CN115068628B - Preparation method of slow-release carrier of reduction-responsive quercetin medicine - Google Patents
Preparation method of slow-release carrier of reduction-responsive quercetin medicine Download PDFInfo
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- CN115068628B CN115068628B CN202210718150.0A CN202210718150A CN115068628B CN 115068628 B CN115068628 B CN 115068628B CN 202210718150 A CN202210718150 A CN 202210718150A CN 115068628 B CN115068628 B CN 115068628B
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- mesoporous silicon
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- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 title claims abstract description 74
- 239000003814 drug Substances 0.000 title claims abstract description 52
- 235000005875 quercetin Nutrition 0.000 title claims abstract description 37
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 title claims abstract description 36
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 title claims abstract description 36
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 229960001285 quercetin Drugs 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 230000009467 reduction Effects 0.000 title claims abstract description 12
- 208000006411 Hereditary Sensory and Motor Neuropathy Diseases 0.000 claims abstract description 66
- 208000021995 hereditary motor and sensory neuropathy Diseases 0.000 claims abstract description 66
- 238000001179 sorption measurement Methods 0.000 claims abstract description 56
- 229940079593 drug Drugs 0.000 claims abstract description 39
- 229910052710 silicon Inorganic materials 0.000 claims abstract description 21
- 239000010703 silicon Substances 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 230000004048 modification Effects 0.000 claims abstract description 9
- 238000012986 modification Methods 0.000 claims abstract description 9
- 239000003937 drug carrier Substances 0.000 claims abstract description 7
- 230000004043 responsiveness Effects 0.000 claims abstract description 5
- 239000006087 Silane Coupling Agent Substances 0.000 claims abstract description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000012153 distilled water Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 239000000377 silicon dioxide Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 7
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- -1 2,2' -bipyridyl disulfide Chemical compound 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- 235000012239 silicon dioxide Nutrition 0.000 claims description 4
- UUEWCQRISZBELL-UHFFFAOYSA-N 3-trimethoxysilylpropane-1-thiol Chemical compound CO[Si](OC)(OC)CCCS UUEWCQRISZBELL-UHFFFAOYSA-N 0.000 claims description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 238000005119 centrifugation Methods 0.000 claims description 2
- 229910052681 coesite Inorganic materials 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 229910052906 cristobalite Inorganic materials 0.000 claims description 2
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 229910052682 stishovite Inorganic materials 0.000 claims description 2
- 229910052905 tridymite Inorganic materials 0.000 claims description 2
- 238000005303 weighing Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 1
- 238000013268 sustained release Methods 0.000 abstract description 3
- 239000012730 sustained-release form Substances 0.000 abstract description 3
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 26
- 229960003180 glutathione Drugs 0.000 description 13
- 239000012876 carrier material Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 8
- 238000004833 X-ray photoelectron spectroscopy Methods 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 108010024636 Glutathione Proteins 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 238000011068 loading method Methods 0.000 description 5
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 3
- 238000003917 TEM image Methods 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- 229910018557 Si O Inorganic materials 0.000 description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000012844 infrared spectroscopy analysis Methods 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000001878 scanning electron micrograph Methods 0.000 description 2
- 238000004626 scanning electron microscopy Methods 0.000 description 2
- LIVNPJMFVYWSIS-UHFFFAOYSA-N silicon monoxide Inorganic materials [Si-]#[O+] LIVNPJMFVYWSIS-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000000026 X-ray photoelectron spectrum Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000011856 silicon-based particle Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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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- 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
- A61K47/6951—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 using cyclodextrin
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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Abstract
The invention discloses a preparation method of a reduction-responsive quercetin drug sustained-release carrier, which uses a silane coupling agent to carry out functional modification on hollow mesoporous silicon, utilizes the exchange reaction of sulfhydryl-disulfide bond to modify beta-CD-SH on the surface of the hollow mesoporous silicon to prepare the drug carrier HMSN-ss-CD with reduction responsiveness, and the carrier has excellent adsorption capacity and release performance on Quercetin (QUE), thereby providing basis for preparing related drugs.
Description
Technical Field
The invention relates to the field of chemical drug synthesis, in particular to a preparation method of a slow-release carrier of a reduction-responsive quercetin drug.
Background
It is known that there is a difference between the physiological environment of the tumor diseased part and normal tissue, such as that the temperature of the tumor part and the inflammatory tissue is slightly higher than that of the normal part, the pH value of the diseased part is lower, the Glutathione (GSH) content in the tumor cells is 100-1000 times as high as that of the normal part, and the tumor cells can secrete excessive enzyme, etc. Due to the fact that the differences exist, a thought is provided for the subsequent design of environment response row carriers. According to the existing research, the inorganic nanoparticle hollow mesoporous silicon has the advantages of larger cavity structure, capability of loading more anticancer drugs in later stage, adjustable size, easy surface modification and the like, and provides a matrix for the subsequent preparation of environment-responsive carriers. The environment-responsive medicine slow release carrier can damage the carrier material structure aiming at different stimulations, so that the medicine is released at the diseased part, and the leakage of the anticancer medicine in the transportation process is effectively reduced.
Quercetin (QUE), also known as 2- (3, 4-dihydroxyphenyl) -3,5, 7-trihydroxy-4H-chromen-4-one, is a polyhydroxy flavonoid compound, and is commonly found in natural environments. The research on the medicinal principle of quercetin shows that the quercetin not only has the antioxidation function, but also has the functions of resisting cancer, inflammation, virus, blood sugar, blood pressure and immunity, and the like, and has a great research prospect.
Disclosure of Invention
The invention aims to: an environment response type medicine carrier aiming at quercetin is designed, so that the accurate release of medicines is realized.
The invention adopts the following technical scheme: the preparation method of the reduction-responsive quercetin drug sustained release carrier comprises the steps of performing functional modification on hollow mesoporous silicon by using a silane coupling agent, modifying beta-CD-SH on the surface of the hollow mesoporous silicon by utilizing exchange reaction of sulfhydryl-disulfide bond, preparing a part of HMSN-ss-CD by using the drug carrier HMSN-ss-CD with reduction responsiveness, accurately weighing 0.50 part of hollow mesoporous silicon g, dispersing the part of the hollow mesoporous silicon into 30 mL anhydrous toluene, then dropwise adding 3 mL of 3-mercaptopropyl trimethoxy silane MPTMS, reacting 12h at 80 ℃ in nitrogen atmosphere, separating and washing, and drying at 50 ℃ to obtain the sulfhydryl-modified hollow mesoporous silicon HMSN-SH; adding 0.30 g of the sample into 30 mL methanol solution, adding 0.10 g of 2,2' -bipyridyl disulfide, reacting at 25 ℃ for 24h, centrifugally washing, and drying to obtain a material HMSN-py; then HMSN-py and beta-CD-SH were dispersed in N, N-dimethylformamide DMF, reacted at 30℃for 24: 24h, followed by centrifugal washing and drying to obtain vector HMSN-ss-CD.
The preparation method of the hollow mesoporous silicon HMSN comprises the steps of adding 30 mL distilled water, 214 mL absolute ethyl alcohol and 5 mL ammonia water into a flask according to a proportion, slowly dropwise adding 5 mL tetraethyl silicate (TEOS), stirring at room temperature for 2h, centrifuging, washing and drying to obtain solid SiO2; dissolving the 0.30 g sample in 60 mL distilled water, ultrasonically dispersing for 30 min, dissolving 0.45 g hexadecyl trimethyl ammonium bromide (CTAB) in 90 mL absolute ethyl alcohol, 1.65 mL ammonia water and 90 mL distilled water, adding the ultrasonic silicon dioxide solution, continuously reacting for 0.5 h, accurately sucking 0.75 mL tetraethoxysilane, slowly adding into the reaction, and continuously stirring for 6 h; then centrifugally washing, re-dispersing the precipitate in distilled water, adding 0.64 g anhydrous sodium carbonate (Na 2CO3), magnetically stirring at 50 ℃ for reaction for 10 h, and centrifugally collecting the precipitate; concentrated hydrochloric acid and methanol were mixed with the above samples, refluxed at 80 ℃ under condensation for 12 h, and then centrifugally washed and dried.
Further said HMSN-py amount is 0.10 g and β -CD-SH amount is 0.07 g.
Further, the adsorption amount of the carrier to the quercetin is controlled by changing the drug concentration and the temperature, wherein the adsorption temperature is 30 ℃, and the quercetin concentration is 140 mg/L.
Compared with the prior art, the preparation method has the advantages that the drug carrier HMSN-ss-CD with reduction responsiveness is prepared, the Quercetin (QUE) has excellent adsorption capacity and release performance, and a basis is provided for preparing related drugs.
Drawings
FIG. 1 is a graph showing the effect of HMSN-py amounts on HMSN-ss-CD adsorption;
FIG. 2 is a graph showing the effect of β -CD-SH amount on HMSN-ss-CD adsorption performance;
FIG. 3 is a schematic diagram showing the effect of reaction temperature on HMSN-ss-CD adsorption performance;
FIG. 4 HMSN, HMSN-SH and HMSN-ss-CD are infrared analysis charts;
FIG. 5 HMSN and HMSN-ss-CD are schematic XPS spectra;
SEM and TEM images of the carrier of fig. 6;
(a) -HMSN SEM images; (b) SEM image of-HMSN-ss-CD;
(c) -HMSN TEM image; (d) TEM image of-HMSN-ss-CD;
The XRD pattern of fig. 7 HMSN;
FIG. 8 is a graph of HMSN-ss-CD versus QUE adsorption at various temperatures;
FIG. 9 HMSN-ss-CD isothermal adsorption graph;
FIG. 10 HMSN-ss-CD is a graph of a QUE adsorption thermodynamic model fit;
(a) -Langmuir isothermal adsorption model; (b) -Freundlich isothermal adsorption model;
(c) -Temkin isothermal adsorption model;
FIG. 11 QUE@HMSN-ss-CD drug release profile at different GSH levels.
Detailed Description
The present invention will be described in further detail by way of examples and comparative examples.
The influence of 3 factors such as HMSN-py, beta-CD-SH and reaction temperature on the maximum equilibrium adsorption amount of the carrier material is sequentially examined by using a single-factor experiment method, the optimal preparation condition is explored, and the process optimization step is carried out on the carrier HMSN-ss-CD.
1) Effect of HMSN-py amount on the adsorption properties of Carrier Material HMSN-ss-CD
0.1 G beta-CD-SH was added, the amount of HMSN-py was changed at a reaction temperature of 30 ℃, and 0.04 g, 0.07 g, 0.10 g, 0.13 g and 0.16 g were added respectively, and the adsorption of different products to quercetin solutions was analyzed, and the results are shown in FIG. 1. As can be seen from FIG. 1, the amount HMSN-py affects the amount of QUE adsorbed by the support. The sample mass and the adsorption amount show a trend of forward correlation and then gradually reverse correlation. The analytical reasons suggest that when HMSN-py mass is increased, the resulting HMSN-ss-CD vector has less external obstruction and the vector is able to adsorb more drug. When the mass of the hollow mesoporous silicon modified pyridine is 0.10 g, the adsorption quantity can reach the highest value. Thus, the optimal amount of sample HMSN-py is 0.10 g.
2) Effect of beta-CD-SH amount on adsorption Properties of Carrier Material HMSN-ss-CD
The QUE solution was then analyzed by varying the amount of beta-CD-SH added at a reaction temperature of 30℃with 0.10 g HMSN-py, and the results are shown in FIG. 2. The highest adsorption capacity of the drug carrier material is closely related to the hollow mesoporous silicon and the externally added modification material. It can be seen from the figure that as the mass of β -CD-SH increases from 0.04 g to 0.07 g, the drug loading increases due to the larger cavities and more pores in the material, while the mass of β -CD-SH continues to increase, causing the external finishing material of the support to interfere with the adsorption of QUE by HMSN. Therefore, when the mass of β -CD-SH is 0.07 g, the adsorption amount of the carrier is maximum.
3) Influence of the reaction temperature on HMSN-ss-CD adsorption Properties
0.10 G HMSN-py and 0.10 g. Beta. -CD-SH were added, respectively, and the results were shown in FIG. 3 by changing the reaction temperatures to 20 ℃, 25 ℃, 30 ℃, 35 ℃ and 40 ℃, respectively.
The drug loading and adsorption temperature show a tendency of positive correlation followed by negative correlation, with the highest drug loading when the adsorption temperature reaches 30 ℃, and the carrier adsorption amount decreases instead when the temperature continues to increase. The analytical reasons are that the molecular movement speed is increased due to the existence of the thermal movement of the molecules, the temperature is increased, and the drug loading is increased accordingly. When the temperature continues to rise, the thermal movement of the medicine adsorbed in the cavity is accelerated, so that the medicine originally packaged in the cavity of the carrier material leaks, the adsorption amount is reduced, and when the temperature is 30 ℃, the adsorption of the carrier reaches a dynamic equilibrium state, and the result shows that the temperature of 30 ℃ is the optimal preparation temperature of the carrier.
Infrared spectroscopic analysis
The chemical bonds and functional groups of the samples HMSN, HMSN-SH and HMSN-ss-CD were detected by infrared spectroscopic analysis (FT-IR) and the results are shown in FIG. 4. In FIG. 4, it can be seen from the FT-IR of the hollow mesoporous silica and the functionalized modified sample that the peak at 1083 cm-1 is due to the stretching vibration of the Si-O bond, and the peak at 960 cm-1 is due to the vibration of the Si-O bond. Then carrying out sulfhydrylation modification on HMSN, wherein the 2983 cm-1 and 2923 cm-1 are characteristic peaks of-CH 3 and-CH 2 in 3-mercaptopropyl trimethoxy silane, but the infrared characteristic absorption peaks of mercapto groups are weaker and cannot be observed from the figure, so that further detection and verification are carried out by utilizing X-ray photoelectron spectroscopy analysis. Compared with hollow mesoporous silicon, 1157 cm-1 is the C-O-C telescopic vibration peak, and the peak position of the telescopic vibration peak is basically consistent with the peak position of the characteristic peak of cyclodextrin through comparison analysis with the standard infrared spectrum of beta-CD, so that the successful grafting of the beta-CD to the surface of the carrier is proved, and the successful preparation of the drug carrier HMSN-ss-CD is shown.
X-ray photoelectron spectroscopy
The presence of elements on the surfaces of the carriers HMSN and HMSN-ss-CD was determined by X-ray photoelectron spectroscopy (XPS), the results of which are shown in FIG. 5. From the XPS full spectrum of the carrier, compared with unmodified hollow mesoporous silicon, peaks of S2S and S2p orbital electrons of sulfur element appear on the XPS curve of the hollow mesoporous silicon after sulfhydrylation modification, and analysis shows that HMSN-SH has been successfully prepared.
Electron microscope analysis
The microscopic morphology of the support material HMSN and the polymer modified support HMSN-ss-CD was observed using Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM), and the results are shown in FIG. 6.
As can be seen from the observation of fig. 6 (a), the synthesized hollow mesoporous silicon particles are in a uniformly dispersed state and have a good spherical shape. In FIG. 6 (b), HMSN-ss-CD had a slightly increased particle size, but was less pronounced. It can be seen in fig. 6 (c) that the particles have a clear white cavity portion, a wall thickness of about 25 nm, and good dispersibility between the microspheres. As can be seen from fig. 6 (d), after modification of β -CD, a new ghost appears outside the hollow mesoporous silica, indicating that β -CD is uniformly wrapped on the surface of the hollow mesoporous silica.
Powder diffraction analysis by X-ray
The crystalline structure of the hollow mesoporous silica was examined by X-ray diffraction analysis (XRD), and the results are shown in fig. 7. As can be seen from fig. 7, there is a distinct diffraction peak at 2.16 °, the shape of the peak is strong and broad, and no other distinct impurity peaks are seen from the XRD pattern, and the result shows that the prepared carrier particles HMSN belong to the mesoporous structure.
Influence of temperature on adsorption Performance
The adsorption amount of the carrier at different temperatures was examined by experiment, and the influence of temperature on the drug molecules loaded on the carrier was examined, and the result is shown in fig. 8. The adsorption results of the carrier material on the drug molecules under different temperature conditions are shown in the graph. The slow release carrier material HMSN-ss-CD has weaker adsorption capacity to the drug molecule quercetin QUE at 20 ℃. The adsorption capacity of the support for QUE reached the highest at an adsorption temperature of 30℃and the adsorption capacity was 64.9 mg/g. After that, the temperature continues to increase, and the adsorption amount decreases slightly. This phenomenon occurs mainly because the higher the temperature, the faster the drug molecules diffuse, increasing the amount of drug adsorbed.
Adsorption thermodynamic study
QUE solutions of different concentrations (10 mg/L, 20 mg/L, 30 mg/L, 40 mg/L, 50 mg/L, 100 mg/L, 120 mg/L, 140 mg/L and 160 mg/L) were prepared, HMSN-ss-CD of 10 mg was weighed and dispersed into the above solutions of different concentrations of 10 mL, followed by shaking adsorption 24 h, and centrifugation to collect the supernatant. The residual medicine content in the supernatant is measured by ultraviolet, the adsorption quantity, medicine carrying rate and encapsulation rate of the carrier on medicine molecules are calculated, and the adsorption mechanism of the carrier is analyzed by establishing an adsorption model.
The relationship between the initial solubility of the drug molecules and the adsorption amount of the carrier was examined by subjecting the carrier HMSN-ss-CD to adsorption in drug solutions of different initial concentrations, and the results are shown in FIG. 9.
As can be seen in FIG. 9, the carrier HMSN-ss-CD shows a positive correlation with the initial concentration of the drug solution. When the initial concentration of the drug is 140 mg/L, the adsorption capacity of the carrier to QUE reaches the strongest, and the saturated adsorption quantity is 130.2 mg/g. And then increasing the concentration of the drug molecules, wherein the adsorption reaches saturation, and the adsorption quantity is basically unchanged. The behavior of the carrier to adsorb drug molecules was fitted by modeling, and the results are shown in fig. 10 and table 4.
TABLE 4 HMSN-ss-CD on QUE adsorption thermodynamic parameters
By drawing different adsorption fitting curve graphs, the fitting degree of the Langmuir adsorption isothermal model is obviously higher than that of other two models. Through analysis and listing of the table III, it can be seen from the data that the linear correlation coefficient (R2) of the first adsorption isothermal model is higher than that of the other two adsorption equations, and the theoretical value Qm and the actual value calculated according to the equations are more accurate, which indicates that the adsorption process of the carrier to the drug molecules QUE is more consistent with Langmuir isothermal adsorption, namely the adsorption capacity of the drug molecules on all parts of the surface of the carrier is consistent.
In vitro drug delivery study of QUE@HMSN-ss-CD
1) Drug release performance of QUE@HMSN-ss-CD under different glutathione GSH
The drug release amounts of the carriers at different GSH contents (0 mM, 10 mM and 20 mM) were studied, and the relationship between the drug release rate of the carriers and glutathione was studied, and the results are shown in FIG. 11.
In order to better illustrate the slow release and controlled release effects of GSH on the drug carrier, the carrier material is subjected to in vitro drug release research, and the in vitro release performance under different GSH concentrations is examined. As can be seen from fig. 11, after the drug is adsorbed, the cumulative release rate of the drug in the phosphate buffer solution without glutathione is low because the drug molecules QUE are adsorbed in the channels and cavities of the hollow mesoporous silicon, when the carrier material is placed in the PBS buffer solution of 10mM GSH, the presence of glutathione can react with disulfide bonds to cause breakage of disulfide bonds, the adsorbed drug molecules can be released to the outside from the mesoporous channels and cavities of the carrier material, at this time, the cumulative release amount of the drug molecules reaches 59.90%, and when the GSH content in the phosphate buffer solution increases to 20 mM, the cumulative release amount of the drug molecules also increases to 89.05%, thus analyzing that the drug sustained release system has a reduction responsiveness.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (2)
1. The preparation method of the slow release carrier of the reduction responsive quercetin medicament is characterized by comprising the following steps: performing functional modification on hollow mesoporous silicon by using a silane coupling agent, modifying beta-CD-SH on the surface of the hollow mesoporous silicon by utilizing exchange reaction of sulfhydryl-disulfide bond, preparing a drug carrier HMSN-ss-CD with reduction responsiveness, preparing a part of HMSN-ss-CD according to a proportion, accurately weighing 0.50 g of hollow mesoporous silicon, dispersing the hollow mesoporous silicon in 30 mL anhydrous toluene, dropwise adding 3 mL of 3-mercaptopropyl trimethoxysilane MPTMS into the 30 anhydrous toluene, reacting 12 h at 80 ℃ in nitrogen atmosphere, separating and washing, and drying at 50 ℃ to obtain the sulfhydrylation modified hollow mesoporous silicon HMSN-SH; adding 0.30 g of the sample into 30 mL methanol solution, adding 0.10 g of 2,2' -bipyridyl disulfide, reacting at 25 ℃ for 24 h, centrifugally washing, and drying to obtain a material HMSN-py; then HMSN-py and beta-CD-SH are dispersed in N, N-dimethylformamide DMF to react for 24 h at 30 ℃, and then centrifugal washing and drying are carried out to obtain the carrier HMSN-ss-CD, wherein the HMSN-py dosage is 0.10 g, the beta-CD-SH dosage is 0.07 g, the quercetin drug concentration is 140 mg/L, and the adsorption temperature is 30 ℃.
2. The method for preparing the slow release carrier of the reduction-responsive quercetin medicine according to claim 1, wherein the preparation method of the hollow mesoporous silicon HMSN is characterized in that 30 mL distilled water, 214 mL absolute ethyl alcohol and 5 mL ammonia water are added into a flask in proportion, 5 mL tetraethyl silicate (TEOS) is slowly added dropwise, stirring is carried out for 2h at room temperature, and then centrifugation, washing and drying are carried out to obtain solid SiO2; dissolving the 0.30 g sample in 60 mL distilled water, ultrasonically dispersing for 30 min, dissolving 0.45 g hexadecyl trimethyl ammonium bromide CTAB in 90 mL absolute ethyl alcohol, 1.65 mL ammonia water and 90 mL distilled water, then adding the ultrasonic silicon dioxide solution to continue the reaction for 0.5 h, accurately sucking 0.75 mL tetraethoxysilane, slowly adding the mixture into the reaction, and continuously stirring for 6 h; then centrifugally washing, re-dispersing the precipitate in distilled water, adding 0.64 g anhydrous sodium carbonate Na 2CO3, magnetically stirring at 50 ℃ for reaction for 10 h, and centrifugally collecting the precipitate; concentrated hydrochloric acid and methanol were mixed with the above samples, refluxed at 80 ℃ under condensation for 12h, and then centrifugally washed and dried.
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