AU2022211878B1 - Targeting Degradable Nano-Drug Carrier for Chemo/Photothermal Synergistic Therapy and Preparation Method Thereof - Google Patents
Targeting Degradable Nano-Drug Carrier for Chemo/Photothermal Synergistic Therapy and Preparation Method Thereof Download PDFInfo
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- AU2022211878B1 AU2022211878B1 AU2022211878A AU2022211878A AU2022211878B1 AU 2022211878 B1 AU2022211878 B1 AU 2022211878B1 AU 2022211878 A AU2022211878 A AU 2022211878A AU 2022211878 A AU2022211878 A AU 2022211878A AU 2022211878 B1 AU2022211878 B1 AU 2022211878B1
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- polydopamine
- mesoporous silica
- doped mesoporous
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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Abstract
The present invention discloses a targeting degradable nanometer drug carrier for optic-thermal
collaborative chemotherapy and a preparation method thereof The preparation method of the
targeting degradable nanometer drug carrier for optic-thermal collaborative chemotherapy
comprises: (1) preparing polydopamine-doped mesoporous silica; (2) conducting amination
modification on the polydopamine-doped mesoporous silica; (3) loading an anti-cancer drug; (4)
conducting modification by using activated carboxymethyl chitosan and folic acid in sequence;
and (5) dispersing a product in the step (4) into a PBS solution, and conducting filtering to obtain
the targeting degradable nanometer drug carrier for optic-thermal collaborative chemotherapy. For
the targeting degradable nanometer drug carrier for optic-thermal collaborative chemotherapy and
the preparation method thereof of the present invention, the drug carrier has high biocompatibility,
degradability and targeting characteristic and is an effective way of improving the effect of
treating tumors.
14
Description
DCC-22/03/2023
Targeting Degradable Nano-Drug Carrier for Chemo/Photothermal Synergistic Therapy and Preparation Method Thereof
Description
Technical Field The present invention belongs to the technical field of nanometer drug carriers and particularly relates to a targeting degradable nano-drug carrier for chemo/photothermal synergistic therapy and a preparation method thereof.
Background Art International Agency for Research on Cancer has issued a report on global cancer burden of 2020 on December 15, 2020. By excerpting data related to cervical cancer in the world and in China, the number of new cancer cases in the world in 2020 is 19.29 million, wherein 4.57 million new cancer cases occurred in China, accounting for 23.7% of new incident cases in the world. Finding a more effective cancer treatment method has already become a major subject required to be overcome. At present, chemotherapy and radiotherapy are two mainstream treatment modes at this stage, but are limited in further development due to their side effects of low efficiency, causing general toxicity and the like. However, researches on a nanometer drug carrier will hopefully solve the problems of low efficiency and causing the general toxicity. The nanometer drug carrier has designable physical properties, chemical properties and biological properties, improves distribution of a drug in tissues and organs in a body to a certain degree, effectively increases the utilizing rate of the drug and thus improving the biosafety of a chemotherapeutic drug. Nanometer tumor treatment takes a nanometer material, synthesized by a chemical method and being of a stable structure, as a drug carrier; the carrier in a nanometer scale can be effectively enriched nearby tumor vessels through the EPR effect, and the drug is specifically released in a microenvironment, in which a tumor is located; and therefore, the side effects of the drug on a human body are weakened, and a certain purpose of inhibiting tumor cells may further be achieved. However, nanometer particles which exert the effect and do not exert the effect after a silica-based nanometer carrier drug enters the body can accumulate
DCC-22/03/2023
in the tissues and organs of the human body; although the drug have to be released, various physiological reactions such as inflammations can be triggered due to long-time accumulation; so that the biosafety cannot be solved. Therefore, it is very important to improve a silica-based carrier so as to solve the degradation problem; whereas surface modification on the carrier is a key of promoting body circulation and improving the therapeutic efficiency. The degradable nanometer drug carrier can be effectively degraded and eliminated in an own microenvironment in the human body after exerting the effective effect in the human body; and therefore, the degradable nanometer drug carrier attracts more and more attention and has become a research hotspot in recent years. Numerous researches show that the outer surface of a tumor cell shows weakly acidic pH, a targeting matter (such as biotin with -NH-, folic acid and other matters) may access the tumor cell by using the features of such microenvironment. Such matter can specifically recognize a tumor due to the special responsiveness to pH, and then the purpose of accurate and active targeting is achieved. The mesoporous silica has the characteristics of high porosity, high specific surface area, thermal stability, large drug loading capacity, stable structure, good biocompatibility and no toxic or side effect, but is short in cycling time in the body and prone to accumulating in the organs. After the carrier enters the human body with singly loading the mesoporous silica, diseases cannot be effectively treated. Therefore, it requires to comprehensively consider a design of a nanometer carrier from the aspects of degradation, circulation, targeting and the like. In view of this, the present invention provides a novel targeting degradable nano-drug carrier for chemo/photothermal synergistic therapy and a preparation method thereof, so as to meet the requirement for degradability, targeting, chemo/photothermal synergistic treatment, improve the efficiency and reduce the side effects, which has an important significance of treating the tumor.
Summary of the Invention One or more embodiments of the present invention provide a targeting degradable nano drug carrier for chemo/photothermal synergistic therapy and preparation method thereof. .By using a structured design, a nanometer drug carrier for treating a tumor with photothermal/chemotherapy collaboration is obtained, so as to remedy the defects of low utilization rate and strong toxic or side effect of a traditional drug and solve the problem that
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a silica-based material cannot be degraded for a long time; and through carboxymethyl chitosan as a biomass, the stability and the degradability of the nanometer carrier are realized, and the purpose of efficiently treating a cancer is achieved.
The present invention provides a preparation method for a targeting degradable nano-drug carrier for chemo/photothermal synergistic therapy, comprising the following steps: (1) preparing polydopamine-doped mesoporous silica; a method of preparing the polydopamine-doped mesoporous silica comprises the following steps: adding dopamine hydrochloride for uniform mixing after uniformly mixing CTAC, ultrapure water and triethanolamine; and then dropwise adding 20 v/v% TEOS/cyclohexane solution for reaction for 12 h, and then sequentially conducting centrifugal washing, washing-off for the CTAC and vacuum drying to obtain the polydopamine-dopsed mesoporous silica; (2) conducting amination modification on the polydopamine-doped mesoporous silica to obtain amino-modified polydopamine-doped mesoporous silica; (3) loading an anti-cancer drug: adding the amino-modified polydopamine-doped mesoporous silica to an anti-cancer drug aqueous solution for stirring for 24 h to obtain polydopamine-doped mesoporous silica loading an anti-cancer drug; the anti-cancer drug is an anti-cancer drug DOX; a mass ratio of the amino-modified polydopamine-doped mesoporous silica to the anti-cancer drug to water is 1:1.5:1.5; (4) modifying the polydopamine-doped mesoporous silica loading the anti-cancer drug with activated carboxymethyl chitosan and folic acid in sequence to obtain folic acid modified polydopamine-doped mesoporous silica with a carboxymethyl chitosan layer; a mass ratio of the carboxymethyl chitosan to the polydopamine-doped mesoporous silica loading the anti-cancer drug is 1:1; a mass ratio of the activated folic acid to the carboxymethyl chitosan modified polydopamine-doped mesoporous silica is 1:1and (5) dispersing the folic acid modified polydopamine-doped mesoporous silica with the carboxymethyl chitosan layer into a PBS solution, and conducting filtering to obtain the targeting degradable nano-drug carrier for chemo/photothermal synergistic therapy.Further, in the step (1), a method of preparing the polydopamine-doped mesoporous silica comprises the following steps: adding dopamine hydrochloride for uniform mixing after uniformly mixing CTAC, ultrapure water and triethanolamine; and then dropwise adding 20 v/v% TEOS/cyclohexane solution for reaction for 12 h, and then sequentially conducting centrifugal washing, washing-off for
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the CTAC and vacuum drying to obtain the polydopamine-dopsed mesoporous silica. Further, in the step (1), a method of washing off the CTAC comprises the following steps: using 6 g/L nitrate-ethanol solution for stirring for 12 h at 60°C, and then conducting centrifugal washing. Further, in the step (1), before centrifugal washing, a temperature in the mixing and reaction process is 60±2°C. Further, in the step (1), the dopamine hydrochloride is added by several times. Further, in the step (1), a vacuum drying temperature is not higher than 40°C. Further, in the step (2), a temperature in the amination modification process is 60±2°C. Further, in the step (3), the anti-cancer drug is an anti-cancer drug DOX; In the step (4), the carboxymethyl chitosan and the folic acid are activated by EDC and NHS for 4 h and 16 h respectively. Further, in the step (3), a mass ratio of the amino-modified polydopamine-doped mesoporous silica to the anti-cancer drug to water is 1:1.5:1.5; In the step (4), a mass ratio of the carboxymethyl chitosan to the polydopamine-doped mesoporous silica loading the anti-cancer drug is 1:1; A mass ratio of the activated folic acid to the carboxymethyl chitosan modified polydopamine-doped mesoporous silica is 1:1. Another embodiment of the present invention provides a targeting degradable nano-drug carrier for chemo/photothermal synergistic therapy, which is prepared by using the above preparation method and is a multifunctional nanometer drug carrier for treating the tumor with photothermal/chemotherapy collaboration. With modification with the carboxymethyl chitosan, synthesized nanometer particles may have very low haemolytic activity and good dispersibility in a body fluid environment; and with targeting, efficient accumulation of the nanometer particles in the tumor can be achieved. Therefore, the biocompatibility as well as the stability and the degradable characteristic in a human body of the drug carrier are greatly improved, and the drug carrier may be used for drug delivery in tumor cells. Compared with the prior art, the present invention has the beneficial effects that: 1. In the technical solution of the present invention, the used polydopamine-doped mesoporous silica is prepared with an oil-water two phase method, has large specific surface area, is of a structure with rich pore canals and is mainly used for increasing the drug loading capacity of the drug carrier. 2. In the technical solution of the present invention, with modification with the CMCS, the
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synthesized nanometer particles may be effectively dispersed into a body fluid simulation environment; so that good dispersibility and biocompatibility of the nanometer particles are achieved, and efficient accumulation of the nanometer particles in the tumor is facilitated. 3. In the technical solution of the present invention, with modification with targeting molecule folic acid, the drug carrier conducts active targeting, and then aggregation of the drug carrier at a tumor site is further improved. In embodiments of the present invention, it shows that the biocompatibility, the degradability and aggregation at the tumor site of the carrier are improved, and the carrier may be used for drug delivery to the tumor site.
Brief Description of the Drawings Fig. 1 is a diagram showing surface potential change conditions of PDA/MSN, PDA/MSN NH2, PDA/MSN-CMCS, PDA/MSN-CMCS-FA in embodiment 1. Fig. 2 is a transmission electron micrograph of PDA/MSN-CMCS-FA nanometer particles in embodiment 2 with a map scale of 200 nanometers. Fig. 3 is a diagram showing a photo-thermal effect curve of PDA/MSN-CMCS-FA in embodiment 3. Fig. 4 is a diagram showing size distribution of nanometer particles of PDA/MSN-CMCS and PDA/MSN-CMCS-FA in embodiment 4. Fig. 5 is a diagram showing a drug releasing condition of DOX@PDA/MSN-CMCS-FA in embodiment 4. Fig. 6 is a schematic diagram of degradation after 14 d in an acid environment in embodiment 4. Fig. 7 is a diagram showing cytotoxicity of PDA/MSN-CMCS, PDA/MSN-CMCS-FA, DOX@PDA/MSN-CMCS and DOX@PDA/MSN-CMCS-FA in embodiment 5.
Detailed Description of the Invention To further describe the targeting degradable nano-drug carrier for chemo/photothermal synergistic therapy and preparation method thereof of the present invention and achieve an expected inventive purpose, the specific implementations, the structures, the features and the efficacies of the targeting degradable nano-drug carrier for chemo/photothermal synergistic therapy and the preparation method thereof according to the present invention are stated in detail in combination with preferred embodiments below. In the following descriptions, different "one embodiment" or "embodiment" does not necessarily refer to a same
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embodiment. In addition, specific features, structures or characteristics in one or more embodiments may be combined in any suitable manner. The targeting degradable nano-drug carrier for chemo/photothermal synergistic therapy and the preparation method thereof of the present invention will be further introduced in detail in combination with the specific embodiments below. Aiming to the problem of low effective utilizing rate of a clinical drug at present, the present invention is directed to designing a degradable nanometer drug carrier with a targeting function, so as to improve the effective utilizing rate and the biosafety of the drug. In current cancer treatment, the clinical drug faces the problems of low efficiency and severe side effects. Researches on the nanometer drug carrier will hopefully solve such problems. The nanometer drug carrier has designable physical properties, chemical properties and biological properties, and thus increasing the utilizing rate of the drug and improving distribution of the drug in tissues and organs and the biosafety of the drug. Aiming to the problems that the nanometer drug carrier is difficult to degrade and low in anti-tumor efficiency, with a multi-stage structure as a research object, the present invention uses the polydopamine-doped mesoporous silica to prepare a nanometer carrier with adjustable porous wormlike pore canals and good biocompatibility, uses the nanometer carrier to load an anti-cancer drug to achieve drug release and degradation and then uses a coupling stability coating and targeting folic acid on the polydopamine-doped mesoporous silica to obtain photothermal/chemotherapy collaborative treatment; and then drug carrier can be effectively degraded. By using the drug carrier, tumor cells are efficiently killed, the efficiency is improved, and the biotoxicity is weakened. The method is simple in preparation process and safe and effective in material preparation, has the characteristic of a personalized nanometer carrier, provides a research thought and basis for designing a nanometer drug carrier with a practical application value and is mainly used for thefield of nanomedicine. The specific technical solution is as follows: A preparation method for a targeting degradable nano-drug carrier for chemo/photothermal synergistic therapy comprises the following steps: (1) preparing polydopamine-doped mesoporous silica; (2) conducting amination modification on the polydopamine-doped mesoporous silica to obtain amino-modified polydopamine-doped mesoporous silica; (3) loading an anti-cancer drug: adding the amino-modified polydopamine-doped mesoporous silica to an anti-cancer drug aqueous solution for stirring for 24 h to obtain
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polydopamine-doped mesoporous silica loading an anti-cancer drug; (4) modifying the polydopamine-doped mesoporous silica loading the anti-cancer drug with activated carboxymethyl chitosan and folic acid in sequence to obtain folic acid modified polydopamine-doped mesoporous silica with a carboxymethyl chitosan layer (the used activated carboxymethyl chitosan should not be dried after modification and washing, is dispersed into water and is preserved in an environment with a temperature of 4°C according to a concentration of 1 mg/mL); and (5) dispersing the folic acid modified polydopamine-doped mesoporous silica with the carboxymethyl chitosan layer into a PBS solution, and conducting filtering to obtain the targeting degradable nano-drug carrier for chemo/photothermal synergistic therapy. Preferably, in the step (1), a method of preparing the polydopamine-doped mesoporous silica comprises the following steps: adding dopamine hydrochloride for uniform mixing after uniformly mixing CTAC, ultrapure water and triethanolamine; and then dropwise adding 20 v/v% TEOS/cyclohexane solution for reaction for 12 h, and then sequentially conducting centrifugal washing, washing-off for the CTAC and vacuum drying to obtain the polydopamine-dopsed mesoporous silica. The mesoporous silica takes hexadecyl trimethyl ammonium chloride (CTAC) as a template, tetraethyl orthosilicate as a silicon source and polydopamine deposit on the surface of the template, and then the template is extracted to obtain polydopamine-deoped mesoporous silica nanometer particles. The mesoporous silica has large specific surface area, is of a structure with rich pore canals and is mainly used for increasing the drug loading capacity of the drug carrier. Purities and reaction temperatures of all drugs should be rigorously followed. TEOS necessarily has a GC purity; a purity of the CTAC is necessarily 99%; and after being dissolved, the TEOS and the CTAC are necessarily in a quality of thick gel. When the TEOS/cyclohexane is added dropwise, a rotating speed of a magneton is necessarily low. Further preferably, in the step (1), a method of washing off the CTAC comprises the following steps: using 6 g/L nitrate-ethanol solution for stirring for 12 h at 60°C, and then conducting centrifugal washing. Further preferably, in the step (1), before centrifugal washing, a temperature in the mixing and reaction process is 60±2°C. Further preferably, in the step (1), the dopamine hydrochloride is added by several times. Further preferably, in the step (1), a vacuum drying temperature is not higher than 40°C.
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Preferably, in the step (2), a method of aminating the polydopamine-doped mesoporous silica comprises the following steps: adjusting a pH value of anhydrous ethanol with acetic acid to 4, dispersing 150 mg of polydopamine-doped mesoporous silica into 40 mL of ethanol-acetic acid solution, adding 1g of APTES for stirring for 24 h at 60°C, and then conducting centrifugal washing. Preferably, in the step (2), a temperature in the amination modification process is 60±2°C. Preferably, in the step (3), the anti-cancer drug is an anti-cancer drug DOX; In the step (4), the carboxymethyl chitosan and the folic acid are activated by EDC and NHS for 4 h and 16 h respectively. Further preferably, in the step (3), a mass ratio of the amino-modified polydopamine-doped mesoporous silica to the anti-cancer drug to water is 1:1.5:1.5; In the step (4), a mass ratio of the carboxymethyl chitosan to the polydopamine-doped mesoporous silica loading the anti-cancer drug is 1:1; A mass ratio of the activated folic acid to the carboxymethyl chitosan modified polydopamine-doped mesoporous silica is 1:1. In the present invention, through PDA doping, anti-cancer drugs with benzene rings can be effectively closely bound, generate the photo-thermal effect under irradiation of near infrared light and are effectively released in an acid environment of the tumor; so as to achieve photothermal/chemotherapy collaborative treatment for tumor tissues, improve the treatment efficiency of the carrier loading the drugs and have certain biodegradability. Through linking with the carboxymethyl chitosan, the synthesized nanometer particles may be effectively dispersed into a body fluid simulation environment. Through modification with the folic acid, active targeting is conducted, and then aggregation of the drugs at a tumor site is further improved. On the basis of establishing the biosafety, the present invention greatly improves the biocompatibity of the drug carrier and prolongs a cycling time of the drug carrier in a human body. By being doped with the polydopamine as an organic molecule, the drug carrier has the biosafety and the optothermal therapy effect and further provides an important site for degradation of the nanometer particles in the tumor acid environment. Embodiment 1. The specific operation steps are as follows: (1) polydopamine-doped mesoporous silica (PDA/MSN) was prepared: 8 mL of 25wt% CTAC (with a purity of 99%), 12 mL of ultrapure water and 48 L of
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triethanolamine were mixed for stirring for 1 h at 60°C; and after uniform stirring, 50-150 mg of dopamine hydrochloride (with a purity of 98%) was added for continuous stirring for min. Then, 20 v/v% TEOS/cyclohexane (a purity of the TEOS was GC) was added dropwise with a constant-pressure funnel for reaction for 12 h at 60°C, and then centrifugal washing was conducted; and then, stirring was conducted by using 6 g/L ammonium nitrate/ethanol solution for 12 h at 60°C, the CTAC was washed off, and centrifugal washing was conducted. Finally, vacuum drying was conducted at a temperature not higher than 40°C to obtain grey and black polydopamine-doped mesoporous silica. (2) Amination modified Polydopamine-doped mesoporous silica (PDA/MSN-NH2) was prepared: a pH value of anhydrous ethanol was adjusted with acetic acid to 4, 150 mg of polydopamine-doped mesoporous silica was dispersed into 40 mL of ethanol-acetic acid solution, 1 g of APTES was added for stirring for 24 h at 60°C, and then centrifugal washing was conducted to obtain the amination modified polydopamine-doped mesoporous silica (PDA/MSN-NH2). (3) Polydopamine-doped mesoporous silica loading an anti-cancer drug DOX (DOX@PDA/MSN) was prepared: the aminated polydopamine-doped mesoporous silica nanometer particles and the anti cancer drug DOX were added to water (a mass ratio of the aminated polydopamine-doped mesoporous silica nanometer particles to the anti-cancer drug DOX to the water was 1:1.5:1.5) for stirring for 24 h, and the anti-cancer drug was loaded under the effect of static electricity and H-H conjugation to obtain the polydopamine-doped mesoporous silica loading the anti-cancer drug DOX (DOX@PDA/MSN). By determining the absorbance of a supernate, the adsorption amount of the DOX loaded on the nanometer particles was further quantified. (4) CMCS modified polydopamine-doped mesoporous silica (PDA/MSN-CMCS) was prepared: activated carboxymethyl chitosan (CMCS for short) was prepared: 10 mg of CMCS was dispersed into 5 mL of water; 25 mg of EDC and 25 mg of NHS were added; a mixture was activated for 4 h at a room temperature under the protection of N 2 ; 10 mg of DOX@PDA/MSN-NH2 was added for ultrasonic treatment for 5 min; continuous stirring was conducted for 12 h; a product was washed and then preserved in an environment with a temperature of 4°C according to a concentration of 1 mg/mL.
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(5) Folic acid active ester (FA-NHS) was prepared: folic acid was activated: 3 g of folic acid was dissolved into 30 mL of DMSO, and 12 g of EDC and 12 g of NHS were added. After activation for 16 h, 15 v/v% acetone/diethyl ether was washed off by the DMSO, and a thick yellow fluid was left; and the yellow fluid was subjected to vacuum drying at 20°C to obtain the folic acid active ester (FA-NHS), and the folic acid active ester (FA-NHS) was preserved in a refrigerator. (6) The folic acid active ester was modified (DOX@PDA/MSN-CMCS-FA): mg of FA-NHS and 10 mL of (1 mg/mL) PDA/MSN-CMCS were subjected to ultrasonic mixing for 3 min and were uniformly stirred for 12 h, and then centrifugal washing was conducted. After a washed product was dispersed into a sterile PBS, filtering was conducted with a 0.45 m filter membrane to obtain sterile folic acid modified polydopamine-doped mesoporous silica with a carboxymethyl chitosan layer which is the targeting degradable nano-drug carrier for chemo/photothermal synergistic therapy. Finally, the nanometer particles are good in dispersibility and have good stability at the same time. To prolong the shelf life of the product, the product was preserved at 4°C. Surface potential change tests were conducted on PDA/MSN, PDA/MSN-NH2, PDA/MSN CMCS and PDA/MSN-CMCS-FA in the preparation method in embodiment 1; and results are shown in Fig. 1. In combination with Fig. 1, characterization of Zeta potential further shows the preparation process of the nanometer particles. Embodiment 2. A drug loading property test was conducted on the targeting degradable nano-drug carrier for chemo/photothermal synergistic therapy prepared in embodiment 1. Morphologies of the prepared DOX@PDA/MSN-CMCS-FA nanometer particles were analyzed, and a result is shown in Fig. 2. The polydopamine-doped mesoporous silica with high specific surface area was prepared; and with wrapping of the carboxymethyl chitosan, a polymer membrane appears on the surface, the drug loading capacity may be about 10% to the maximum, and the polydopamine-doped mesoporous silica has high drug loading capacity. The nanometer drug carrier prepared by the present invention is good in drug loading effect, which provides the possibility for loading drugs, other macromolecules, proteins and the like in the future. Embodiment 3: Photothermal performance The photothermal performance of the DOX@PDA/MSN-CMCS-FA nanometer particles, which are the targeting degradable nanometer drug carrier for chemo/photothermal
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synergistic therapy and prepared in embodiment 1, was determined in 808 nm infrared light. A result is shown as a photo-thermal effect curve of PDA/MSN-CMCS-FA in Fig. 3. In 808 nm infrared light, as an irradiation time is prolonged, the concentration of the nanometer particles is higher, and a temperature of a solution is rapidly raised, which shows that the nanometer particles obtained by the method has stronger photothermal conversion ability; and with irradiation of the infrared light, damages on an organism are reduced. In irradiation of the near-infrared light (808 nm), as the time goes on, the concentration is higher, and the temperature raising effect is more obvious; and therefore, the nanometer particles have good photothermal performance and may effectively inhibit growth of tumors. Embodiment 4: Determination on stability of DOX@PDA/MSN-CMCS-FA nanometer particles (1) The nanometer particles of the folic acid modified polydopamine-doped mesoporous silica wrapped with the carboxymethyl chitosan, which is the targeting long-circulating nanometer drug carrier (DOX@PDA/MSN-CMCS-FA) for chemo/photothermal synergistic therapy and prepared in embodiment 1, were fully dispersed into 10% FBS solution, and size distribution of the nanometer particles was determined at two time points which are the time that preparation was completed and the time 24 h after preparation. Results are shown in a diagram showing the stability and size distribution of the nanometer particles of DOX@PDA/MSN-CMCS-FA of DOX@PDA/MSN-CMCS in Fig. 4. Size distribution has no obvious change; a size curve is in normal distribution; the particle size accords with the situation of efficiently using the nanometer particles if being in 200 nm; and the nanometer particles nay achieve stable distribution and existence in a body fluid state. (2) Experimental tests of releasing DOX@PDA/MSN-CMCS-FA in PBS solutions with different pH values were conducted; and results are shown in Fig. 5. Fig. 5 is a diagram showing the releasing conditions of DOX@PDA/MSN-CMCS-FA in the PBS solutions with pH values of 5, 6.5 and 7.4 over time. From Fig. 5, it may be known the release effect that the DOX@PDA/MSN-CMCS-FA prepared in the present invention may make acid responses under different pH values. Fig. 6 is a degradation picture of DOX@PDA/MSN-CMCS-FA after being in a PBS solution with a pH value of 5 after 14 d, in a size of 500 nm (right). From Fig. 6, under the acid condition, the DOX@PDA/MSN-CMCS-FA prepared in the present invention may be degraded.
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Embodiment 5: Determination on cytotoxicity of nanometer particles of core-shell structure When different concentrations of DOX@PDA/MSN-CMCS and DOX@PDA/MSN CMCS-FA prepared in embodiment 1 were used for co-incubation with Hela cells respectively, the cytotoxicity was detected, and two different conditions were set: without irradiation of near-infrared light and with the irradiation of near-infrared light. Results are shown in Fig. 7, a left diagram shows results without irradiation of the near-infrared light, and a right diagram shows results with irradiation of the near-infrared light. From Fig. 7, the nanometer particles after loading the drug have better effect of killing the tumor cells with increase in concentrations of the DOX@PDA/MSN-CMCS and the DOX@PDA/MSN-CMCS-FA. As the DOX@PDA/MSN-CMCS-FA has the targeting effect, the cell viability (about 11%) is lower than that (about 20%) of the DOX@PDA/MSN-CMCS; and thus the DOX@PDA/MSN-CMCS-FA has stronger cytotoxicity and is for effectively increasing the bioavailability of the drug carrier. Under irradiation of the near-infrared light, the generated photo-thermal effect has stronger inhibition effect on the cells; and in a DOX@PDA/MSN-CMCS-FA+NIR group, with the concentration of 100 [g/mL, the cell viability is lower (about 8.5%). From the embodiments of the present invention, the present invention uses biomass materials such as CMCS and polydopamine to prepare a degradable targeting nanometer carrier. By regulating a ratio of the added dopamine hydrochloride and hexadecyl trimethyl ammonium chloride (serving as a surfactant), doped mesoporous silica is prepared, and high drug loading property of the nanometer particles is achieved. By introducing the folic acid, an acid microenvironment nearby the tumor is used to achieve accurate targeting of the nanometer particles. The nanometer particles in a macroscale are formed through combination, wrapping and anchoring of the above matters, so that the drug-carrying nanometer carrier has the targeting and degradable characteristics; and individuation of the drug carrier may be achieved at the same time, and the non-specific toxicity of a patient to the nanometer drug carrier is weakened. The foregoing are only preferred embodiments of the present invention and is not for use in limiting the embodiments of the present invention in any form. Any simple alteration, equivalent change and modification made on the above embodiments according to the technical essence of the embodiments of the present invention should still fall within the scope of the technical solution of the embodiments of the present invention.
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Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavor to which this specification relates.
The reference numerals in the following claims do not in any way limit the scope of the respective claims.
Claims (8)
1. A preparation method for a targeting degradable nano-drug carrier for chemo/photothermal synergistic therapy, comprising the following steps: (1) preparing polydopamine-doped mesoporous silica; a method of preparing the polydopamine-doped mesoporous silica comprises the following steps: adding dopamine hydrochloride for uniform mixing after uniformly mixing CTAC, ultrapure water and triethanolamine; and then dropwise adding 20 v/v% TEOS/cyclohexane solution for reaction for 12 h, and then sequentially conducting centrifugal washing, washing-off for the CTAC and vacuum drying to obtain the polydopamine-dopsed mesoporous silica; (2) conducting amination modification on the polydopamine-doped mesoporous silica to obtain amino-modified polydopamine-doped mesoporous silica; (3) loading an anti-cancer drug: adding the amino-modified polydopamine-doped mesoporous silica to an anti-cancer drug aqueous solution for stirring for 24 h to obtain polydopamine-doped mesoporous silica loading an anti-cancer drug; the anti-cancer drug is an anti-cancer drug DOX; a mass ratio of the amino-modified polydopamine-doped mesoporous silica to the anti-cancer drug to water is 1:1.5:1.5; (4) modifying the polydopamine-doped mesoporous silica loading the anti-cancer drug with activated carboxymethyl chitosan and folic acid in sequence to obtain folic acid modified polydopamine-doped mesoporous silica with a carboxymethyl chitosan layer; a mass ratio of the carboxymethyl chitosan to the polydopamine-doped mesoporous silica loading the anti-cancer drug is 1:1; a mass ratio of the activated folic acid to the carboxymethyl chitosan modified polydopamine-doped mesoporous silica is 1:1and (5) dispersing the folic acid modified polydopamine-doped mesoporous silica with the carboxymethyl chitosan layer into a PBS solution, and conducting filtering to obtain the targeting degradable nano-drug carrier for chemo/photothermal synergistic therapy.
2. The preparation method according to claim 1, wherein in the step (1), a method of washing off the CTAC comprises the following steps: using 6 g/L nitrate-ethanol solution for stirring for 12 h at 60°C, and then conducting centrifugal washing.
3. The preparation method according to claim 1, wherein
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in the step (1), before centrifugal washing, a temperature in the mixing and reaction process is 60±2°C.
4. The preparation method according to any one of claims 1-3, wherein in the step (1), the dopamine hydrochloride is added by several times.
5. The preparation method according to any one of claims 1-4, wherein in the step (1), a vacuum drying temperature is not higher than 40°C.
6. The preparation method according to any one of claims 1-5, wherein in the step (2), a temperature in the amination modification process is 60±2°C.
7. The preparation method according to any one of claims 1-6, wherein in the step (4), the carboxymethyl chitosan and the folic acid are activated by EDC and NHS for 4 h and 16 h respectively.
8. A targeting degradable nano-drug carrier for chemo/photothermal synergistic therapy, which is prepared by using the preparation method of any one of claims 1-7.
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| CN114010799A (en) | 2022-02-08 |
| CN114010799B (en) | 2023-12-22 |
| AU2022211878B9 (en) | 2023-05-18 |
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