CN111012923A - Method for synthesizing tumor treating nano preparation by DNA crosslinking - Google Patents

Method for synthesizing tumor treating nano preparation by DNA crosslinking Download PDF

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CN111012923A
CN111012923A CN201911330342.9A CN201911330342A CN111012923A CN 111012923 A CN111012923 A CN 111012923A CN 201911330342 A CN201911330342 A CN 201911330342A CN 111012923 A CN111012923 A CN 111012923A
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dna
microgel
solution
crosslinking
polymer chain
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郑斌
彭文畅
明东
刘爽
甘霖
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Tianjin University
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    • 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
    • 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
    • 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
    • A61K47/6921—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 the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
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Abstract

The invention discloses a method for synthesizing a tumor treatment nano preparation by DNA crosslinking. The main steps include 1) preparation of DNA-A polymer chain; 2) preparing a DNA-B polymer chain; 3) and the DNA-A polymer chain and the DNA-B polymer chain are crosslinked with Linker DNA to form the DNA microgel nano-particles. Connecting DNA-A and DNA-B with Linker DNA by using the principle of DNA base complementary pairing, thereby forming microgel particles through crosslinking; 4) loading of chemotherapeutic drug DOX. The particle size of the microgel synthesized by the invention is below 100nm, and the microgel can be gathered at a tumor part after intravenous injection and has a passive targeting effect on tumors. And the aptamer targeting the surface of the 4T1 tumor on the DNA-A polymer chain can realize active targeting on the tumor, thereby more efficiently delivering chemotherapeutic drugs to the tumor part and reducing the damage to normal tissues.

Description

Method for synthesizing tumor treating nano preparation by DNA crosslinking
Technical Field
The invention relates to the technical field of preparation, in particular to a method for synthesizing a tumor treatment nano preparation by connecting DNA-A and DNA-B with connecting DNA by using the principle of DNA base complementary pairing.
Background
The microgel is polymer colloid particles with the size of micron or nanometer grade, and has the characteristics of high loading efficiency, good biocompatibility, excellent biological stability and the like. And the microgel has higher sensitivity to external stimulation and can quickly respond to the change of the external environment through larger deformation. These characteristics all make the microgel have great advantages and potential in the field of drug delivery. Chemical agents are mostly used as crosslinking agents for microgel particles, and the potential toxicity of the chemical agents limits the application of the microgel particles in human bodies.
The invention adopts a base complementary pairing mechanism to connect DNA-A and DNA-B with Linker DNA, thereby forming microgel particles through crosslinking. Excellent biocompatibility, no toxicity and harm to human body, and opens up a new idea of the application of the cross-linking agent.
The aptamer is a DNA sequence. Usually oligonucleotide fragments obtained from libraries of nucleic acid molecules using in vitro screening techniques, i.e., the technique of ligand phylogeny with exponential enrichment. The nucleic acid aptamers can be combined with various target substances with high specificity and high selectivity, so that the nucleic acid aptamers are widely applied to the field of biosensors. The particle size of the microgel synthesized by the invention is below 100nm, and the microgel can be gathered at a tumor part after intravenous injection and has a passive targeting effect on tumors. And the aptamer targeting the surface of the 4T1 tumor on the DNA-A polymer chain can realize active targeting on the tumor, thereby more efficiently delivering chemotherapeutic drugs to the tumor part and reducing the damage to normal tissues.
Disclosure of Invention
The invention relates to a method for synthesizing a tumor treatment nano preparation by connecting DNA-A and DNA-B with connecting DNA by using the principle of DNA base complementary pairing.
The technical scheme of the invention is a method for synthesizing a tumor treatment nano preparation by DNA crosslinking, which synthesizes microgel nano particles wrapping chemotherapeutic drugs by DNA base complementary pairing, and comprises the following steps:
1) preparing a DNA-A @ aptamer polymer chain;
2) preparing a DNA-B polymer chain;
3) preparing and collecting DNA microgel;
4) dissolving the microgel powder in 3ml of 20-40mg/ml DOX solution, dialyzing, stirring at 300r/min overnight, and collecting at 1000r/min for ten minutes.
The step 1) is as follows:
(1) mixing 4uL of 10-12mg/mL DNA-A aqueous solution, 3uL of 5-8mg/mL aptamer aqueous solution, 2uL of 1-2mg/mL N-isopropylacrylamide, 1uL of 1% 2-carboxy-40- (2-carboxyethoxy) -2-methyl-propiophenone initiator aqueous solution, 10-15uL of Tris buffer (pH 8.0) and 25-30uL of ultrapure water at room temperature, and stirring at 400 rpm;
(2) the mixed solution was then irradiated under an ultraviolet lamp with a wavelength of 365nm for 5 min.
The step 2) is as follows:
(1) mixing 10uL of 10-12mg/mL DNA-B aqueous solution, 1uL of 0.5-1mg/mL N-isopropylacrylamide, 1uL of 1% 2-carboxy-40- (2-carboxyethoxy) -2-methyl-propiophenone initiator aqueous solution, 20-25uL of Tris buffer (pH 8.0) and 25-30uL of ultrapure water at room temperature, and stirring at 400 rpm;
(2) the mixed solution was then irradiated under an ultraviolet lamp with a wavelength of 365nm for 5 min.
The step 3) is as follows:
(1) at room temperature, 50uL of DNA-A solution, 5uL of DNA-B solution and 5u of aqueous solution of 3-4mg/ml of ligated DNA were mixed thoroughly to obtain a mixed solution.
(2) The mixed solution was incubated in a water bath at 80 ℃ for 5min, followed by slow cooling to room temperature.
(3) Putting the obtained microgel solution into a dialysis bag with the molecular weight cutoff of 8000, dialyzing in a Tris buffer solution for 2-3 days, finally centrifuging and collecting, and washing with clear water for three times.
(4) And (3) freeze-drying the collected microgel particles in a vacuum drying oven at the temperature of-55 ℃ to form powder.
The base sequence is specifically as follows:
DNA-A:5'-Acrydite-GTACCTCTCC-3'
DNA-B:5'-Acrydite-CCGTTCCTGACGTT-3'
Linker DNA:5'-Acrydite-GGCAAGGACTGCAAGGAGAGGTAC-3'
Aptamer:
5'-Acrydite-CCTGACAGTCGAGACCGTGGCGGTGGCTTAAACCGACGGCCGGGCCACCGGGGTCCTAGG-3'。
the invention has the advantages that:
1) the complementary pairing of DNA is used as a crosslinking principle, so that the potential toxicity of a chemical crosslinking agent is avoided, and the biocompatibility of the microgel is improved.
2) The nano-scale particle size of the microgel has a passive targeting effect on a tumor region, so that the medicine can be gathered in the tumor region.
3) The aptamer has an active targeting effect on a tumor region, acts on the tumor region more accurately, and avoids damage to normal tissues.
4) The microgel can sensitively sense in the acidic condition of a tumor area, and the volume is reduced, so that the medicine is released.
Drawings
FIG. 1: scanning electron micrographs of microgel particles.
Detailed Description
The invention is further described below with reference to the following figures and specific examples.
Example 1:
preparation of DNA-A @ aptamer Polymer chain
(1) 4uL of a 10mg/mL aqueous DNA-A solution, 3uL of a 5mg/mL aqueous aptamer solution, 2uL of 1mg/mL N-isopropylacrylamide, 1uL of a 1% aqueous solution of 2-carboxy-40- (2-carboxyethoxy) -2-methyl-propiophenone initiator, 15uL of Tris buffer (pH 8.0) and 25uL of ultrapure water were mixed at room temperature and stirred at 400 rpm;
(2) the mixed solution was then irradiated under an ultraviolet lamp with a wavelength of 365nm for 5 min.
Example 2:
preparation of DNA-B Polymer chains
(1) 10uL of a 12mg/mL aqueous DNA-B solution, 1uL of 0.5mg/mL N-isopropylacrylamide, 1uL of a 1% aqueous 2-carboxy-40- (2-carboxyethoxy) -2-methyl-propiophenone initiator solution, 25uL of Tris buffer (pH 8.0) and 25uL of ultrapure water were mixed at room temperature and stirred at 400 rpm;
(2) the mixed solution was then irradiated under an ultraviolet lamp with a wavelength of 365nm for 5 min.
Example 3:
preparation and collection of DNA microgels
(1) At room temperature, 50uL DNA-A solution, 5uL DNA-B solution and 5u 4mg/ml of the ligation DNA aqueous solution were mixed well to obtain a mixed solution.
(2) The mixed solution was incubated in a water bath at 80 ℃ for 5min, followed by slow cooling to room temperature.
(3) Putting the obtained microgel solution into a dialysis bag with the molecular weight cutoff of 8000, dialyzing in a Tris buffer solution for 2-3 days, finally centrifuging and collecting, and washing with clear water for three times.
(4) And (3) freeze-drying the collected microgel particles in a vacuum drying oven at the temperature of-55 ℃ to form powder.
Example 4:
microgel loading
(1) The microgel powder was dissolved in 3ml of 40mg/ml DOX solution and dialyzed, stirring at 300r/min overnight.
(2) Ten minutes of centrifugation was performed at 1000 r/min.
Sequence listing
<110> Tianjin university
<120> method for synthesizing tumor treatment nano preparation by DNA crosslinking
<160>4
<170>SIPOSequenceListing 1.0
<210>1
<211>10
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>1
gtacctctcc 10
<210>2
<211>14
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>2
ccgttcctga cgtt 14
<210>3
<211>24
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>3
ggcaaggact gcaaggagag gtac 24
<210>4
<211>60
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>4
cctgacagtc gagaccgtgg cggtggctta aaccgacggc cgggccaccg gggtcctagg 60

Claims (5)

  1. The method for synthesizing the nano preparation for treating tumor by DNA crosslinking is characterized in that microgel nano particles wrapping chemotherapeutic drugs are synthesized by complementary pairing of DNA bases, and the method comprises the following specific steps:
    1) preparing a DNA-A @ aptamer polymer chain;
    2) preparing a DNA-B polymer chain;
    3) preparing and collecting DNA microgel;
    4) dissolving the microgel powder in 3ml of 20-40mg/ml DOX solution, dialyzing, stirring at 300r/min overnight, and collecting at 1000r/min for ten minutes.
  2. 2. The method for synthesizing nano preparation for treating tumor by crosslinking DNA according to claim 1, wherein the step 1) is as follows:
    (1) mixing 4uL of 10-12mg/mL DNA-A aqueous solution, 3uL of 5-8mg/mL aptamer aqueous solution, 2uL of 1-2mg/mL N-isopropylacrylamide, 1uL of 1% 2-carboxy-40- (2-carboxyethoxy) -2-methyl-propiophenone initiator aqueous solution, 10-15uL of Tris buffer (pH 8.0) and 25-30uL of ultrapure water at room temperature, and stirring at 400 rpm;
    (2) the mixed solution was then irradiated under an ultraviolet lamp with a wavelength of 365nm for 5 min.
  3. 3. The method for synthesizing nano preparation for treating tumor by crosslinking DNA according to claim 1, wherein the step 2) is as follows:
    (1) mixing 10uL of 10-12mg/mL DNA-B aqueous solution, 1uL of 0.5-1mg/mL N-isopropylacrylamide, 1uL of 1% 2-carboxy-40- (2-carboxyethoxy) -2-methyl-propiophenone initiator aqueous solution, 20-25uL of Tris buffer (pH 8.0) and 25-30uL of ultrapure water at room temperature, and stirring at 400 rpm;
    (2) the mixed solution was then irradiated under an ultraviolet lamp with a wavelength of 365nm for 5 min.
  4. 4. The method for synthesizing nano preparation for treating tumor by crosslinking DNA according to claim 1, wherein the step 3) is as follows:
    (1) at room temperature, fully mixing 50uL of DNA-A solution, 5uL of DNA-B solution and 5u of connecting DNA aqueous solution with the concentration of 3-4mg/ml to obtain a mixed solution;
    (2) incubating the mixed solution in a water bath at 80 ℃ for 5min, and then slowly cooling to room temperature;
    (3) putting the obtained microgel solution into a dialysis bag with the molecular weight cutoff of 8000, dialyzing in a Tris buffer solution for 2-3 days, finally centrifuging and collecting, and washing with clear water for three times;
    (4) and (3) freeze-drying the collected microgel particles in a vacuum drying oven at the temperature of-55 ℃ to form powder.
  5. 5. The method for synthesizing nano preparation for treating tumor by crosslinking DNA as claimed in claim 1, wherein the base sequence is as follows:
    DNA-A:5'-Acrydite-GTACCTCTCC-3'
    DNA-B:5'-Acrydite-CCGTTCCTGACGTT-3'
    Linker DNA:5'-Acrydite-GGCAAGGACTGCAAGGAGAGGTAC-3'
    Aptamer:
    5'-Acrydite-CCTGACAGTCGAGACCGTGGCGGTGGCTTAAACCGACGGCCGGGCCACCGGGGTCCTAGG-3'。
CN201911330342.9A 2019-12-20 2019-12-20 Method for synthesizing tumor treating nano preparation by DNA crosslinking Pending CN111012923A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106474050A (en) * 2016-11-09 2017-03-08 中国药科大学 A kind of it is loaded with temperature sensing in situ gel rubber intratumor injection preparation of aptamer doxorubicin conjugates and preparation method thereof
CN109745567A (en) * 2017-11-01 2019-05-14 沈阳药科大学 A kind of DNA fixation nano-hydrogel microballoon and its preparation and application with aptamer compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106474050A (en) * 2016-11-09 2017-03-08 中国药科大学 A kind of it is loaded with temperature sensing in situ gel rubber intratumor injection preparation of aptamer doxorubicin conjugates and preparation method thereof
CN109745567A (en) * 2017-11-01 2019-05-14 沈阳药科大学 A kind of DNA fixation nano-hydrogel microballoon and its preparation and application with aptamer compound

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HUANGHAO YANG 等: "Engineering Target-Responsive Hydrogels Based on Aptamer-Target Interactions", 《J. AM. CHEM. SOC》 *
廖晓玲等: "《材料化学基础实验指导》", 28 February 2015, 冶金工业出版社 *
赵海旭等: "刺激响应型DNA水凝胶及其在生物传感和药物控释方面的应用", 《沈阳药科大学学报》 *

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Application publication date: 20200417