepared in example two and example three were the same as in example one.
Under the condition of no light irradiation, the nano-drug CuS @ EPO NPs absorbed by tumor cells can still slowly release singlet oxygen in the cells, and photo-thermal-photodynamic combined treatment can be carried out under the condition of light irradiation. Even if no infrared light causes photothermal effect, the nano-drug can still carry out PDT treatment, the dependence of the traditional light excitation treatment mode on a light source is overcome, and the damage of the light source to the skin is reduced. The photo-thermal reagent CuS enriched in the tumor part can carry out PTT and accelerate the release of singlet oxygen, enhances the treatment effect and realizes the cooperative treatment of PTT/PDT on the tumor part.
The present invention is not limited to the above-described specific embodiments, and various modifications and variations are possible. Any modifications, equivalents, improvements and the like made to the above embodiments in accordance with the technical spirit of the present invention should be included in the scope of the present invention.

Claims (2)

1. A method for controllably synthesizing a CuS @ EPO nano material through electrostatic assembly is characterized by comprising the following steps:
(1) mixing sodium citrate, copper chloride dihydrate and sodium sulfide nonahydrate, and reacting at 89-95 ℃ for 20-35 min to obtain nano CuS;
(2) mixing 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, adding carboxylated pyridone endoperoxide, carrying out activation reaction, adding polyacrylamide hydrochloride, uniformly mixing, and centrifuging to obtain polyacrylamide hydrochloride EPO-PAH modified by the pyridone endoperoxide;
(3) mixing the pyridinone endoperoxide modified polyacrylamide hydrochloride EPO-PAH obtained in the step (2) and the nano CuS obtained in the step (1) to obtain a pyridinone endoperoxide modified CuS @ EPO nano material;
wherein the molar ratio of the sodium citrate, the copper chloride dihydrate and the sodium sulfide nonahydrate in the step (1) is 1: 0.9-1.2: 0.9-1.2, the concentration of the copper chloride dihydrate is 1-2 mol/L; the temperature of the activation reaction in the step (2) is 0-2 ℃, the reaction time is 1-1.3h, the molar ratio of the activation of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide and carboxylated pyridone endoperoxide is 1.9-2.2: 1.9-2.2:1, and the molar ratio of the carboxylated pyridone endoperoxide to the polyacrylamide hydrochloride is 1:1; the molar ratio of the pyridinone endoperoxide modified polyacrylamide hydrochloride EPO-PAH to the nano CuS in the step (3) is 2-4: 1.
2. The method for controllably synthesizing the CuS @ EPO nanomaterial by electrostatic assembly according to claim 1, wherein the nano CuS in the step (1) has a particle size of 10-30 nm.
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