CN110665011A - Nano compound for delivery of small molecule anticancer drugs - Google Patents
Nano compound for delivery of small molecule anticancer drugs Download PDFInfo
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- CN110665011A CN110665011A CN201911105787.7A CN201911105787A CN110665011A CN 110665011 A CN110665011 A CN 110665011A CN 201911105787 A CN201911105787 A CN 201911105787A CN 110665011 A CN110665011 A CN 110665011A
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Images
Classifications
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- 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
- A61K47/6949—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0089—Particulate, powder, adsorbate, bead, sphere
- A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
- A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y20/00—Nanooptics, e.g. quantum optics or photonic crystals
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
The invention discloses preparation of a nano-composite based on a cation conjugated polymer and a DNA nano-cage and application of the nano-composite in drug loading. It comprises a cationic conjugated polymer and a DNA nanocage. The polymer in the method has strong fluorescence and stability, the side chain of the polymer is positively charged, and the polymer can be combined with phosphate groups with negative charges in a DNA nano cage through electrostatic adsorption to form a nano compound, and the nano compound can deliver the anti-cancer drug into tumor cells by utilizing the interaction of the anti-cancer drug and DNA double chains to kill the tumor cells. The nano-composite disclosed by the invention has good biocompatibility, high stability and low biotoxicity, and can realize rapid delivery of various types of medicines.
Description
Technical Field
The invention belongs to the field of molecular biology, and particularly relates to a nano-composite for delivery of small-molecule anticancer drugs.
Background
Cancer, also known as malignant tumor, grows rapidly, easily spreads in vivo, and is very difficult to cure. In recent years, the incidence of cancer is gradually increased, the life health of human beings is seriously threatened, and the cure rate can be increased by timely and effective treatment. The existing traditional drug delivery system has poor stability, has the problem that the drug is not released in advance when reaching a target part, and can generate serious side effects on normal cells and tissues; on the other hand, part of the drugs do not have good fluorescence property and cannot be timely and effectively monitored in cells. There is therefore a need to develop stable, fast and monitorable drug delivery systems.
Due to the EPR effect of tumors, the nano material can realize passive targeting and is widely used as a carrier of small-molecule anticancer drugs. Currently, the nano-carriers are various, but most of the materials have uncertainty of dimension and shape and strong biological toxicity, which greatly limits the application of the nano-carriers in the field of precise drug delivery. The cationic conjugated polymer has excellent light stability, high fluorescence intensity, good biocompatibility and water solubility, and can be widely applied to biological imaging. The DNA nanostructure can be programmed, has highly precise dimensions, good biocompatibility, and no cytotoxicity or immunostimulation. For example, the DNA tetrahedron has the advantages of controllable size, stable structure, easy modification and the like, and is widely applied to delivery of small molecule drugs, but the DNA nanostructure does not emit light, has poor stability and is easily degraded in blood.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: how to provide a novel drug delivery system, thereby improving the stability and the uploading speed of a DNA nano structure, leading therapeutic drugs to timely and accurately reach a target part and reducing the toxic and side effects on normal cells and tissues.
The technical scheme of the invention is as follows:
a nanocomplex for small molecule anticancer drug delivery comprising a Cationic Conjugated Polymer (CCP) and a DNA nanocage (TD). The synthesized cationic conjugated polymer has strong fluorescence and stability, the side chain of the cationic conjugated polymer is positively charged, the cationic conjugated polymer can be combined with phosphate groups with negative charges in a DNA nano cage through electrostatic adsorption, and the spectral antibiotic adriamycin for treating tumors can be embedded into a DNA double helix structure to form a TD-CCP nano complex.
Further, the molar ratio of the cationic conjugated polymer to the DNA nanocage is 4: 1.
Further, the cationic conjugated polymer is PFBT.
Further, the DNA nanocage is formed by self-assembly of four nucleotides, wherein the four nucleotides are P1-63, P2-63, P3-63 and P4-63; wherein, the nucleotide sequence of P1-63 is shown as SEQ ID No.1, the nucleotide sequence of P2-63 is shown as SEQ ID No.2, the nucleotide sequence of P3-63 is shown as SEQ ID No.3, and the nucleotide sequence of P4-63 is shown as SEQ ID No. 4;
further, the assembly method of the DNA nano cage comprises the following steps: a50. mu.l system was added with 25. mu.M P1-63, 25. mu.M P2-63, 25. mu.M P3-63, and 25. mu.M P4-63, respectively, and annealed in 10 XTM buffer to self-assemble into 1. mu.M DNA nanocages by PCR.
Further, the PCR annealing procedure is: 10min at 90 ℃ and 30min at 4 ℃.
Further, the method for compounding the cation conjugated polymer and the DNA nanocages comprises the following steps: and (3) uniformly mixing the cation conjugated polymer and the DNA nano cage according to the molar ratio of 4:1, and standing for 30-60min in a dark place at room temperature to obtain the nano compound based on the cation conjugated polymer and the DNA nano cage.
The cationic conjugated polymer is poly [ (9, 9-dioctylfluorenyl-2, 7-diyl) -alt-co- (1, 4-benzo- {2, 1', 3} -thiadiazole) ]. The specific synthetic steps of the cationic conjugated polymer are not particularly limited in the present invention, and can be accomplished by the technical routes well known in the art, and can also be prepared by the following methods:
firstly, carrying out nucleophilic substitution reaction on 1, 6-dibromohexane and 2, 7-dibromofluorene to obtain a compound 1; secondly, carrying out a boronization reaction by taking the compound 1 as a raw material to obtain a compound 2; thirdly, carrying out polymerization reaction on the compound 2 serving as a raw material and 4, 7-dibromobenzothiadiazole to obtain a compound 3; and fourthly, taking the compound 3 as a raw material, modifying a side chain of the compound, and introducing a positive electric group to obtain the cationic conjugated polymer.
More specifically, the specific method of synthesis of the cationic conjugated polymer is as follows:
synthesis of compound 1: 45.2g of 1, 6-dibromohexane and 6.48g of 2, 7-dibromofluorene are reacted in 600mg of tetrabutylammonium bromide and 200mL of 50% potassium hydroxide solution at 75 ℃ with stirring for 50 min;
synthesis of compound 2: 9.75g of Compound 1, 9g of Biserpinacolboronic acid ester, 10.5g of potassium acetate and 0.8g of Pd (dppf) Cl2Stirring and reacting with 120mL of dioxane at 85 ℃ for 14h under the protection of nitrogen;
synthesis of compound 3: 558mg of compound 2, 220.5mg of 4, 7-dibromobenzothiadiazole and 15mg of Pd (pph3)4 are reacted with stirring at 85 ℃ for 24h in 8mL of toluene, 8mL of tetrahydrofuran and 9mL of a 2 mol.L-1 solution of potassium carbonate under nitrogen;
synthesis of cationic conjugated polymer: 70mg of compound 3, 10mL of THF is added under the protection of nitrogen, and the mixture is stirred to be dissolved; at minus 78 ℃, in 5.6mL of 2mol L-1 trimethylamine THF solution, the temperature is returned to room temperature, and the reaction is stirred at room temperature for 24 hours; 10mL of water was added to dissolve the resulting solid; at minus 78 ℃, 5.6mL of 2 mol. L-1 trimethylamine THF solution is added, the temperature is returned to room temperature, and the reaction is stirred at room temperature for 12h, so as to obtain the cation conjugated polymer.
The design principle of the nano-composite of the invention is as follows:
in one aspect, the nanocomplex for small molecule anticancer drug delivery of the present invention can deliver a small molecule anticancer drug. DOX is a spectrum antibiotic, can inhibit the synthesis of DNA and RNA, can be embedded into a DNA double-helix structure, and can be well embedded into a DNA nano cage, the DNA nano cage is combined with a conjugated polymer with fluorescence through electrostatic adsorption, the luminescent polymer and the DNA nano cage are used as carriers to deliver DOX into cells, the drug loading rate is increased, and the DOX can better reach a target position.
Compared with the prior art, the invention has the following beneficial effects:
the nano-composite for delivering the small-molecule anti-cancer drug disclosed by the invention has high stability and good fluorescence property, and can rapidly enter eukaryotic cells. The space-time distribution of the vectors in the cells can be monitored by using a fluorescence microscope. The carrier can deliver the small molecular drug doxorubicin to the tumor cells, effectively kill the tumor cells and regulate the gene expression in the tumor cells. The nano carrier is safe and nontoxic, has high drug loading capacity, and has wider application prospect compared with the traditional drug carrier.
Drawings
FIG. 1 is a simplified diagram of the loading of DOX by the nanocomposite TD-CCP disclosed herein.
FIG. 2 is a schematic diagram of the electrophoresis characterization of the nanocomposite TD-CCP disclosed by the invention.
FIG. 3 is a fluorescence spectrum of the disclosed nanocomposite TD-cy5 with CCP.
FIG. 4 is a stability study of the disclosed nanocomposite TD-CCP in FBS.
FIG. 5 is a graph of cellular uptake of A549 by the nanocomposite TD-CCP disclosed herein.
FIG. 6 is a graph of cell viability of nanocomposite TD-CCP loaded DOX versus A549 disclosed herein.
Detailed Description
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The sequences of the nucleic acids employed in the present invention are shown in Table 1.
TABLE 1 nucleic acid sequences
The present invention provides a nano-composite for small molecule anticancer drug delivery, which comprises a Cationic Conjugated Polymer (CCP) and a DNA nanocage (TD). The synthesized cationic conjugated polymer has strong fluorescence and stability, the side chain of the cationic conjugated polymer is positively charged, the cationic conjugated polymer can be combined with phosphate groups with negative charges in a DNA nano cage through electrostatic adsorption, and the spectral antibiotic adriamycin for treating tumors can be embedded into a DNA double helix structure to inhibit the expression of DNA and RNA, so that the TD-CCP nano compound is formed. As shown in fig. 1.
Example 1
The invention provides a preparation method of a nano-composite for delivering small-molecule anticancer drugs, which comprises the following steps:
firstly, synthesizing the cationic conjugated polymer with fluorescence, the specific synthetic steps of the polymer are not particularly limited in the invention, and the synthesis is completed by adopting a technical route which is well known in the field. The synthesis of DNA nanocages is formed by PCR annealing self-assembly of four DNA strands.
The DNA nano cage is formed by self-assembly of four nucleotides, wherein the four nucleotides are P1-63, P2-63, P3-63 and P4-63 respectively; wherein, the nucleotide sequence of P1-63 is shown as SEQ ID No.1, the nucleotide sequence of P2-63 is shown as SEQ ID No.2, the nucleotide sequence of P3-63 is shown as SEQ ID No.3, and the nucleotide sequence of P4-63 is shown as SEQ ID No. 4.
The assembly method of the DNA nano cage comprises the following steps: a50. mu.l system was added with 25. mu.M P1-63, 25. mu.M P2-63, 25. mu.M P3-63, and 25. mu.M P4-63, respectively, and annealed in 10 XTM buffer to self-assemble into 1. mu.M DNA nanocages by PCR. The PCR annealing program is: 10min at 90 ℃ and 30min at 4 ℃.
The preparation method of 10 × TM buffer is as follows: 968.8mg of tris (hydroxymethyl) aminomethane and 4.066g of magnesium chloride hexahydrate are precisely weighed, poured into a 50ml centrifuge tube, dissolved by adding 40ml of deionized water, and adjusted to pH 8 with glacial acetic acid.
The method for compounding the cation conjugated polymer and the DNA nanocage comprises the following steps: and (3) uniformly mixing the cation conjugated polymer and the DNA nano cage according to the molar ratio of 4:1, and standing for 30-60min in a dark place at room temperature to obtain the nano compound based on the cation conjugated polymer and the DNA nano cage.
The cationic conjugated polymer is poly [ (9, 9-dioctylfluorenyl-2, 7-diyl) -alt-co- (1, 4-benzo- {2, 1', 3} -thiadiazole) ]. The specific synthetic steps of the cationic conjugated polymer are not particularly limited in the present invention, and can be accomplished by the technical routes well known in the art, and can also be prepared by the following methods:
firstly, carrying out nucleophilic substitution reaction on 1, 6-dibromohexane and 2, 7-dibromofluorene to obtain a compound 1; secondly, carrying out a boronization reaction by taking the compound 1 as a raw material to obtain a compound 2; thirdly, carrying out polymerization reaction on the compound 2 serving as a raw material and 4, 7-dibromobenzothiadiazole to obtain a compound 3; and fourthly, taking the compound 3 as a raw material, modifying a side chain of the compound, and introducing a positive electric group to obtain the cationic conjugated polymer. Specifically, the specific method of synthesis of the cationic conjugated polymer is as follows:
synthesis of compound 1: 45.2g of 1, 6-dibromohexane and 6.48g of 2, 7-dibromofluorene are reacted in 600mg of tetrabutylammonium bromide and 200mL of 50% potassium hydroxide solution at 75 ℃ with stirring for 50 min;
synthesis of compound 2: 9.75g of Compound 1, 9g of Biserpinacolboronic acid ester, 10.5g of potassium acetate and 0.8g of Pd (dppf) Cl2Stirring and reacting with 120mL of dioxane at 85 ℃ for 14h under the protection of nitrogen;
synthesis of compound 3: 558mg of compound 2, 220.5mg of 4, 7-dibromobenzothiadiazole and 15mg of Pd (pph3)4 are reacted with stirring at 85 ℃ for 24h in 8mL of toluene, 8mL of tetrahydrofuran and 9mL of a 2 mol.L-1 solution of potassium carbonate under nitrogen;
synthesis of cationic conjugated polymer: 70mg of compound 3, 10mL of THF is added under the protection of nitrogen, and the mixture is stirred to be dissolved; at minus 78 ℃, in 5.6mL of 2mol L-1 trimethylamine THF solution, the temperature is returned to room temperature, and the reaction is stirred at room temperature for 24 hours; 10mL of water was added to dissolve the resulting solid; at minus 78 ℃, 5.6mL of 2 mol. L-1 trimethylamine THF solution is added, the temperature is returned to room temperature, and the reaction is stirred at room temperature for 12h, so as to obtain the cation conjugated polymer.
In the invention, diluted DOX and TD-CCP are incubated for 30min at room temperature in a dark place, so that DOX is loaded on the TD-CCP to form a TD-CCP-DOX drug delivery system.
EXAMPLE 1 characterization of TD-CCP nanocomposites by Polyacrylamide gel electrophoresis
Assembling P1-63, P2-63, P3-63 and P4-63 into a TD nano cage, adjusting the concentration to 100nM, wherein the molar ratio of TD to CCP in the TD-CCP is 1:4, characterizing by 8% polyacrylamide gel electrophoresis, and setting a power supply voltage to be constant voltage 150V and time to be 90min by 0.5 xTBE electrophoresis solution. As shown in FIG. 2, DS is double-stranded DNA, when TD binds to CCP, we can see no electrophoretic band, DNA is negatively charged, the electrophoretic band is generated by anode movement under the action of electric field, the polymer is positively charged, so we can see that the lane where the polymer is located has no band.
Experimental example 2 fluorescence Property measurement of TD-cy5-CCP nanocomposite
The polymer selected in the invention has fluorescence, the maximum excitation wavelength is 480nm, the maximum emission wavelength is 560nm, the maximum excitation wavelength of cy5 is 620nm, the emission wavelength is 640-720nm, and the FRET can be generated between TD-cy5 and CCP. The method comprises the following specific steps:
first, 1. mu.M/L TD-Cy5 was synthesized, and then 25. mu.M P1-63, 25. mu.M P2-Cy5, 25. mu.M P3-63, and 25. mu.M P4-63 were added to 50. mu.l of the system, respectively, and then self-assembled by PCR annealing using 10 XTM buffer as a buffer to form 1. mu.M DNA nanocages. The PCR annealing program is: 10min at 90 ℃ and 30min at 4 ℃.
20 mul of TD-cy5 multiplied by 100nM is added into a 200 mul centrifuge tube, CCP is respectively added into the centrifuge tube in the amount of 100nM, 200nM, 300nM, 400nM, 500nM, 600nM, 700nM, 800nM, 900nM and 1 mul, the mixture is centrifuged and shaken to be mixed evenly after the sample addition is finished, the mixture is incubated for 30min in a dark place at room temperature, and the fluorescence spectrum of the mixture is measured by a microplate reader. As shown in FIG. 3, when the ratio of TD to CCP is 1:4, the effect of FRET is the best, and the ratio of TD to CCP is finally selected to be 1: 4.
Experimental example 3 stability of TD-CCP nanocomposites in FBS
First, TD-CY5-BHQ3 was synthesized using chains labeled CY5 and BHQ3, and P1-BHQ3 at a concentration of 25. mu.M, P2-Cy5 at a concentration of 25. mu.M, P3-63 at a concentration of 25. mu.M, and P4-63 at a concentration of 25. mu.M were added to 50. mu.l of the system, and then self-assembled by PCR annealing using 10 XTM buffer as a buffer to form 1. mu.M DNA nanocages. The PCR annealing program is: 10min at 90 ℃ and 30min at 4 ℃.
20 mu L of TD-CY5-BHQ3 with the amount of CCP being 400nM is added into a 200 mu L centrifuge tube, the mixture is respectively kept stand for 1h, 2h, 3h, 4h, 5h, 6h and 26h in FBS buffer solution, and the fluorescence spectrum of the mixture is measured by a microplate reader. As shown in FIG. 4, the fluorescence of CY5 was 7.23% after 1h of incubation with CCP and 50.12% without CCP. CCP is able to protect TD from enzymatic degradation in FBS.
Experimental example 4 cellular uptake of A549 by TD-CCP nanocomposite
Selecting A549 lung cancer cells, taking out adherent cells from an incubator, adding 1ml of pancreatin for digestion, adding 3ml of prepared culture medium, blowing uniformly, sucking 200 mu l of the culture medium into a confocal culture dish by using a liquid transfer gun, and culturing for 12 hours in a cell incubator to make the cells adhere to the wall; taking out the two dishes of cells, respectively adding 200 muL of TD-CCP with 100nM TD and 200 muL of TD-CCP with the ratio of 1:4 into a confocal culture dish, putting the confocal culture dish into a constant temperature incubator for incubation for 2h, and then putting the confocal culture dish under a total internal reflection fluorescence microscope for shooting, wherein the lens is a 100 x oil lens, the cy5 excitation wavelength is 620nM, the emission wavelength is 640-720nM, the cy3 excitation wavelength is 520nM, and the emission wavelength is 540-640 nM. Hoechst 33342 excites at 350nm and emits at 460 nm. As shown in FIG. 5, A in FIG. 5 indicates that TD-cy5 entered the cell, but the cell fluorescence was very weak and almost no fluorescence was observed; in FIG. 5, B shows the fluorescence superposition of cy5 and cy3 after the TD-CCP nanocomplex enters the cell, and it can be seen that cy3 and cy5 have very strong fluorescence, which indicates that the loading rate of TD-CCP is high and the cell can be more easily entered; in FIG. 5C it can be seen that TD and CCP are not disintegrated in the cells, and the FRET image is very bright, indicating that TD-CCP is more stable.
Experimental example 5 cytotoxicity test of TD-CCP nanocomposite-loaded DOX for A549
Will be 5X 103A549 cells of each well are inoculated in a 96-well plate, the edge of the 96-well plate is volatile, the periphery is filled with PBS, and the inoculated cells are placed in 5% CO2And culturing in a constant temperature incubator at 37 ℃ overnight for 12-18 hours. Aspirating the culture medium by using a pipette, adding PBS for washing, setting 5 groups of control experiments, and respectively adding 100 mu L multiplied by 100nM TD, 100 mu L multiplied by 400nM CCP, 100 mu L multiplied by 2 mu M DOX, 100 mu L multiplied by 1:4 TD-CCP and 2 mu M TD-CCP-DOX into each hole; putting the mixture into an incubator for incubation for 12h, taking out a 96-well plate, adding 10 mu L of CCK8 into each well, and slightly shaking the 96-well plate to fully mix CCK8 with the culture medium; the 96-well plate added with the CCK8 is placed in a constant-temperature incubator for color development for 3h, and the CCK8 detects the absorbance at 450nm by using a microplate reader. As shown in FIG. 6, the TD-CCP-DOX drug delivery system had the best cell killing effect on A549.
Sequence listing
<110> Beijing university of chemical industry
<120> a nanocomposite for small molecule anticancer drug delivery
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Claims (7)
1. A nano-composite for delivering small-molecular anticancer medicine is composed of cationic conjugated polymer and DNA nano-cage, and features that the cationic conjugated polymer is combined with DNA nano-cage by electrostatic adsorption to form the nano-composite.
2. The nanocomposite of claim 1, wherein the molar ratio of the cationic conjugated polymer to the DNA nanocage is 4: 1.
3. The nanocomposite of claim 1, wherein the cationic conjugated polymer is PFBT.
4. The nanocomplex of claim 1, wherein the DNA nanocage consists of a self-assembly of four nucleotides, P1-63, P2-63, P3-63 and P4-63; wherein, the nucleotide sequence of P1-63 is shown as SEQ ID No.1, the nucleotide sequence of P2-63 is shown as SEQ ID No.2, the nucleotide sequence of P3-63 is shown as SEQ ID No.3, and the nucleotide sequence of P4-63 is shown as SEQ ID No. 4.
5. The nanocomplex of claim 4, wherein the assembly method of the DNA nanocage is: a50. mu.l system was added with 25. mu.M P1-63, 25. mu.M P2-63, 25. mu.M P3-63, and 25. mu.M P4-63, respectively, and annealed in 10 XTbuffer to self-assemble into 1. mu.M DNA nanocages by PCR.
6. The nanocomposite of claim 5, wherein the PCR annealing program is: 10min at 90 ℃ and 30min at 4 ℃.
7. The nanocomplex according to any one of claims 1 to 6, wherein the cationic conjugated polymer is complexed to the DNA nanocage by: and (3) uniformly mixing the cation conjugated polymer and the DNA nano cage according to the molar ratio of 4:1, and standing for 30-60min in a dark place at room temperature to obtain the nano compound based on the cation conjugated polymer and the DNA nano cage.
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| WO2007143669A3 (en) * | 2006-06-05 | 2008-05-08 | California Inst Of Techn | Real time micro arrays |
| CN101885913A (en) * | 2009-05-13 | 2010-11-17 | 韩国科学技术研究院 | Nanoparticles of light emissive polymers and preparation method thereof |
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| WO2007143669A3 (en) * | 2006-06-05 | 2008-05-08 | California Inst Of Techn | Real time micro arrays |
| CN101885913A (en) * | 2009-05-13 | 2010-11-17 | 韩国科学技术研究院 | Nanoparticles of light emissive polymers and preparation method thereof |
| CN107432935A (en) * | 2017-09-12 | 2017-12-05 | 四川大学 | A kind of cationic polymer/TDNs carries medicine compound and preparation method thereof |
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