CN109675056B - Controlled release system based on base pairing rule and preparation method and application thereof - Google Patents
Controlled release system based on base pairing rule and preparation method and application thereof Download PDFInfo
- Publication number
- CN109675056B CN109675056B CN201910001287.2A CN201910001287A CN109675056B CN 109675056 B CN109675056 B CN 109675056B CN 201910001287 A CN201910001287 A CN 201910001287A CN 109675056 B CN109675056 B CN 109675056B
- Authority
- CN
- China
- Prior art keywords
- msn
- icg
- dox
- controlled release
- release system
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- 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
- A61K47/51—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 the non-active ingredient being a modifying agent
- A61K47/54—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 the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- 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
- A61K47/69—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 the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a controlled release system based on a base pairing rule and a preparation method and application thereof. The controlled release system is prepared by encapsulating thymine modified Mesoporous Silica Nanoparticles (MSN) serving as a carrier, chemotherapeutic drugs DOX and thermotherapeutic drugs ICG loaded in the pore canals of the nanoparticles in polyadenylic acid according to a base pairing principle. The mesoporous silica nano material has the advantages of ultra-large mesoporous volume, high specific surface area, good biocompatibility, easy surface modification and the like, can encapsulate a large amount of drugs, is a good carrier platform, and poly A as a gating plugging object can effectively plug the mesopores and control the release of the drugs, so that after near infrared light irradiation of the controlled release system disclosed by the invention, the breakage of the A-T hydrogen bonds is triggered, the DOX and the ICG of the drugs are released, the release of the drugs is better controlled, and chemotherapy and photothermal therapy synergistic treatment is realized.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a controlled release system based on a base pairing rule, a preparation method thereof and application thereof in the field of tumor combined treatment.
Background
Aiming at tumor treatment, more remarkable treatment effect can be obtained by developing multi-mode treatment, such as chemotherapy and thermotherapy combination. The reasons are mainly as follows: high temperature can affect the function of the plasma membrane of the tumor cell, increase the membrane permeability and facilitate the drug intake; many drugs have heat-sensitizing property, which can improve drug toxicity; when the medical device is used for treating tumors in vivo, the central part of tumor tissues is easily heated and reaches a higher temperature, while the peripheral parts have more blood vessels, the heat diffusion is faster, and the thermotherapy effect is not obvious. Therefore, the combination of chemotherapy and thermotherapy can effectively cover the whole tumor part and achieve the effect of synergistic treatment.
The nucleic acid as biological macromolecule has the characteristics of good molecular recognition capability, specific base sequence structure and easy modification and synthesis, and can respond to a series of stimulation signals including temperature, ribozyme, light, pH, target substance and the like. Therefore, the nucleic acid is often used as a stopper to be modified on the surface of the mesopores for controlling the opening and closing of the mesopores. However, base pairing rules have not been used to design MSN smart drug delivery systems or other nanomedicines. The base pairing rules are when the nucleotide strands of DNA, RNA or both are linked by base pairing, i.e., AT pairing of adenine A with thymine T and CG pairing of cytosine C with guanine G. This pairing is stable at physiological temperatures but can be disrupted by heating, which is the basic mechanism of Polymerase Chain Reaction (PCR) for the amplification of specific portions of DNA or RNA.
Indocyanine green (ICG) is a near-infrared fluorescent dye, can be excited by external light with wavelength of 750-810nm, emits near-infrared light with wavelength of about 850nm, and can be used as a near-infrared fluorescent contrast agent for clinical use. Clinically, ICG is widely used for assisted diagnosis of liver function, cardiac output, and vasculature of the retina, and in recent years, is widely used for photodynamic and photothermal therapy of cancer, while having characteristics of near-infrared imaging and photoacoustic imaging. However, ICG is very unstable in aqueous solution, is easily cleared rapidly in blood circulation, and easily forms dimers between molecules to cause fluorescence quenching. These deficiencies severely limit the use of ICG in tumor diagnosis and therapy. Researchers have tried to carry ICG with various nano-carriers in recent years in order to improve their stability, prolong their blood circulation time and impart their tumor targeting properties.
Doxorubicin hydrochloride (doxorubicin hydrochloride, DOX) is a broad-spectrum antitumor agent, can produce a wide range of biochemical effects on the body, and has a strong cytotoxic effect. The mechanism of action is mainly that the product intercalates into DNA to inhibit nucleic acid synthesis. The traditional Chinese medicine composition is clinically used for treating acute lymphocytic leukemia, acute myelocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, breast cancer, lung cancer, ovarian cancer, soft tissue sarcoma, osteogenic sarcoma, rhabdomyosarcoma, nephroblastoma, neuroblastoma, bladder tumor, thyroid tumor, chorioepithelial cancer, prostatic cancer, testicular cancer, gastric cancer, liver cancer and the like. However, the chemotherapy drug is easy to generate drug resistance after being singly used for a long time, and is often used in combination with other anticancer drugs.
The mesoporous silica nano Material (MSN) has the advantages of super large mesoporous volume, controllable appearance and size, high specific surface area, good biocompatibility, easy surface modification and the like, can encapsulate a large amount of drugs, can be functionally modified by using different materials such as nanoparticles, polymers, biomolecules and the like as a gate-controlled plugging object to effectively plug the mesopores, controls the release of the drugs under proper stimulation conditions, improves the durability of the drug effect, and is a good carrier platform. Therefore, MSN has a wide application prospect in biotechnology, biomedicine, and the like, and particularly, has attracted great attention in developing an intelligent drug delivery system with highly specific controlled release in cancer treatment.
Disclosure of Invention
The invention aims to solve the defects in the prior art and provides a controlled release system DOX & ICG @ MSN-T @ polyA based on a base pairing rule aiming at a gate control system with complex assembly, and a preparation method and application thereof. After the DOX and the ICG carry the MSN-T together, the poly A encapsulated composite nano particles DOX & ICG @ MSN-T @ poly A are used by utilizing the base complementary pairing principle, the temperature of an ICG photothermal conversion release system is raised by the photothermal effect, the hydrogen bonds between A and T are triggered to break, and the DOX and the ICG are released, so that the chemotherapy and photothermal therapy synergistic treatment is realized.
The invention is described by the following examples in order to illustrate the invention, but not to limit it in any way.
The technical scheme of the invention is as follows:
a controlled release system based on a base pairing rule and a mesoporous silica nanoparticle controlled release system designed based on the base pairing rule comprise thymine modified mesoporous silica nanoparticles serving as a carrier, and chemotherapy drugs DOX and thermotherapy drugs ICG loaded in the pore channels of the nanoparticles, wherein the drug-loaded mesoporous silica particles are encapsulated by polyA through the base pairing rule.
Further, the structure of the controlled release system is as follows:
the base pairing rules in the structure are that polynucleotide strands of DNA, RNA or both are linked by base pairing, i.e., adenine (A) is paired with AT of thymine (T) and cytosine (C) is paired with CG of guanine (G).
Further, the preparation method of the controlled release system comprises the following specific steps:
1) preparation of MSN: adding NaOH into CTAB aqueous solution, and heating; TEOS is dripped into the solution, continuously stirred, centrifugally collected, and washed by distilled water and methanol to obtain a MSN crude product; dispersing the MSN crude product in a mixture of methanol and concentrated HCl, and refluxing to remove CTAB;
2) preparation of thymine modified MSN: mixing thymine-1-acetic acid, EDC and NHS in distilled water, and stirring at room temperature to obtain a mixture; mixing the MSN solution obtained in the step 1) and ATPES in anhydrous toluene, and adding the mixture into N2Refluxing under atmosphere, centrifuging and washing to obtain amino modified MSN, adding into the mixture, and continuously stirring to obtain MSN-T;
3) construction of DOX & ICG @ MSN-T @ polyA controlled release system: mixing DOX, ICG, MSN-T and distilled water together, stirring, centrifuging, and washing to obtain DOX and ICG carried MSN-T; adding polyadenylic acid, dispersing in distilled water, continuously stirring, centrifuging to obtain DOX & ICG @ MSN-T @ polyA, and washing with distilled water.
Further, the volume ratio of the methanol to the concentrated HCl in the step 1) is 100:1, and the concentration of the concentrated HCl is 37.2 wt%.
Further, the mass concentration of MSN in the methanol in the step 1) is 0.01 g/ml.
Further, the mass ratio of DOX, ICG, MSN-T and distilled water in the step 3) is 0.6:1:2: 1000.
Further, the mass ratio of the polyadenylic acid to the distilled water in the step 3) is 1: 500.
Further, the base pairing rule-based controlled release system is used for preparing tumor drugs.
Further, the base pairing rule-based controlled release system is used for preparing chemotherapy-photothermal therapy medicines.
The controlled release system based on the base pairing rule is a composite nanoparticle suitable for intravenous injection.
The controlled release system based on the base pairing rule prepared by the invention has the following advantages:
1. the controlled release system DOX & ICG @ MSN-T @ polyA based on the base pairing rule is based on base pairing, the gating assembly is simple, and the drug release operation is controllable.
2. The DOX & ICG @ MSN-T @ polyA of the present invention has excellent photothermal conversion effects, providing sufficient heat for a = T interaction to trigger drug release and provide synergistic PTT activity for cancer therapy.
3. The controlled release system based on the base pairing rule utilizes A-T pairing to rapidly close the pore channel of MSN by polyA. DOX & ICG @ MSN-T @ poly A can be kept stable at physiological temperature, and can ensure that the medicine can not be released in the blood transmission process, and the medicine can be effectively released through the photothermal effect after reaching the tumor tissue part.
4. The base pairing rule-based controlled release system DOX & ICG @ MSN-T @ polyA has better targeting effect and identification capability on tumors than free ICG and DOX.
5. The controlled release system DOX & ICG @ MSN-T @ polyA based on the base pairing rule can realize effective chemotherapy-photothermal therapy synergistic treatment of solid tumors.
6. The controlled release system DOX & ICG @ MSN-T @ polyA based on the base pairing rule can activate anti-tumor immunity through chemotherapy-photothermal therapy synergistic treatment.
Drawings
FIG. 1 is a schematic diagram of a process flow for the preparation of a DOX & ICG @ MSN-T @ polyA controlled release system of the present invention;
FIG. 2 is a transmission electron micrograph (scale =50 nm) of a DOX & ICG @ MSN-T @ polyA controlled release system of the present invention;
FIG. 3 is an infrared thermal image of a DOX & ICG @ MSN-T @ polyA controlled release system and a physiological salt blank control group of the present invention injected into tumor-bearing mice, respectively, under continuous 808nm laser irradiation;
FIG. 4 is a graph of the fluorescence images of DOX & ICG @ MSN-T @ polyA controlled release system of the present invention and control group free ICG after injection into mice;
FIG. 5 DOX of the present invention&The relative cell survival rates (. about.P.. about.0.01 and. about.P.. about.0.001 blank group) of the ICG @ MSN-T @ polyA controlled release system and other control groups (controlled release group, DOX group, ICG @ MSN-T @ polyA group, DOX @ MSN-T @ polyA group, MSN-T @ polyA group and MSN-T @ polyA group) were compared with those of the other administration groups;##p＜0.01 DOX&ICG @ MSN-T @ polyA controlled release system vs other groups);
FIG. 6 is a graph showing the trend of tumor volume changes after the DOX & ICG @ MSN-T @ polyA controlled release system of the present invention and other control groups (controlled release group, DOX group, ICG @ MSN-T @ polyA group, DOX @ MSN-T @ polyA group) are injected into each group of tumor-transplanted model mice, respectively.
FIG. 7 DOX of the present invention&(IL-10 and IL-12B distribution maps in mice after injecting the ICG @ MSN-T @ polyA controlled release system and other control groups (controlled release group, DOX group, ICG @ MSN-T @ polyA group) into each group of tumor transplantation model mice respectively*P＜0.05, **P < 0.01 and***p is less than 0.001 blank group compared with other administration groups;#p<0.05，##p<0.01 and###p<0.001 DOX&ICG @ MSN-T @ polyA controlled release system vs. other groups).
Detailed Description
The following examples and specific examples are given to illustrate specific embodiments of the present invention, but should not be construed as limiting the scope of the invention. The reagents and test equipment used are commercially available unless otherwise indicated.
In the examples:
DOX is the abbreviation of doxorubicin hydrochloride;
ICG is abbreviation of indocyanine green;
MSN is short for mesoporous silica nano particle;
polyA is short for polyadenylic acid;
CTAB (cetyltrimethylammonium bromide) is an abbreviation for cetyltrimethylammonium bromide;
TEOS (tetraethyl orthosilicate) is short for ethyl orthosilicate;
ATPES ([ 3- (2-aminoethyl) aminopropy ] triethoxysilane) is an abbreviation for 3-aminopropyltriethoxysilane;
EDC (N- (3-methylenepropyl) -N' -ethylcarbodiimide hydrochloride) is abbreviated as 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride;
NHS (N-Hydroxysuccinimide) is short for N-Hydroxysuccinimide
Example 1A method for preparing a base pairing based DOX & ICG @ MSN-T @ polyA controlled release system according to FIG. 1, comprising the steps of:
first, MSN is prepared. Dissolving 0.5g CTAB in 240mL of distilled water, magnetically stirring, adding 1.75mL of NaOH, heating to 80 ℃ to obtain a CTAB/NaOH mixed solution; dropwise adding 2.5ml of TEOS, continuously stirring for 2 hours, centrifugally collecting precipitates, washing with distilled water and methanol to obtain a crude product of MSN; the resulting MSN0.7g was dispersed in 70mL methanol and a concentrated HCl mixture of 0.70mL and 37.2wt% and refluxed for 12 hours to remove the template CTAB, and the resulting solid was washed with distilled water 6 times after centrifugation to obtain purified MSN.
In the second step, thymine modified MSN (MSN-T) is prepared. 0.5g of purified MSN and 0.5mL of ATPES were mixed in 50mL of dry toluene, N 2Refluxing at 80 deg.C for 24 hr under atmosphere, and separatingThe core was washed 3 times with distilled water and methanol; reacting 0.26mg of thymine-1-acetic acid with neutral pH, 48mgEDC and 18mgNHS in 1mL of distilled water, and stirring at room temperature for 1 hour; 10mg of the obtained amino-modified MSN was added to the mixture, and stirring was continued for 12 hours to obtain MSN-T, which was centrifuged and washed 6 times with distilled water.
And thirdly, constructing a DOX & ICG @ MSN-T @ polyA controlled release system. Mixing and stirring 0.6mg DOX, 1mg ICG and 2mg MSN-T in 1mL of distilled water for 12 hours, centrifuging at 9600rpm for 5 minutes to obtain DOX and ICG carried MSN-T, and washing with distilled water; the obtained DOX & ICG @ MSN-T and 2mgpolyA are dispersed in 1mL of distilled water and continuously stirred for 2 hours; centrifugation was carried out at 9600rpm for 5 minutes to obtain DOX & ICG @ MSN-T @ polyA, which was washed with distilled water.
Example 2: to better understand the properties of the target substance obtained in this example 1, characterization was performed by the following tests:
topography test of DOX & ICG @ MSN-T @ polyA controlled release system
The specific testing steps are as follows: DOX & ICG @ MSN-T @ poly A is washed with distilled water for multiple times and is subjected to ultrasonic treatment for 10min, then the DOX & ICG @ MSN-T @ poly A is dripped on a copper net, the DOX & ICG @ MSN-T @ poly A is naturally dried after the water content of the DOX & ICG @ MSN-T @ poly A is dried, the DOX & ICG @ MSN-T @ poly A is operated on a JOEL JEM-2100F high-resolution transmission electron microscope at an accelerating voltage of 200kV, and a high-resolution TEM (HRTEM) image is shot.
As shown in FIG. 2, the transmission electron microscope is used for observing the size, morphology and pore blocking condition of the nanoparticles, and the results show that the nanoparticles have regular morphology, good dispersion and uniform size, the pores are blocked, and the edges are blurred, thereby indicating that the drug is successfully loaded and the surface is successfully modified.
Testing photo-thermal conversion capability of DOX & ICG @ MSN-T @ polyA controlled release system
The specific testing steps are as follows: and respectively injecting the DOX & ICG @ MSN-T @ poly A controlled release system and the physiological saline into a tumor-bearing white mouse through a tail vein, and shooting an infrared thermal imaging image under the irradiation of laser at 808nm after 6 hours.
As shown in fig. 3, the temperature of the tumor site gradually increased with the increase of the irradiation time. In contrast, only slight temperature changes were detected in the saline-injected group. These results suggest that the effective photothermal conversion effect of DOX & ICG @ MSN-T @ poly a can provide sufficient heat for the a = T interaction to trigger drug release and provide synergistic PTT activity for cancer therapy.
3, testing the targeting and identifying capability of the DOX & ICG @ MSN-T @ polyA controlled release system on tumors
The specific testing steps are as follows: DoX & ICG @ MSN-T @ poly A controlled release system and ICG were injected separately into tumor bearing white mice tail vein. On the third day, white mice were dissected and fluoroscopic images were taken.
As shown in FIG. 4, DOX & ICG @ MSN-T @ polyA is significantly superior to free ICG in tumor targeting and recognition.
Comparison of in vitro antitumor Activity of DOX & ICG @ MSN-T @ polyA and other drug groups
The specific testing steps are as follows: DOX & ICG @ MSN-T @ polyA and other administration groups were added to lung cancer cell line (NA549) respectively, and a group of blank control groups was set. After 4h, the cells were incubated for 24h under 808nm laser irradiation, and the cell viability was measured by the MTT method.
As shown in figure 5, the controlled release system DOX & ICG @ MSN-T @ poly A has the best anticancer activity, and can realize the effective chemotherapy-photothermal therapy synergistic treatment of solid tumors.
5. Research on in vivo anti-tumor activity of a white mouse transplanted tumor model animal, comparison of tumor growth inhibition capacity of DOX & ICG @ MSN-T @ polyA controlled release system
The specific testing steps are as follows: DoX & ICG @ MSN-T @ poly A and other drug control groups were injected into the tail vein of mice transplanted with tumor model animals, respectively, to set a group of blank control groups. After 6h, the tumor site on one side was irradiated under 808nm laser and the tumor size was recorded daily.
As shown in FIG. 6, the research result of the antitumor activity in vivo of the mice transplanted tumor model animal shows that the DOX & ICG @ MSN-T @ polyA nanoparticles inhibit the tumor growth and are remarkably stronger than those of other drug control groups.
6. Immune activation research of white mouse transplantation tumor model animal
The specific testing steps are as follows: the mice transplanted with tumor model animals were divided into four groups, and the tumor sites on one side were irradiated with 808nm laser after 6 hours by injecting physiological saline (control group), DOX, ICG @ MSN-T @ polyA and DOX & ICG @ MSN-T @ polyA into the tail vein, respectively. And on the third day, dissecting the white rat, picking the side which is not irradiated with the laser tumor, extracting tumor homogenate, and measuring the content of IL-10 and IL-12B in the white rat tumor by adopting an ELISA method.
As shown in FIGS. 7(A) and (B), the concentration of IL-10 and the concentration of IL-12 in the DOX & ICG @ MSN-T @ polyA controlled release system were relatively low and high, respectively, relative to the control group. Macrophages that infiltrate tumor cells are predominantly polarized to M2 type in the tumor microenvironment, which underlies the ability to promote tumor growth. Macrophages of type M2 secrete mainly the anti-inflammatory cytokine IL-10 and display anti-inflammatory functions associated with tissue repair, tumor promotion and anti-tumor immunosuppression. Macrophages of type M1 and Cytotoxic T Lymphocytes (CTL) promote tumor suppression by activating anti-tumor immunity, mainly secreting the cytokine IL-12. IL-12 is an effective immunotherapy antitumor cytokine, can activate natural killer NK cells and cytotoxic T lymphocytes, and promote suppression of M1 type immune response. Experimental results show that M2 type macrophages are polarized into M1 type after DOX & ICG @ MSN-T @ polyA controlled release system is injected, and chemotherapy-photothermal therapy synergistic treatment can activate anti-tumor immunity.
Claims (4)
1. A preparation method of a controlled release system based on a base pairing rule is characterized in that: comprises the following steps of (a) carrying out,
1) preparing mesoporous silica nano particles MSN: dissolving 0.5g CTAB in 240mL of distilled water, magnetically stirring, adding 1.75mL of NaOH, heating to 80 ℃ to obtain a CTAB/NaOH mixed solution; dropwise adding 2.5ml of TEOS, continuously stirring for 2 hours, centrifugally collecting precipitates, washing with distilled water and methanol to obtain a crude product of MSN; dispersing 0.7g of the prepared MSN in 70mL of methanol and a mixture of 0.70mL of concentrated HCl and 37.2wt%, refluxing for 12 hours to remove a template CTAB, and washing the obtained solid with distilled water for 6 times after centrifugation to obtain purified MSN;
2) preparation of thymine modified MSN: 0.5g of purified MSN and 0.5mL of ATPES were mixed in 50mL of dry toluene, N 2Refluxing at 80 deg.C for 24 hr under atmosphere, centrifuging, and distillingWater and methanol for 3 times; reacting 0.26mg of thymine-1-acetic acid with neutral pH, 48mgEDC and 18mgNHS in 1mL of distilled water, and stirring at room temperature for 1 hour; adding 10mg of the obtained amino-modified MSN into the mixture, continuously stirring for 12 hours to obtain MSN-T, centrifuging and washing with distilled water for 6 times;
3) construction of DOX & ICG @ MSN-T @ polyA controlled release system: mixing and stirring 0.6mg DOX, 1mg ICG and 2mg MSN-T in 1mL of distilled water for 12 hours, centrifuging at 9600rpm for 5 minutes to obtain DOX and ICG carried MSN-T, and washing with distilled water; the obtained DOX & ICG @ MSN-T and 2mg of poly A were dispersed in 1mL of distilled water and continuously stirred for 2 hours; centrifugation was carried out at 9600rpm for 5 minutes to obtain DOX & ICG @ MSN-T @ polyA, which was washed with distilled water.
2. Controlled release system based on base pairing rules, obtained by the method according to claim 1, characterized in that: the preparation method comprises the following steps of taking thymine modified mesoporous silica nanoparticles as a carrier, encapsulating the carrier by using polyadenylic acid according to a base pairing rule, and loading chemotherapeutic drugs DOX and thermotherapy drugs ICG in the nanoparticle pore channel of the carrier.
3. Use of the base pairing rules based controlled release system of claim 2 for the preparation of a medicament for the treatment of tumors.
4. Use of the base pairing rules based controlled release system of claim 3 for the manufacture of a medicament for chemotherapy-photothermal therapy.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910001287.2A CN109675056B (en) | 2019-01-02 | 2019-01-02 | Controlled release system based on base pairing rule and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910001287.2A CN109675056B (en) | 2019-01-02 | 2019-01-02 | Controlled release system based on base pairing rule and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109675056A CN109675056A (en) | 2019-04-26 |
| CN109675056B true CN109675056B (en) | 2022-03-18 |
Family
ID=66190343
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910001287.2A Active CN109675056B (en) | 2019-01-02 | 2019-01-02 | Controlled release system based on base pairing rule and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109675056B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103920153A (en) * | 2014-05-06 | 2014-07-16 | 中国科学院上海硅酸盐研究所 | Chitosan-modified pH responsive medicine-loading controlled release material and preparation method thereof |
| CN105327356A (en) * | 2014-08-11 | 2016-02-17 | 南京理工大学 | Magnetic polysaccharide nanometer gel material preparation method |
| US9725577B1 (en) * | 2016-08-30 | 2017-08-08 | International Business Machines Corporation | Self-healing thermal interface materials |
| CN107050464A (en) * | 2016-11-09 | 2017-08-18 | 中国药科大学 | It is a kind of to be loaded with aptamers modifying DNA nanocages of adriamycin and preparation method thereof |
-
2019
- 2019-01-02 CN CN201910001287.2A patent/CN109675056B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103920153A (en) * | 2014-05-06 | 2014-07-16 | 中国科学院上海硅酸盐研究所 | Chitosan-modified pH responsive medicine-loading controlled release material and preparation method thereof |
| CN105327356A (en) * | 2014-08-11 | 2016-02-17 | 南京理工大学 | Magnetic polysaccharide nanometer gel material preparation method |
| US9725577B1 (en) * | 2016-08-30 | 2017-08-08 | International Business Machines Corporation | Self-healing thermal interface materials |
| CN107050464A (en) * | 2016-11-09 | 2017-08-18 | 中国药科大学 | It is a kind of to be loaded with aptamers modifying DNA nanocages of adriamycin and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| Mesoporous silica nanoparticles functionalized with a thymidine derivative for controlled release;Young Lan Choi等;《J. Mater. Chem.》;20120315;第22卷;摘要，第9455页右栏第10-33行，示意图1，支撑材料第2页第1段至第3页第3段，示意图S1 * |
| Photothermal-triggered Controlled Drug Release From Mesoporous Silica nanoparticles Based On Base-pairing Rules;Xiaoting Li等;《ACS Biomaterials Science & Engineering》;20190418;第5卷(第5期);第2399-2408页 * |
| 基于poly(A)功能化介孔二氧化硅的控制释放及抗肿瘤应用研究;杨淑娜;《中国优秀硕士学位论文全文数据库医药卫生科技辑》;20150415(第4期);摘要 * |
| 基于介孔二氧化硅载药体系的抗肿瘤活性研究和生物分子作用机制;李晓婷;《中国优秀硕士学位论文全文数据库工程科技I辑》;20200215(第02期);第B016-684页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109675056A (en) | 2019-04-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Jiang et al. | Intelligent MoS2–CuO heterostructures with multiplexed imaging and remarkably enhanced antitumor efficacy via synergetic photothermal therapy/chemodynamic therapy/immunotherapy | |
| Yang et al. | Recent advances in nanosized metal organic frameworks for drug delivery and tumor therapy | |
| CN108042810B (en) | Acid-response hydrogen release nano-medicament and preparation method thereof | |
| CN110755613A (en) | Preparation and application of light-triggered erythrocyte membrane-coated NO nano bionic donor material | |
| CN110215438B (en) | Preparation method and application of mesoporous silicon nanoparticles carrying anthracyclines and photosensitizers | |
| CN106139144A (en) | A kind of hyaluronic acid decorated golden Nano carbon balls with synergistic antitumor characteristic and preparation method and application | |
| Chen et al. | Nanomaterials: small particles show huge possibilities for cancer immunotherapy | |
| Gao et al. | AuNRs@ MIL-101-based stimuli-responsive nanoplatform with supramolecular gates for image-guided chemo-photothermal therapy | |
| CN111744010B (en) | Preparation method of nano-bacterium hybrid system | |
| CN112791061B (en) | Preparation method of multi-stage bionic nano-drug carrier with targeting long circulation | |
| CN109091674B (en) | Multifunctional drug carrier and preparation method and application thereof | |
| CN112294776B (en) | Reduction response type carbon dot drug-loaded nanocluster coated with cell membrane and preparation and application thereof | |
| WO2021083370A1 (en) | Preparation and use of nanomaterial specifically activating immune system | |
| CN111249467A (en) | Tumor self-targeting multi-stage response type mesoporous silicon drug delivery system and preparation method thereof | |
| CN110368501B (en) | RGD peptide modified boron drug-loading system and preparation and application thereof | |
| Li et al. | A near-infrared-II fluorescent nanocatalyst for enhanced CAR T cell therapy against solid tumor by immune reprogramming | |
| Dai et al. | GM-CSF augmented the photothermal immunotherapeutic outcome of self-driving gold nanoparticles against a mouse CT-26 colon tumor model | |
| Hang et al. | Mesoporous nanodrug delivery system: a powerful tool for a new paradigm of remodeling of the tumor microenvironment | |
| CN111686249B (en) | Nano carrier material, preparation method thereof and application thereof in preparing anti-tumor drugs | |
| CN115192708B (en) | Nanocomposite loaded with antitumor drug, nano drug-carrying system, preparation and application | |
| CN109675056B (en) | Controlled release system based on base pairing rule and preparation method and application thereof | |
| CN110251672B (en) | Nano diagnosis and treatment agent and preparation method and application thereof | |
| CN111529508A (en) | Black phosphorus nanosheet/gold nanoparticle composite material and preparation method and application thereof | |
| CN110575546A (en) | preparation method and application of high nuclear targeting anti-tumor nano-drug | |
| CN107243000B (en) | Drug-loaded hybrid nanoparticles and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
Inventor after: Zhou Jiahong Inventor after: Li Xiaoting Inventor after: Zhou Lin Inventor after: Wei Shaohua Inventor before: Zhou Jiahong Inventor before: Zhou Lin Inventor before: Li Xiaoting Inventor before: Wei Shaohua |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |