CN112717143A - Biodegradable nano-carrier and targeting drug-loading system thereof - Google Patents
Biodegradable nano-carrier and targeting drug-loading system thereof Download PDFInfo
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- 239000002539 nanocarrier Substances 0.000 title claims abstract description 19
- 230000008685 targeting Effects 0.000 title claims abstract description 17
- 238000011068 loading method Methods 0.000 title description 3
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- 238000002360 preparation method Methods 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 12
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- 239000002105 nanoparticle Substances 0.000 claims description 59
- 238000003756 stirring Methods 0.000 claims description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 55
- 239000008367 deionised water Substances 0.000 claims description 54
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- 239000000243 solution Substances 0.000 claims description 54
- 229920002873 Polyethylenimine Polymers 0.000 claims description 41
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
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- 238000005406 washing Methods 0.000 claims description 32
- 239000001110 calcium chloride Substances 0.000 claims description 31
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 31
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 26
- 238000001035 drying Methods 0.000 claims description 23
- 238000001179 sorption measurement Methods 0.000 claims description 19
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 13
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- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 4
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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
- 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
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
The invention relates to the field of biomedical materials, in particular to a nano-carrier with biodegradability and targeting capability and a preparation method thereof. The nano-carrier is prepared by preparing a CaP @ CaO2 mesoporous sphere through hydrolysis precipitation, biomineralization and a template method, and then modifying PEI and PEG on the surface of the nanosphere. The mesoporous nanosphere prepared by the invention has good targeting performance and cancer cell growth inhibition capability, can protect the medicament from being invaded by lysosomes and promote the medicament to enter cell nucleuses; meanwhile, PEI and PEG on the surface of the nanosphere can improve biocompatibility and make the nanosphere have pH sensitivity. Therefore, the invention has great significance in the aspect of carrying the drug by using the nano drug carrier for cancer targeted therapy.
Description
Technical Field
The invention belongs to the field of biomedical materials, and particularly relates to a nano-carrier with biodegradability and targeting capability and a preparation method thereof.
Background
Hepatocellular carcinoma (HCC) is a common malignant tumor in China, and the morbidity and mortality of the HCC are listed in the death related to tumors. Today the most effective and common treatment is surgical resection, but there is a high risk of recurrence and metastasis after surgery. Studies have shown that patient survival can be improved to some extent by surgery in combination with treatment with chemical drugs. 5-fluorouracil is a kind of antitumor drug which is well known in clinic and still remains the first choice drug for most tumors. Its structure is similar to that of uracil, which is the necessary metabolic structure for tumor cell, and they compete mutually in the same system enzyme to block metabolic link and block DNA synthesis, so as to inhibit proliferation of tumor cell. However, drugs exist during use such as: the fat solubility is small, the selectivity is poor, the half-life period in vivo is short, the toxic and side effects are large and the like, which seriously limits the wide application of the compound in clinic.
To overcome the above disadvantages, drug loading with biodegradable nanocarriers is considered to be an effective approach. Calcium phosphate (Ca3(PO4)2, CaP for short) is used as a pH-sensitive and degradable biological material, and becomes an ideal choice for nano-drug carriers. Related research finds that: the CaP can keep a stable chemical structure in the blood circulation of a human body, and ensures that the carried medicine can not be released, thereby reducing the toxicity of the medicine in the body. When the tumor is in a micro environment (weak acidity), the Cap is gradually degraded, and the drug is rapidly released from the Cap. Zhang et al incorporate gold nanorods, DNA origami and molecular targeted drugs into phospholipid molecule modified Cap, utilize the characteristics of Cap, fully protect DNA origami from degradation, greatly retain the therapeutic effect of drugs.
In the complex microenvironment in vivo, calcium ion (Ca2+) plays a crucial role as a second messenger for intracellular signaling in regulating various physiological functions of the body. Many functions of cells depend on the change of the concentration of Ca2+ in the cytoplasm, and once the change of the concentration is uncontrolled, the functions of cells are disturbed and even cell death is caused. At present, the treatment of tumors by ion interference has been partially studied. Typically, nano-CaO2Under the acidic condition, the particles can be decomposed into Ca +, excessive Ca + can inhibit the tumor, and the tumor Ca + can die, and the tumor microenvironment condition of weak acid creates a favorable strip for the tumorAnd (3) a component.
On the other hand, because of the existence of lysosomes in organisms, the drug-loaded nanoparticles have the possibility of being degraded at any time in vivo and the instability of drug release and other factors, thus greatly reducing the curative effect of the nano-drug. Therefore, researchers improve the stability of the drug in a tumor microenvironment and ensure the positioning release of the drug by modifying the surface of the drug-loaded nanoparticles, so that the targeting effect of the drug is realized, but at present, few effective polymers are developed. Polyethyleneimine (PEI) is the most commonly used cationic polymer non-viral vector, commonly used for transfection or delivery of plasmid DNA. PEI can be adsorbed to the surface of tumor cells through electrostatic interaction and enter the interior of the tumor cells through passive endocytosis. Since PEI can not be degraded in phagocytic vesicles, the drug can be protected from lysosome degradation; in addition, PEI has the effect of osmotic swelling, which causes the rupture of phagocytic vacuoles and promotes the entry of loaded drugs into cell nucleus, thereby having good anti-tumor efficacy.
Disclosure of Invention
In order to overcome the defects of the technical defects, the invention provides a nano-carrier with biodegradability and targeting capability and a preparation method thereof.
In order to achieve the above purpose, in one aspect, the key technology of the nano-carrier capable of biodegradation and targeting is as follows: the nano carrier is formed by calcium chloride through a biomineralization method and a template method to form mesoporous hybrid nanospheres; then the nano composite medicine is adsorbed by static electricity; and modifying PEI and PEG on the surface.
On the other hand, the key point is to provide a nano-carrier with biodegradability and targeting ability and a preparation method thereof, and the method comprises the following steps:
step one, preparing CaO2 nanoparticles:
adding CaCl2Adding into deionized water and stirring; dropwise adding ammonia water and hydrogen peroxide solution, stirring, then dropwise adding 0.5mL of sodium hydroxide solution, stirring for 10min, sequentially centrifugally washing the obtained white precipitate with sodium hydroxide (1M), deionized water and absolute ethyl alcohol, drying at 50 ℃ to obtain CaO2 nanoparticles, and storing in a low-temperature refrigerator at 4 ℃.
Preferably, the mass ratio is (0.01-0.1): 10 CaCl2Adding into deionized water.
Preferably, CaCl2Dropwise adding ammonia water and 10-50 wt% of hydrogen peroxide solution in the mixture according to the mass ratio (0.01-0.1): (0.5-2): (0.1-1) stirring for 1-5 h.
Step two, mesoporous hybrid nanospheres:
CaO prepared in the step one2Adding nanoparticles and Cetyl Trimethyl Ammonium Bromide (CTAB) into sugar-free DMEM medium (containing sodium dihydrogen phosphate and calcium chloride), dispersing uniformly, and sealing; after standing, adding CaCl2Continuously standing to obtain a coarse product of the mesoporous hybrid nanosphere; after the reaction is finished, washing the reaction product for several times by using deionized water; ultrasonically dispersing the nanoparticles in an absolute ethyl alcohol solution (or methanol), sealing, heating and repeatedly removing a CTAB template agent; and finally, washing with deionized water, and drying the product at 50 ℃ to obtain the CaP @ CaO2 mesoporous hybrid nanospheres.
Preferably, the mass ratio of 2: (1-20): (1-5) CaO2Adding nanoparticles and Cetyl Trimethyl Ammonium Bromide (CTAB) into sugar-free DMEM medium (containing sodium dihydrogen phosphate and calcium chloride), dispersing uniformly, sealing,
preferably, the mixture is placed for 10-60 min at the temperature of 35-39 ℃; then adding 0.5-3 g of CaCl2
Preferably, the mixture is continuously placed in an environment with the temperature of 35-39 ℃ for 12-48 hours; after the reaction is finished, washing the reaction product for several times by using deionized water; then, the nanoparticles are ultrasonically dispersed in an absolute ethyl alcohol solution for 5-15 min, and are hermetically heated at 70-80 ℃ for 3-10 h
Step three, preparing CaP @ CaO by electrostatic adsorption2@5-FU nanocomposite drug:
the CaP @ CaO prepared in the step two2Dispersing the nano particles and the 5-fluorouracil in deionized water and methanol; then stirring at room temperature for 18-36 h, washing the obtained powder with deionized water, and drying at 50 ℃ to obtain CaP @ CaO2@5-FU nanocomposite drug.
Preferably, the mass ratio is (50-200): (50-200): (1-5) CaP @ CaO2Nanoparticles and 5-fluoroDispersing uracil in deionized water and methanol;
step four, electrostatic adsorption of PEG:
dissolving methoxy-polyethylene glycol-maleimide (mPEG-Mal) in 20mL of deionized water, adding N-hydroxysuccinimide (NHS) for activation, and adjusting the pH to 7-9; stirring for 10-50 min, and adding the CaP @ CaO prepared in the third step2Continuously stirring the @5-FU aqueous solution for 4-24 hours; finally, washing and drying the obtained compound to obtain CaP @ CaO2@5-FU @ PEG, oven dried at 30 ℃.
Preferably, methoxy-polyethylene glycol-maleimide (mPEG-Mal), deionized water, N-hydroxysuccinimide (NHS) and Cap @ CaO2The mass ratio of the @5-FU aqueous solution is as follows: (1-6): (5-10): (1-6).
Step five, graft polymerization of PEI:
the CaP @ CaO prepared in the fourth step2Dispersing the @5-FU @ PEG nanoparticles into dimethyl sulfoxide (DMSO), and magnetically stirring to obtain a solution A; dispersing Polyethyleneimine (PEI) in a PBS (phosphate buffer solution) to obtain a solution B; dropwise adding the solution A into the solution B, and stirring; finally, the obtained mixed solution is dialyzed and centrifuged in turn to obtain CaP @ CaO2@5-FU@PEG@PEI。
Preferably, CaP @ CaO2The mass ratio of the @5-FU @ PEG nanoparticles to the solutions of dimethyl sulfoxide (DMSO), Polyethyleneimine (PEI) and PBS is (20-80): (1-5): (10-60): (2-6);
preferably, the solution A is dripped into the solution B, and the mixture is stirred for 1 to 24 hours at the temperature of 10 to 60 ℃; finally, the powder was lyophilized by dialysis and centrifugation.
Drawings
FIG. 1 TEM picture of CaP @ CaO2
FIG. 2 TEM (i), TEM (ii) and element Mapping images (iii-ix) of Cap @ CaO2@5-FU @ PEG @ PEI
FIG. 3 is a graph of cumulative release rate versus time for various pH values for the CaP @ CaO2@5-FU @ PEG @ PEI nanocomposite: the left panel is 5-FU; the right picture is Ca2+
Detailed Description
Example 1 preparation of a biodegradable and Targetable Nanocarrier I
Step one, CaO preparation2Nano-particles:
adding 0.01g of CaCl2Adding 10g of deionized water and stirring; dropwise adding 0.5g of ammonia water and 0.1g of 10% wt hydrogen peroxide solution, stirring for 1h, then dropwise adding 0.5mL of sodium hydroxide solution, stirring for 10min, centrifugally washing the obtained white precipitate with sodium hydroxide (1M), deionized water and absolute ethyl alcohol in sequence, and drying at 50 ℃ to obtain CaO2And (4) storing the nano particles in a low-temperature refrigerator at 4 ℃.
Step two, mesoporous hybrid nanospheres:
2g of CaO2Adding nanoparticles and 1g of cetyltrimethylammonium bromide (CTAB) into 1g of sugar-free DMEM medium (containing sodium dihydrogen phosphate and calcium chloride), uniformly dispersing, sealing, and standing at 35 deg.C for 10 min; then 0.5g of CaCl2Adding into the mixture, and standing at 35 deg.C for 12 hr; after the reaction is finished, washing the reaction product for several times by using deionized water; then the nano-particles are dispersed in absolute ethyl alcohol solution by ultrasonic for 5min, sealed and heated for 3h at 70 ℃, and the precipitate is obtained by centrifugation. This step was repeated several times to remove the CTAB template; finally, the product is washed by deionized water and dried at 50 ℃. Obtaining CaP @ CaO2The mesoporous hybrid nanosphere.
Step three, preparing CaP @ CaO by electrostatic adsorption2@5-FU nanocomposite drug:
50g of CaP @ CaO2The nanoparticles and 50g of 5-fluorouracil were dispersed in 1g of deionized water and methanol; then stirring for 18h at room temperature, washing the obtained powder with deionized water, and drying at 50 ℃ to obtain CaP @ CaO2@5-FU nanocomposite drug. Step four, electrostatic adsorption of PEG:
dissolving 1g of methoxy-polyethylene glycol-maleimide (mPEG-Mal) in 20mL of deionized water, adding 5g N-hydroxysuccinimide (NHS) for activation, and adjusting the pH value to 7; stirring for 10min, and adding the CaP @ CaO prepared in the third step2Continuously stirring the @5-FU aqueous solution for 4 hours; finally, washing and drying the obtained compound to obtain CaP @ CaO2@5-FU @ PEG, oven dried at 30 ℃.
Step five, graft polymerization of PEI:
20g of CaP @ CaO2@5-FU @ PEG nanoparticles are dispersed in 1g of dimethyl sulfoxide (DMSO), and the solution A is obtained by magnetic stirring; dispersing 10g of Polyethyleneimine (PEI) in 2g of PBS solution to obtain a solution B; dropwise adding the solution A into the solution B, and stirring for 1h at 10 ℃; finally, the obtained mixed solution is dialyzed and centrifuged in turn to obtain CaP @ CaO2@5-FU@PEG@PEI。
EXAMPLE 2 preparation of a biodegradable and Targetable Nanocarrier II
Step one, CaO preparation2Nano-particles: 0.05g of CaCl2Adding 10g of deionized water and stirring; dropwise adding 1g of ammonia water and 0.5g of 30% wt hydrogen peroxide solution, stirring for 3h, then dropwise adding 0.5mL of sodium hydroxide solution, stirring for 10min, centrifugally washing the obtained white precipitate with sodium hydroxide (1M), deionized water and absolute ethyl alcohol in sequence, and drying at 50 ℃ to obtain CaO2And (4) storing the nano particles in a low-temperature refrigerator at 4 ℃.
Step two, mesoporous hybrid nanospheres:
2g of CaO2Adding nanoparticles and 20g cetyltrimethylammonium bromide (CTAB) into 5g sugar-free DMEM medium (containing sodium dihydrogen phosphate and calcium chloride), uniformly dispersing, sealing, and standing at 36 deg.C for 20 min; then 3g of CaCl2Adding into the mixture, and standing at 36 deg.C for 48 h; after the reaction is finished, washing the reaction product for several times by using deionized water; then the nano-particles are dispersed in absolute ethyl alcohol solution by ultrasonic for 15min, sealed and heated for 5h at 80 ℃, and the precipitate is obtained by centrifugation. This step was repeated several times to remove the CTAB template; finally, the product is washed by deionized water and dried at 50 ℃. Obtaining CaP @ CaO2The mesoporous hybrid nanosphere.
Step three, preparing CaP @ CaO by electrostatic adsorption2@5-FU nanocomposite drug:
200g of CaP @ CaO2The nanoparticles and 200g of 5-fluorouracil were dispersed in 5g of deionized water and methanol; then stirring for 36h at room temperature, washing the obtained powder with deionized water, and drying at 50 ℃ to obtain CaP @ CaO2@5-FU nanocomposite drug. Step four, electrostatic adsorption of PEG:
6g of methoxy-polyethyleneDissolving diol-maleimide (mPEG-Mal) in 20mL of deionized water, adding 10g N-hydroxysuccinimide (NHS) for activation, and adjusting the pH to 8; stirring for 50min, and adding the CaP @ CaO prepared in the third step2Continuously stirring the @5-FU aqueous solution for 24 hours; finally, washing and drying the obtained compound to obtain CaP @ CaO2@5-FU @ PEG, oven dried at 30 ℃.
Step five, graft polymerization of PEI:
80g of CaP @ CaO2@5-FU @ PEG nanoparticles are dispersed in 5g of dimethyl sulfoxide (DMSO), and the solution A is obtained by magnetic stirring; dispersing 60g of Polyethyleneimine (PEI) in 6g of PBS solution to obtain a solution B; dropwise adding the solution A into the solution B, and stirring for 24 hours at 60 ℃; finally, the obtained mixed solution is dialyzed and centrifuged in turn to obtain CaP @ CaO2@5-FU@PEG@PEI。
EXAMPLE 3 preparation of a biodegradable and Targetable Nanocarrier III
Step one, CaO preparation2Nano-particles:
adding 0.1g of CaCl2Adding 10g of deionized water and stirring; dropwise adding 2g of ammonia water and 1g of 20% wt hydrogen peroxide solution, stirring for 2h, then dropwise adding 0.5mL of sodium hydroxide solution, stirring for 10min, sequentially centrifugally washing the obtained white precipitate with sodium hydroxide, deionized water and absolute ethyl alcohol, and drying at 50 ℃ to obtain CaO2And (4) storing the nano particles in a low-temperature refrigerator at 4 ℃.
Step two, mesoporous hybrid nanospheres:
2g of CaO2Adding nanoparticles and 10g cetyltrimethylammonium bromide (CTAB) into 3g sugar-free DMEM medium (containing sodium dihydrogen phosphate and calcium chloride), uniformly dispersing, sealing, and standing at 37 deg.C for 30 min; then 1.5g of CaCl2Adding into the mixture, and standing at 37 deg.C for 24 hr; after the reaction is finished, washing the reaction product for several times by using deionized water; then the nano-particles are dispersed in absolute ethyl alcohol solution by ultrasonic for 10min, sealed and heated for 10h at 80 ℃, and the precipitate is obtained by centrifugation. This step was repeated several times to remove the CTAB template; finally, the product is washed by deionized water and dried at 50 ℃. Obtaining CaP @ CaO2The mesoporous hybrid nanosphere.
Step three, preparing the CaP @ CaO2@5-FU nano composite medicine by electrostatic adsorption:
100g of CaP @ CaO2The nanoparticles and 100g of 5-fluorouracil were dispersed in 1g of deionized water and methanol; then stirring for 24 hours at room temperature, washing the obtained powder with deionized water, and drying at 50 ℃ to obtain CaP @ CaO2@5-FU nanocomposite drug. Step four, electrostatic adsorption of PEG:
dissolving 2g of methoxy-polyethylene glycol-maleimide (mPEG-Mal) in 20mL of deionized water, adding 7g N-hydroxysuccinimide (NHS) for activation, and adjusting the pH to 9; stirring for 30min, and adding the CaP @ CaO prepared in the third step2Continuously stirring the @5-FU aqueous solution for 12 hours; finally, washing and drying the obtained compound to obtain CaP @ CaO2@5-FU @ PEG, oven dried at 30 ℃.
Step five, graft polymerization of PEI:
50g of CaP @ CaO2@5-FU @ PEG nanoparticles are dispersed in 1g of dimethyl sulfoxide (DMSO), and the solution A is obtained by magnetic stirring; dispersing 40g of Polyethyleneimine (PEI) in 3g of PBS solution to obtain a solution B; dropwise adding the solution A into the solution B, and stirring for 3h at 30 ℃; finally, the obtained mixed solution is dialyzed and centrifuged in turn to obtain CaP @ CaO2@5-FU@PEG@PEI。
Example 4 preparation of a biodegradable and targetable nanocarrier IV:
step one, CaO preparation2Nano-particles:
adding 0.03g of CaCl2Adding 10g of deionized water and stirring; dropwise adding 0.8g of ammonia water and 0.6g of 40% wt hydrogen peroxide solution, stirring for 4h, then dropwise adding 0.5mL of sodium hydroxide solution, stirring for 10min, centrifugally washing the obtained white precipitate with sodium hydroxide (1M), deionized water and absolute ethyl alcohol in sequence, and drying at 50 ℃ to obtain CaO2And (4) storing the nano particles in a low-temperature refrigerator at 4 ℃.
Step two, mesoporous hybrid nanospheres:
2g of CaO2Adding nanoparticles and 5g cetyltrimethylammonium bromide (CTAB) into 2g sugar-free DMEM medium (containing sodium dihydrogen phosphate and calcium chloride), dispersing, sealing, and standing at 39 deg.C30 min; then 2.5g of CaCl2Adding into the mixture, and standing at 39 deg.C for 24 hr; after the reaction is finished, washing the reaction product for several times by using deionized water; then the nano-particles are dispersed in absolute ethyl alcohol solution by ultrasonic for 8min, sealed and heated for 9h at 75 ℃, and the precipitate is obtained by centrifugation. This step was repeated several times to remove the CTAB template; finally, the product is washed by deionized water and dried at 50 ℃. Obtaining CaP @ CaO2Mesoporous hybrid nanosphere
Step three, preparing CaP @ CaO by electrostatic adsorption2@5-FU nano composite medicine
150g of CaP @ CaO2Nanoparticles and 150g of 5-fluorouracil were dispersed in 3g of deionized water and methanol; then stirring for 20h at room temperature, washing the obtained powder with deionized water, and drying at 50 ℃ to obtain CaP @ CaO2@5-FU nanocomposite drug. Step four, electrostatic adsorption of PEG:
dissolving 3g of methoxy-polyethylene glycol-maleimide (mPEG-Mal) in 20mL of deionized water, adding 5g N-hydroxysuccinimide (NHS) for activation, and adjusting the pH to 8; stirring for 45min, and adding the CaP @ CaO prepared in the third step2Continuously stirring the @5-FU aqueous solution for 20 hours; finally, washing and drying the obtained compound to obtain CaP @ CaO2@5-FU @ PEG, oven dried at 30 ℃.
Step five, graft polymerization of PEI:
60g of CaP @ CaO2@5-FU @ PEG nanoparticles are dispersed in 3g of dimethyl sulfoxide (DMSO), and the solution A is obtained by magnetic stirring; dispersing 50g of Polyethyleneimine (PEI) in 5g of PBS solution to obtain a solution B; dropwise adding the solution A into the solution B, and stirring for 12 hours at 50 ℃; finally, the obtained mixed solution is dialyzed and centrifuged in turn to obtain CaP @ CaO2@5-FU@PEG@PEI。
Example 5 preparation of a biodegradable and targetable nanocarrier V:
step one, CaO preparation2Nano-particles:
0.06g of CaCl2Adding 10g of deionized water and stirring; dropwise adding 2g of ammonia water and 0.8g of 50% wt hydrogen peroxide solution, stirring for 5h, then dropwise adding 0.5mL of sodium hydroxide solution, stirring for 10min, and sequentially adding oxyhydrogen to the obtained white precipitateSodium (1M), deionized water and absolute ethyl alcohol are centrifugally washed and dried at 50 ℃ to prepare CaO2And (4) storing the nano particles in a low-temperature refrigerator at 4 ℃.
Step two, mesoporous hybrid nanospheres:
2g of CaO2Adding nanoparticles and 1g of cetyltrimethylammonium bromide (CTAB) into 1g of sugar-free DMEM medium (containing sodium dihydrogen phosphate and calcium chloride), uniformly dispersing, sealing, and standing at 37 deg.C for 15 min; then 2g of CaCl2Adding into the mixture, and standing at 37 deg.C for 15 hr; after the reaction is finished, washing the reaction product for several times by using deionized water; then the nano-particles are dispersed in absolute ethyl alcohol solution by ultrasonic for 6min, sealed and heated for 7h at 70 ℃, and the precipitate is obtained by centrifugation. This step was repeated several times to remove the CTAB template; finally, the product is washed by deionized water and dried at 50 ℃. Obtaining the CaP @ CaO2 mesoporous hybrid nanosphere.
Step three, preparing CaP @ CaO by electrostatic adsorption2@5-FU nanocomposite drug:
180g of CaP @ CaO2The nanoparticles and 180g of 5-fluorouracil were dispersed in 2g of deionized water and methanol; then stirring for 30h at room temperature, washing the obtained powder with deionized water, and drying at 50 ℃ to obtain CaP @ CaO2@5-FU nanocomposite drug. Step four, electrostatic adsorption of PEG:
dissolving 3g of methoxy-polyethylene glycol-maleimide (mPEG-Mal) in 20mL of deionized water, adding 5g N-hydroxysuccinimide (NHS) for activation, and adjusting the pH to 8; stirring for 45min, and adding the CaP @ CaO prepared in the third step2Continuously stirring the @5-FU aqueous solution for 20 hours; finally, washing and drying the obtained compound to obtain CaP @ CaO2@5-FU @ PEG, oven dried at 30 ℃.
Step five, graft polymerization of PEI:
70g of CaP @ CaO2@5-FU @ PEG nanoparticles are dispersed in 2g of dimethyl sulfoxide (DMSO), and the solution A is obtained by magnetic stirring; dispersing 30g of Polyethyleneimine (PEI) in 5g of PBS solution to obtain a solution B; dropwise adding the solution A into the solution B, and stirring for 10 hours at 20 ℃; finally, the obtained mixed solution is dialyzed and centrifuged in turn to obtain CaP @ CaO2@5-FU@PEG@PEI。
Claims (8)
1. A biodegradable nanocarrier having targeting ability, comprising: the nano carrier is formed by calcium chloride through a biomineralization method and a template method to form mesoporous hybrid nanospheres; then the nano composite medicine is adsorbed by static electricity; and modifying the surface with biocompatible material.
2. The nanocarrier capable of biodegrading and targeting as claimed in claim 1, wherein the mesoporous hybrid nanospheres of the nanoparticle main material are core-shell structures, and the core layer is CaO2The shell layer is CaP, the loaded drug is 5-Fu, and the surface modification materials are PEG and PEI.
3. A method for preparing the nanocarrier with biodegradability and targeting ability according to claim 1 or 2, characterized by comprising the following steps:
step one, CaO preparation2Nano-particles: adding CaCl2Adding into deionized water and stirring; dropwise adding ammonia water and hydrogen peroxide solution, stirring, dropwise adding sodium hydroxide solution to obtain white precipitate, centrifuging, washing and drying to obtain CaO2And (3) nanoparticles.
Step two, mesoporous hybrid nanospheres: CaO prepared in the step one2Adding nanoparticles and Cetyl Trimethyl Ammonium Bromide (CTAB) into sugar-free DMEM medium (containing sodium dihydrogen phosphate and calcium chloride), dispersing uniformly, and sealing; after standing, adding calcium chloride, and continuously standing to obtain a coarse product of the mesoporous hybrid nanosphere; after the reaction is finished, washing the reaction product for several times by using deionized water; ultrasonically dispersing the nanoparticles in an absolute ethyl alcohol solution (or methanol), sealing, heating and repeatedly removing a CTAB template agent; finally washing and drying to obtain CaP @ CaO2The mesoporous hybrid nanosphere.
Step three, preparing CaP @ CaO by electrostatic adsorption2@5-FU nanocomposite drug: the CaP @ CaO prepared in the step two2Nanoparticles and 5-fluorouracil were dispersed in deionized water and methanol (v: v ═ 2: 1); then stirring, washing and drying to obtain CaP @ CaO2@5-FU NaA rice compound medicine.
Step four, electrostatic adsorption of PEG: dissolving methoxy-polyethylene glycol-maleimide (mPEG-Mal), adding N-hydroxysuccinimide (NHS) for activation, and adjusting pH value; after stirring, adding the CaP @ CaO prepared in the third step2@5-FU in water (containing 120mg of nanoparticles), and stirring; finally, washing and drying the obtained compound to obtain CaP @ CaO2@5-FU@PEG。
Step five, graft polymerization of PEI: the CaP @ CaO prepared in the fourth step2Dispersing the @5-FU @ PEG nanoparticles into dimethyl sulfoxide (DMSO), and magnetically stirring to obtain a solution A; dispersing Polyethyleneimine (PEI) in a PBS (phosphate buffer solution) to obtain a solution B; dropwise adding the solution A into the solution B, and stirring; finally, the obtained mixed solution is dialyzed and centrifuged in turn to obtain CaP @ CaO2@5-FU@PEG@PEI。
4. The method for preparing starch nanoparticles with protein adsorption and targeting resistance according to claim 3, characterized in that in step one:
the mass ratio of (0.01-0.1): 10 CaCl2Adding into deionized water;
preferably, CaCl2Dropwise adding ammonia water and 10-50 wt% of hydrogen peroxide solution according to the mass ratio (0.01-0.1): (0.5-2): (0.1-1) stirring for 1-5 h.
5. The method for preparing starch nanoparticles with protein adsorption and targeting resistance as claimed in claim 3 or 4, wherein the step two is that:
the mass ratio is 2: (1-20): (1-5) CaO2Adding the nanoparticles and Cetyl Trimethyl Ammonium Bromide (CTAB) into a sugar-free DMEM medium (containing sodium dihydrogen phosphate and calcium chloride), uniformly dispersing, sealing, and standing at 35-39 ℃ for 10-60 min;
preferably 0.5-3 g of CaCl2Adding the mixture into the reactor, and continuously placing the reactor for 12-48 hours at the temperature of 35-39 ℃; after the reaction is finished, washing the reaction product for several times by using deionized water; then the nano particles are put into the absolute ethyl alcohol solutionPerforming medium ultrasonic dispersion for 5-15 min, sealing and heating at 70-80 ℃ for 3-10 h, and centrifuging to obtain a precipitate. This step was repeated several times to remove the CTAB template; finally, the product is washed by deionized water and dried at 50 ℃.
6. The method for preparing starch nanoparticles with protein adsorption and targeting resistance according to claim 4 or 5, characterized in that the step three comprises:
CaP@CaO2the mass ratio of the nanoparticles to the 5-fluorouracil to the deionized water to the methanol is (50-200): (50-200): (1-5);
preferably, the mixture is stirred at room temperature for 18-36 h, and the obtained powder is washed with deionized water and dried at 50 ℃.
7. The method for preparing starch nanoparticles with protein adsorption and targeting resistance as claimed in claim 5 or 6, wherein the step four comprises:
methoxy-polyethylene glycol-maleimide (mPEG-Mal), N-hydroxysuccinimide (NHS) and Cap @ CaO2The mass ratio of the @5-FU aqueous solution is as follows: (1-6): (5-10): (1-6).
Preferably, after activation, the pH is adjusted to be 7-9; stirring for 10-50 min; adding CaP @ CaO2And (3) continuing stirring the @5-FU aqueous solution for 4-24 hours, and finally washing and drying the compound to obtain the product.
8. The method for preparing starch nanoparticles with protein adsorption and targeting resistance as claimed in claim 6 or 7, characterized in that in step five:
CaP@CaO2the mass ratio of the @5-FU @ PEG nanoparticles to the solutions of dimethyl sulfoxide (DMSO), Polyethyleneimine (PEI) and PBS is (20-80): (1-5): (10-60): (2-6);
preferably, the solution a is added dropwise to the solution B, the stirring temperature: and (2) stirring at 10-60 ℃ for: 1-24 h; finally, the powder was lyophilized by dialysis and centrifugation.
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| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 311200 5th floor, Building 4, No. 617, Jin'er Road, Xiaoshan Economic and Technological Development Zone, Hangzhou, Zhejiang Patentee after: Luoxi medical technology (Hangzhou) Co.,Ltd. Address before: Room 301-304, 3rd Floor, No. 459, Qige Road, Xiasha Street, Economic and Technological Development Zone, Hangzhou City, Zhejiang Province, 310016 Patentee before: Luoxi medical technology (Hangzhou) Co.,Ltd. |