CN107412194A - With stimuli responsive and divide storehouse intelligently nanometer particle of load medicine drug release feature and preparation method thereof - Google Patents
With stimuli responsive and divide storehouse intelligently nanometer particle of load medicine drug release feature and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of with stimuli responsive and the nanometer particle for dividing storehouse intelligently to carry medicine drug release feature and preparation method thereof, the nanometer particle is that surface modification is had stimuli responsive group and the nanometer particle of medicine is carried using the cyclodextrin of alkynyl modification as " nano-valve " point storehouse, and its particle diameter is 80 190nm.Nanometer particle provided by the invention has the carrier system that two parts medicine can be separated to accumulating on the same vector, that is the double medicine even multiple medicines of warehouse separated type carry delivery system altogether, by the response of cyclodextrin nano valve action and stimuli responsive group to extracellular intracellular different stimulated environment, targeting and the intelligent drug delivery to tumour cell can be realized.
Description
Technical field
Technical field of nano material of the present invention, it is more particularly to a kind of that there is stimuli responsive and divide storehouse intelligently to carry medicine drug release feature
Nanometer particle and preparation method thereof.
Background technology
Mesoporous silicon is used as a kind of medicine as a kind of nano material with excellent physicochemical properties in biomedicine
Thing carrier, the potentiality applied to medicine/gene transmission are huge.Nanometer particle has many excellent characteristics, example
As synthetic method is simple and easy, specific surface area is high, pore volume is big, surface is easily modified, nano-particles size mesoporous pore size is easily adjusted,
Property stabilization etc..But traditional mesoporous silicon is nonspecific, can not only release the drug in lesion tissue and can also be released in normal structure
Medicine, drug effect is substantially reduced.Therefore, the mesoporous silicon of functionalization is given birth to because of fortune.
The mesoporous silicon of functionalization has better characteristics, zero release can be realized before targeting moiety is reached, by anticancer
Targeted drug delivery is to tumor locus.Medicine effect can be maximized and played by the method for this targeting drug release, effectively be reduced anti-
The toxic side effect of cancer drug, improve utilization ratio of drug.In order to reach the purpose of targeting drug release, many researchers are in mesoporous silicon face
Different groups, such as sulfydryl, amino, alkynyl are modified, to reach the intelligent responses such as photoresponse, enzyme response, thermal response, reduction response
The purpose of Targeting delivery.
In order to solve drug resistance and reduce poisonous side effect of medicine, the common loading system of the multiple medicine of conveying is concentrated to cause several drugses
The great interest of researcher.Result of study shows that it is resistance to not only to overcome multiple medicine by the multiple medicine drug combination that loading system is realized altogether
The property of medicine, disturb many cells survival route, the compliance for also greatly improving patient because reducing taking dose.Fu Yao and Gong
Tao etc. has carried Perarubicin with human serum albumins nano particle and breast cancer has been studied with taxol drug altogether, hair
Existing medicine enhances the active anticancer of medicine after carrying altogether, reduce the toxicity of system.However, because current medicine passes through mostly
Back loading is mixed on the carriers such as micella, mesoporous silicon, there is the medicine of different biochemical activities because mixing in advance causes medicine
Interphase interaction, affect the treatment.More seriously, the collaboration poisonous effect between different pharmaceutical causes medicine after being blended defeated
Unexpected side reaction may be brought during sending.Therefore, in order to overcome medicine blending transmission to exist the problem of, play medicine
The advantage of synergy anticancer therapy, it is intended that be avoided that the medicine of common load mixes in advance before target spot is reached.
The content of the invention
The technical problems to be solved by the invention are for above shortcomings in the prior art, there is provided one kind has thorn
Swash response and divide storehouse intelligently to carry nanometer particle of medicine drug release feature and preparation method thereof, the present invention is easy to operate, is easy to
Realize, cost is low, and prepared nano-particle can not only intelligent targeting drug release, moreover it is possible to realize that point storehouse carries a medicine and reaches synergistic treatment
Antitumor purpose.
In order to solve the above technical problems, technical scheme provided by the invention is:
A kind of nanometer particle that medicine drug release feature is intelligently carried with stimuli responsive and point storehouse, the mesoporous silicon are provided
Nano-particle is that surface modification has stimuli responsive group and carries medicine using the cyclodextrin of alkynyl modification as " nano-valve " point storehouse
Nanometer particle, its particle diameter is 80-190nm.By such scheme, the stimuli responsive group is disulfide bond.Disulfide bond
For a kind of redox stimuli responsive group, gained nanometer particle is with redox stimuli responsive and divides storehouse intelligent
Carry the medium hole nano particles of medicine drug release.
Present invention additionally comprises the targeted drug prepared according to above-mentioned nanometer particle, the targeted drug is by mesoporous silicon
The some drugs of nanometer particle load 2 obtain, and are separated between 2 some drugs by cyclodextrin.
Present invention additionally comprises the preparation method of above-mentioned targeted drug, its step are as follows:
1) the nanometer particle with surfactant is prepared:By CTAB and NaOH in mass ratio 100:3-7 dissolves
In deionized water, it is then heated to 70-100 DEG C and is stirred vigorously, is uniformly mixing to obtain mixed solution, it is then that TEOS is slow
It is added dropwise in the mixed solution, the TEOS and CTAB mass ratioes are 5-7:1, drop speed is 8-25d/min, is stirred vigorously reaction
2h, centrifugation obtain white solid thing, cleaned respectively with secondary water and methanol, obtain carrying surfactant after vacuum drying
The nanometer particle CTAB@MSN of CTAB MCM-41 types;
2) the nanometer particle of the sulfhydrylation containing surfactant is prepared:CTAB@MSN obtained by step 1) are disperseed
In methanol, ultrasound makes it be uniformly dispersed, and then adds 3-mercaptopropyi trimethoxy silane, at 20-35 DEG C, rotating speed
24h is stirred vigorously under 4000-1000r/min, centrifuges and is cleaned with secondary water and methanol, obtains living containing surface after vacuum drying
The nanometer particle CTAB@MSN-SH of the sulfhydrylation of property agent;
3) the nanometer particle of sulfhydrylation is prepared:CTAB@MSN-SH obtained by step 2) are scattered in methanol, disperseed
After uniformly, concentrated hydrochloric acid is added, after vigorous stirring overnight, reaction is placed at 40-60 DEG C the 24-48h that flows back, by centrifuging, cleaning,
Surfactant CTAB can be effectively extracted after vacuum drying, obtains the nanometer particle MSN-SH of sulfhydrylation;
4) the nanometer particle of double sulfur functionalizations is prepared:MSN-SH obtained by step 3) is scattered in methanol, ultrasound
It is uniformly dispersed, S- (2-aminoethylthio) -2-thiopyridine hydrochloride are then added, violent
In room temperature reaction 24h under stirring condition, centrifuge and cleaned with secondary water and methanol, Jie of double sulfur functionalizations is obtained after vacuum drying
Hole nano silicon particles MSN-SS-NH2;
5) alkynyl-modified double sulfur functionalization nanometer particles are prepared:By MSN-SS-NH obtained by step 4)2It is scattered in
In methanol, ultrasound makes it be uniformly dispersed, and then adds propine bromine and triethylamine (TEA) and is stirred vigorously, reacts at room temperature
24h, centrifuge and cleaned with secondary water and methanol, alkynyl-modified double sulfur functionalization nanometer particles are obtained after vacuum drying
MSN-SS-alkyne;
6) the reduction response type mesoporous silicon controlled drug delivery system A@MSN-SS-CD of carrying medicament A cyclodextrin closure are prepared:
Under the conditions of lucifuge, MSN-SS-alkyne obtained by step 5) is scattered in into methanol and pH value, and for 7.0 PBS, (phosphoric acid delays
Rush solution) mixed solution in, after ultrasonic disperse is uniform, add medicine A salt (such as DOXHCl doxorubicin hydrochlorides), and will be anti-
Answer mixture to be vigorously mixed at room temperature for 24h, then add Azide modification cyclodextrin mono-6-azido- β-CD,
CuSO4·5H2O, sodium ascorbate, in room temperature reaction 3 days under nitrogen atmosphere protection, by centrifuging and with secondary water and methanol
Cleaning, the stimuli responsive type mesoporous silicon controlled drug delivery system of carrying medicament A (such as DOX) cyclodextrin closure is obtained after vacuum drying
A@MSN-SS-CD;
7) prepare with stimuli responsive and the nanometer particle for dividing storehouse intelligently to carry medicine drug release feature:By obtained by step 6)
A@MSN-SS-CD are scattered in methanol and in the mixed solution for the PBS that pH value is 7.0, ultrasonic disperse uniformly adds medicine afterwards
Thing B (such as DMP, 6-MP dimer), 24h being reacted at room temperature, centrifuging 10min, gained solid uses secondary water and first respectively
Alcohol cleans, vacuum drying, and product carries delivery system A@MSN-SS- altogether to be loaded with the double medicines of medicine A and medicine B structure warehouse separated types
CD@B, i.e., with stimuli responsive and the nanometer particle for dividing storehouse intelligently to carry medicine drug release feature.
By such scheme, the step 1) rotating speed being stirred vigorously is 4000-1000r/min.
By such scheme, the step 2) 3-mercaptopropyi trimethoxy silane is 1 with CTAB@MSN mass ratioes:1-2.
By such scheme, the rotating speed of the step 1) centrifugation is 8000r/min-12000r/min, and centrifugation time is
10min。
Preferably, the concentration that step 2) the CTAB@MSN are scattered in methanol is 100mmol/mL.
By such scheme, the rotating speed of the step 2) centrifugation is 8000r/min-12000r/min, and centrifugation time is
10min。
Preferably, described CTAB@MSN-SH obtained by step 2) are scattered in into concentration in methanol is 100mmol/ to step 3)
mL。
By such scheme, step 3) the concentrated hydrochloric acid mass fraction is 37.4%.
Preferably, described MSN-SH obtained by step 3) is scattered in into concentration in methanol is 100mmol/mL to step 4).
Preferably, the step 4) S- (2-aminoethylthio) -2-thiopyridine hydrochloride
It is 1 with MSN-SH mass ratioes:1-2.
By such scheme, the rotating speed of the step 4) centrifugation is 8000r/min-12000r/min, and centrifugation time is
10min。
Preferably, step 5) is by MSN-SS-NH obtained by step 4)2It is 100mmol/mL to be scattered in concentration in methanol.
Preferably, step 5) the propine bromine and triethylamine (TEA) volume ratio are 2-3:1.
By such scheme, the rotating speed of the step 5) centrifugation is 8000r/min-12000r/min, and centrifugation time is
10min。
Preferably, step 6) medicine A salt and MSN-SS-alkyne mass ratioes are 100:3-5.
By such scheme, the rotating speed of the step 6) centrifugation is 8000r/min-12000r/min, and centrifugation time is
10min。
Preferably, the step 6) mono-6-azido- β-CD, CuSO4·5H2O, the mass ratio of sodium ascorbate is
1-2:1:2。
Preferably, step 7) the cancer therapy drug B and cancer therapy drug A mass ratioes are 1:1-2.
By such scheme, the rotating speed of the step 7) centrifugation is 8000r/min, centrifugation time 10min.
By such scheme, it is fast that step 6) and step 7) the medicine A and B are respectively and independently selected from adriamycin, camptothecine, 6- mercaptos
One kind in purine dimer.
First have to control out in the nano-particle for preparing redox stimuli responsive and point storehouse load medicine intelligence targeting drug release
Uniform particle sizes are distributed, the big mesoporous silicon sphere of specific surface area, then can uniformly modify group to be finished in mesoporous silicon
Ball surface.During mesoporous silicon sphere is prepared, CTAB, NaOH, TEOS proportions are controlled, template and silicon source can be ensured
Fully contact, it is all smooth, regular that each mesoporous silicon sphere of formation, which obtains duct, and this release for medicine is particularly significant.
During TEOS is added dropwise, control drop speed is advantageous to nano-particle and forms uniform grading between 8-25d/min.To being situated between
During hole silicon ball surface carries out modification sulfydryl, amino, alkynyl, mercapto reagent, amino agents, alkynyl reagent three are controlled
Ratio between person, so can just make that the modification on mesoporous silicon sphere surface is uniform, and degree of modification reaches 100%, can preferably seal
Medicine in plug-hole, prevent from revealing.The process of the removing template of mesoporous silicon sphere is also vital, controls the dense of concentrated hydrochloric acid
Degree, excessive concentration corrosion mesoporous silicon sphere internal structure, duct inside is uneven, and insoluble drug release is formed and hindered, and concentration is too low
Except Kong Buquan, medicine scarce capacity is loaded.Several final steps regulation experiment schemes, prepare preferable nanometer based on more than
Particle.
The present invention delivery system in the presence of no gst enzyme, cancer therapy drug A (such as adriamycin, DOX) and resist
Cancer drug B (such as 6-MP dimer) is loaded in two no spaces respectively, and one is stored in the hole of mesoporous silicon sphere,
One hydrophobic internal cavities for being stored in cyclodextrin, two kinds of medicines can not be in contact with each other, will not be interfered in cyclic process in vivo,
Mutually have an impact.When reaching in tumour cell, GSH (glutathione) concentration is raised, and mesoporous silicon and ring paste are connected in system
The disulfide bond of essence is chemically reacted by this strong reducible agent of glutathione, disulfide bonds, mesoporous silicon face
" nano-valve " --- cyclodextrin is come off, and the unobstructed cancer therapy drug A releases in duct of mesoporous silicon face, at the same time, cyclodextrin is dredged
Also it is broken simultaneously by GSH stimulation by the cancer therapy drug B of disulfide bond in water inner chamber, the cancer therapy drug of cyclodextrin parcel
B is also discharged, and two kinds of drug adriamycins and 6-MP dimer are released simultaneously, so as to reach the purpose of synergistic treatment.
The beneficial effects of the present invention are:1st, nanometer particle provided by the invention have can be by different pharmaceutical same
The carrier system of accumulating is separated on one carrier, i.e. the double medicine even multiple medicines of warehouse separated type carry delivery system, pass through cyclodextrin nano valve altogether
Effect and response of the stimuli responsive group to extracellular intracellular different stimulated environment, it can realize that the targeting to tumour cell and intelligence are given
Medicine, solves the defects of tradition carries pharmaceutical carrier altogether;2nd, preparation method device provided by the invention be simple and convenient to operate, cost
It is low.
Brief description of the drawings
Fig. 1 is drug release profiles of the DOX@MSN-SS-CD under different GSH concentration prepared by the embodiment of the present invention 1;
Fig. 2 is drug release profiles of the MSN-SS-CD@DMP under different GSH concentration prepared by embodiment 5;
Fig. 3 is drug release profiles of the DOX@MSN-SS-CD@DMP of the preparation of embodiment 1 under different GSH concentration;
Fig. 4 is DOX@MSN-SS-CD, MSN-SS-CD@DMP, DOX@MSN-SS-CD@DMP, MSN-SH tetra- kind material pair
The toxicity profile of A20 cells.
Embodiment
To make those skilled in the art more fully understand technical scheme, the present invention is made below in conjunction with the accompanying drawings into
One step is described in detail.
The mesoporous silicon provided by the invention that medicine targeting drug release characteristic is intelligently carried with redox stimuli responsive and point storehouse is received
Rice corpuscles, its mesoporous silicon have good Drug loading capacity, and stimuli responsive group can receive to stimulate accordingly, are broken at tumour
Stimuli responsive group, also discharged by insoluble drug release in mesoporous silicon duct, and by cyclodextrin packaging medicine, reach collaboration and release
Medicine, the purpose of targeting drug release.
Embodiment 1
Prepare as follows with stimuli responsive and the nanometer particle for dividing storehouse intelligently to carry medicine drug release feature, step:
1) preparation of nanometer particle:0.5gCTAB and 0.015gNaOH is taken to be dissolved in 480mL deionized waters simultaneously
It is stirred vigorously, is then heated to 80 DEG C, be uniformly mixing to obtain mixed solution, then 2.5gTEOS is slowly added dropwise to above-mentioned mixing
In solution, drop speed is 10d/min, reacts on 80 DEG C and is stirred vigorously lower carry out 2h, centrifugation (8000r/min, 10min) obtains white
Solids, cleaned for several times with secondary water and methanol respectively, the MCM-41 with Surfactant CTAB is obtained after vacuum drying
The nanometer particle (CTAB@MSN) of type;
2) preparation of the nanometer particle of the sulfhydrylation containing surfactant:1.3gCTAB@MSN are taken to be scattered in
In 108mL methanol, ultrasound makes it be uniformly dispersed, and it is violent at room temperature then to add 1.3g 3-mercaptopropyi trimethoxy silanes
24h, stir speed (S.S.) 4000r/min are stirred, (8000r/min, 10min) is centrifuged and is cleaned for several times with secondary water and methanol, very
Sky obtains the nanometer particle (CTAB@MSN-SH) of the sulfhydrylation containing surfactant after drying;
3) the nanometer particle of sulfhydrylation is prepared:1.0g CTAB@MSN-SH are weighed to be scattered in 80mL methanol, point
After dissipating uniformly, 3.5mL concentrated hydrochloric acids (mass fraction 37.4%) are added, after vigorous stirring overnight, reaction is placed in 60 DEG C of conditions
Lower backflow 48h, can effectively extract Surfactant CTAB after centrifuging, clean, be dried in vacuo, and obtain Jie of sulfhydrylation
Hole nano silicon particles MSN-SH;
4) preparation (MSN-SS-NH of the nanometer particle of double sulfur functionalizations2):500mg MSN-SH are taken to be scattered in
In 135mL methanol, ultrasound makes it be uniformly dispersed, and then adds 500mg S- (2-aminoethylthio) -2-
Thiopyridine hydrochloride are simultaneously stirred vigorously, and reaction carries out 24h at room temperature, centrifuge (8000r/min,
10min) and with secondary water and methanol clean for several times, the nanometer particle (MSN- of double sulfur functionalizations is obtained after vacuum drying
SS-NH2);
5) preparation (MSN-SS-alkyne) of alkynyl-modified double sulfur functionalization nanometer particles:Take 450mgMSN-
SS-NH2It is scattered in 100mL methanol, ultrasound makes it be uniformly dispersed, and then adds 3mL propine bromine and 1.5mL TEA and acutely stirs
Mix, react 24h at room temperature, centrifuge (8000r/min × 10min) and cleaned for several times with secondary water and methanol, after vacuum drying
Obtain alkynyl-modified double sulfur functionalization nanometer particles (MSN-SS-alkyne);
6) carrying medicament DOX (adriamycin) reduction response type mesoporous silicon controlled drug delivery system (DOX@MSN-SS-CD)
Prepare:Taking 100mgMSN-SS-alkyne to be scattered in the PBS that 5mL methanol and 5mL pH value are 7.0 under the conditions of lucifuge, (phosphoric acid delays
Rush solution) mixed solution in, after ultrasonic disperse is uniform, add 25mg doxorubicin hydrochlorides (DOXHCl), and will reaction mixing
Thing is vigorously mixed at room temperature for 24h, then adds 100mg mono-6-azido- β-CD, 100mg CuSO4·5H2O and
200mg sodium ascorbates, react under nitrogen atmosphere protection in room temperature reaction 3 days, 10min centrifuged under 8000r/min rotating speeds,
Supernatant is removed, bottom white solid thing is obtained, is cleaned for several times with secondary water and methanol, loaded after vacuum drying respectively
The reduction response type mesoporous silicon controlled drug delivery system (DOX@MSN-SS-CD) of medicine DOX cyclodextrin closure;
7) prepare with stimuli responsive and the nanometer particle for dividing storehouse intelligently to carry medicine drug release feature:Weigh 100mg
In the mixed solution for the PBS that DOX@MSN-SS-CD are scattered in 10mL methanol and 10mL pH value is 7.0, after ultrasonic disperse is uniform,
25mgDMP (6-MP dimer) is added, reacts 24h, centrifugation 10min (8000r/min), gained solid difference at room temperature
Cleaned for several times with secondary water and methanol, vacuum drying, product builds warehouse separated type to be loaded with adriamycin and 6-MP dimer
Double medicines carry delivery system (DOX@MSN-SS-CD@DMP) altogether, i.e., with stimuli responsive and Jie for dividing storehouse intelligently to carry medicine drug release feature
Hole silicon nano.
Embodiment 2
Prepared using method similar to Example 1 with stimuli responsive and the mesoporous silicon for dividing storehouse intelligently to carry medicine drug release feature
Nano-particle, difference are:
6) preparation of DOX reduction response type mesoporous silicon controlled drug delivery system (DOX@MSN-SS-CD) is loaded:In lucifuge bar
100mgMSN-SS-alkyne is taken to be scattered in 5mL methanol with the mixed solution for the PBS that 5mLpH values are 7.0, surpassing under part
After sound is uniformly dispersed, 30mg doxorubicin hydrochlorides (DOXHCl) are added, and reactant mixture is vigorously mixed at room temperature for 24h.
Then 50mg mono-6-azido- β-CD, 50mg CuSO are added4·5H2O and 75mg sodium ascorbates, react in blanket of nitrogen
Enclose under protection in room temperature reaction 3 days, by centrifuging and being cleaned for several times with secondary water and methanol, medicine has been loaded after vacuum drying
The reduction response type mesoporous silicon controlled drug delivery system (DOX@MSN-SS-CD) of thing DOX cyclodextrin closure;
7) prepare with stimuli responsive and the nanometer particle for dividing storehouse intelligently to carry medicine drug release feature:Weigh 80mg
DOX@MSN-SS-CD are scattered in 10mL methanol and in the mixed solution for the PBS that 10mL pH value is 7.0, ultrasonic disperse is equal
After even, 60mgDMP is added, reacts 24h at room temperature, gained solid is cleaned for several times with secondary water and methanol respectively after centrifugation, very
Sky is dried, and product builds the double medicines of warehouse separated type and carry delivery system (DOX@MSN- altogether to be loaded with adriamycin and 6-MP dimer
SS-CD@DMP), i.e., with stimuli responsive and the nanometer particle for dividing storehouse intelligently to carry medicine drug release feature.
Embodiment 3
Prepare as follows with stimuli responsive and the nanometer particle for dividing storehouse intelligently to carry medicine drug release feature, step:
1) preparation of nanometer particle:0.2gCTAB and 0.014gNaOH is taken to be dissolved in 480mL deionized waters simultaneously
It is stirred vigorously, is then heated to 80 DEG C, be uniformly mixing to obtain mixed solution, then 1.6gTEOS is slowly added dropwise to above-mentioned solution
In, drop speed be 15d/min, reacts on 70 DEG C and is stirred vigorously lower carry out 2h, centrifuges and obtains white solid thing, respectively with secondary water with
Methanol is cleaned for several times, and the nanometer particle of the MCM-41 types with Surfactant CTAB is obtained after vacuum drying
(CTAB@MSN);
2) preparation (MSN-SH) of the nanometer particle of the sulfhydrylation containing surfactant:Take 1.3gCTAB@MSN
It is scattered in 108mL methanol, ultrasound makes it be uniformly dispersed, and then adds 2.6g 3-mercaptopropyi trimethoxy silanes in room temperature
Under be stirred vigorously 24h, centrifuge and simultaneously cleaned for several times with secondary water and methanol, the sulfydryl containing surfactant is obtained after vacuum drying
The nanometer particle (CTAB@MSN-SH) of change;
3) preparation of the nanometer particle of sulfhydrylation:1.0g CTAB@MSN-SH are weighed to be scattered in 80mL methanol,
After being uniformly dispersed, 5mL concentrated hydrochloric acids (mass fraction 37.4%) are added, after vigorous stirring overnight, reaction is placed in 40 DEG C of conditions
Lower backflow 48h, can effectively extract Surfactant CTAB after centrifuging, clean, be dried in vacuo, and obtain Jie of sulfhydrylation
Hole nano silicon particles MSN-SH;
4) preparation (MSN-SS-NH of the nanometer particle of double sulfur functionalizations2):500mgMSN-SH is taken to be scattered in
In 135mL methanol, ultrasound makes it be uniformly dispersed, and then adds 1000mg S- (2-aminoethylthio) -2-
Thiopyridine hydrochloride are simultaneously stirred vigorously, and reaction carries out 24h at room temperature, are centrifuged and with secondary water and methanol
Cleaning obtains the nanometer particle (MSN-SS-NH of double sulfur functionalizations for several times, after vacuum drying2);
5) preparation (MSN-SS-alkyne) of alkynyl-modified double sulfur functionalization nanometer particles:Take 450mgMSN-
SS-NH2It is scattered in 100mL methanol, ultrasound makes it be uniformly dispersed, and then adds 6mL propine bromine and 2mL TEA and acutely stirs
Mix, react 24h at room temperature, centrifuge and cleaned for several times with secondary water and methanol, alkynyl-modified double sulphur are obtained after vacuum drying
Functional mesoporous nano silicon particles (MSN-SS-alkyne);
6) preparation of DOX reduction response type mesoporous silicon controlled drug delivery system (DOX@MSN-SS-CD) is loaded:In lucifuge bar
Under part, in the mixed solution for taking the PBS that 100mgMSN-SS-alkyne is scattered in 5mL methanol and 5mL pH value is 7.0,
After ultrasonic disperse is uniform, 5mg DOXHCl are added, and reactant mixture is vigorously mixed at room temperature for 24h, are then added
200mg mono-6-azido-β-CD、100mg CuSO4·5H2O and 200mg sodium ascorbates, react and protected in nitrogen atmosphere
In room temperature reaction 3 days under shield, by centrifuging and being cleaned for several times with secondary water and methanol, medicine has been loaded after vacuum drying
The reduction response type mesoporous silicon controlled drug delivery system (DOX@MSN-SS-CD) of DOX cyclodextrin closure;
7) prepare with stimuli responsive and the nanometer particle for dividing storehouse intelligently to carry medicine drug release feature:Weigh 80mg
In the mixed solution for the PBS that DOX@MSN-SS-CD are scattered in 10mL methanol and 10mL pH value is 7.0, after ultrasonic disperse is uniform,
10mgDMP is added, reacts 24h at room temperature, centrifuges 10min, gained solid is cleaned for several times with secondary water and methanol respectively, vacuum
Dry, product builds the double medicines of warehouse separated type and carry delivery system (DOX@MSN-SS- altogether to be loaded with adriamycin and 6-MP dimer
CD@DMP), i.e., with stimuli responsive and the nanometer particle for dividing storehouse intelligently to carry medicine drug release feature.
Embodiment 4
Prepare as follows with stimuli responsive and the nanometer particle for dividing storehouse intelligently to carry medicine drug release feature, step:
1) preparation of nanometer particle:0.78gCTAB and 0.24gNaOH is taken to be dissolved in 480mL deionized waters simultaneously
It is stirred vigorously, is then heated to 80 DEG C, be uniformly mixing to obtain mixed solution, then 1.83gTEOS is slowly added dropwise to above-mentioned molten
In liquid, drop speed is 20d/min, reacts on 100 DEG C and is stirred vigorously lower carry out 2h, centrifugation obtains white solid thing, respectively with secondary
Water and methanol cleaning obtain the nanometer particle of the MCM-41 types with Surfactant CTAB for several times, after vacuum drying
(CTAB@MSN);
2) preparation of the nanometer particle of the sulfhydrylation containing surfactant:1.3gCTAB@MSN are taken to be scattered in
In 108mL methanol, ultrasound makes it be uniformly dispersed, and it is violent at room temperature then to add 2.2g 3-mercaptopropyi trimethoxy silanes
24h, stir speed (S.S.) 8000r/min are stirred, centrifuges and is cleaned for several times with secondary water and methanol, obtained after vacuum drying containing table
The nanometer particle (CTAB@MSN-SH) of the sulfhydrylation of face activating agent;
3) the nanometer particle of sulfhydrylation is prepared:Weigh 1.0gCTAB@MSN to be scattered in 80mL methanol, disperse equal
After even, 4.2mL concentrated hydrochloric acids (mass fraction 37.4%) are added, after vigorous stirring overnight, reaction is placed in 50 DEG C of conditions next time
48h is flowed, Surfactant CTAB can be effectively extracted after centrifuging, clean, be dried in vacuo, obtains the mesoporous silicon of sulfhydrylation
Nano particle (MSN-SH);
4) preparation (MSN-SS-NH of the nanometer particle of double sulfur functionalizations2):500mgMSN-SH is taken to be scattered in
In 135mL methanol, ultrasound makes it be uniformly dispersed, and then adds 800mg S- (2-aminoethylthio) -2-
Thiopyridine hydrochloride are simultaneously stirred vigorously, and reaction carries out 24h at room temperature, are centrifuged and with secondary water and methanol
Cleaning obtains the nanometer particle (MSN-SS-NH of double sulfur functionalizations for several times, after vacuum drying2);
5) preparation (MSN-SS-alkyne) of alkynyl-modified double sulfur functionalization nanometer particles:Take 450mgMSN-
SS-NH2It is scattered in 100mL methanol, ultrasound makes it be uniformly dispersed, and then adds 3mL propine bromine and 1.2mL TEA and acutely stirs
Mix, react 24h at room temperature, centrifuge (12000r/min, 10min) and cleaned for several times with secondary water and methanol, after vacuum drying
Obtain alkynyl-modified double sulfur functionalization nanometer particles (MSN-SS-alkyne);
6) preparation of DOX reduction response type mesoporous silicon controlled drug delivery system (DOX@MSN-SS-CD) is loaded:In lucifuge bar
In the mixed solution that the PBS that 100mgMSN-SS-alkyne is scattered in 5mL methanol and 5mLpH values are 7.0 is taken under part, ultrasonic disperse
After uniformly, 20mg DOXHCl are added, and reactant mixture is vigorously mixed at room temperature for 24h, then add 25mgmono-
6-azido-β-CD、25mg CuSO4·5H2O and 50mg sodium ascorbates, react under nitrogen atmosphere protection in room temperature reaction
3 days, by centrifuging (12000r/min, 10min) and being cleaned for several times with secondary water and methanol, medicine has been loaded after vacuum drying
The reduction response type mesoporous silicon controlled drug delivery system (DOX@MSN-SS-CD) of thing DOX cyclodextrin closure, all processes are kept away as far as possible
Light;
7) prepare with stimuli responsive and the nanometer particle for dividing storehouse intelligently to carry medicine drug release feature:Weigh 100mg
DOX@MSN-SS-CD are scattered in 10mL methanol and in the mixed solution for the PBS that 10mL pH value is 7.0, ultrasonic disperse uniformly adds afterwards
Enter 20mgDMP, react 24h, centrifugation 10min (12000r/min) at room temperature, gained solid uses secondary water and methanol clear respectively
Wash for several times, vacuum drying, product builds the double medicines of warehouse separated type and carry delivery system altogether to be loaded with adriamycin and 6-MP dimer
(DOX@MSN-SS-CD@DMP), i.e., with stimuli responsive and the nanometer particle for dividing storehouse intelligently to carry medicine drug release feature.
Embodiment 5
Prepare MSN-SS-CD@DMP:The MSN-SS-CD for weighing the preparation of 80mg embodiments 1 is scattered in 10mL methanol and 10mL
PH value is in 7.0 PBS mixed solution, after ultrasonic disperse is uniform, adds 25mg DMP, reacts 24h at room temperature,
10min is centrifuged under 8000r/min rotating speeds, supernatant is removed, obtains bottom white solid thing, cleaned respectively with secondary water and methanol
Three times, it is dried in vacuo, products therefrom is the delivery system (MSN-SS-CD@DMP) for being loaded with 6-MP dimer.
Test DOX@MSN-SS-CD (prepared by embodiment 1), MSN-SS-CD@DMP (the present embodiment preparation), DOX@MSN-
The body for the solution (load concentration is 0.005mg/mL) that the concentration that SS-CD@DMP (prepared by embodiment 1) are configured to is 1mmol/mL
Outer Release Performance and cytotoxicity.
First, the double medicament-carried nano intelligent medicine releasing system tablets in vitro of warehouse separated type
In order to study the release Mechanisms of three groups of different materials, and whether enough release the drug simultaneously, release the drug the whether mutual shadow of degree
The characteristics such as sound, it is ad hoc to set to 0 mM GSH, 1M GSH, the GSH of tri- kinds of various concentrations of 10M GSH, research DOX@MSN-SS-CD, MSN-
SS-CD@DMP, DOX@MSN-SS-CD@DMP these three different materials drug release feature.This research uses dialysis, determines medicine
Release, and then evaluate the Release Performance of three kinds of materials, concrete operations are as follows:(1) bag filter of 9 sections of 15cm length 3500, leaching are taken
Bubble treats that bag filter softens completely 3 hours in 50ml PBS (pH7.0) solution, stand-by;(2) precision weighs DOX@MSN-SS-
CD, MSN-SS-CD@DMP, DOX@MSN-SS-CD@each 1mg of DMP, No. 1 sample of numbering in 10mLPBS (pH7.0) is dispersed in respectively
Product, No. 2 samples and No. 3 samples, are uniformly dispersed under ultrasonic vibration, stand-by;(4) 0mM GSH, 1M GSH, 10M are prepared respectively
GSH solution, it is fitted into 9 50ml centrifuge tubes and indicates 1a, 1b, 1c and 2a, 2b, 2c and 3a, 3b, 3c, it is stand-by;
Three kinds of each 1mL of sample are taken, are fitted into bag filter, end-blocking is respectively charged into 3 flexible pipes, and centrifuge tube is put into 37 DEG C of perseverances
In warm concussion instrument, per 1mmL is sampled in 9 centrifuge tubes every other hour, respective concentration GSH solution is then supplemented;(5) will take out
Sample carry out drug concentration analysis, calculate sample medicine realeasing rate using standard curve, make DOX@MSN-SS-CD, MSN-SS-
CD@DMP, DOX@MSN-SS-CD@3 kinds of different samples of DMP drug release profiles.
DOX@MSN-SS-CDs of the Fig. 1 prepared by the embodiment of the present invention 1 drug release profiles, A, B, C under different GSH concentration
Three curves represent material DOX in 10mM, 1mM, 0mMGSH drug release profiles respectively, DOX drug release under the conditions of 10mM GSH
Under the conditions of rate reaches 85% or so, 1mM GSH, only 40% or so drug release, and under 0mM GSH, medicine realeasing rate is 3% or so, this
Illustrate under the conditions of high concentration GSH, intelligence " nano-valve " is opened, and the DOX that medicine is loaded in MSN skies can smoothly discharge
Out.
Drug release figures of MSN-SS-CD@DMPs of the Fig. 2 prepared by embodiment 5 under different GSH concentration, tri- songs of A, B, C
Line represents material DOX in 10mM, 1mM, 0mMGSH drug release profiles respectively, and DMP medicine realeasing rate reaches under the conditions of 10mMGSH
Under the conditions of 85% or so, 1mMGSH, 45% or so drug release, and under 0mM GSH, medicine realeasing rate is 1% or so.This explanation cyclodextrin bag
The DMP wrapped up in can smoothly discharge under GSH stimulation.Under 0mM GSH, DOX@MSN-SS-CD and MSN-SS-CD@DMP this two
The pharmaceutical carrier that kind individually carries medicine has a certain degree of drug release, and DOX drug release amount is more than DMP, because
Medicine can be adsorbed in loading process on the surface of material, and mesoporous silicon is easier to adsorb medicine than the surface of cyclodextrin, so dress
The pharmaceutical carrier for carrying DOX has adsorbed more medicines, and the amount of leakage of medicine is bigger than DMP under 0mM.
Fig. 3 is that DOX@MSN-SS-CD@DMP prepared by embodiment 1 release the drug figure under different GSH concentration, curve A, C, F generation
Table material respectively under 10mM, 1mM, 0mMGSH concentration DOX release profiles, curve B, D, E represent material respectively 10mM,
DMP drug release profiles under 1mM, 0mMGSH concentration, under the conditions of 10mM GSH, the medicine realeasing rate of adriamycin is kept approximately constant, 6-
The release of mercaptopurine is on adriamycin without influenceing, but the drug release amount of 6-MP is affected, and cumulative release amount is less than
80%.Under the conditions of 1mM GSH, the drug release amount of adriamycin is still constant, but the drug release amount of 6-MP only has 15% or so,
Drug release amount of the 6-MP in medicine carrying material is mixed is by a certain degree of suppression, because in the certain condition of GSH concentration
Under, adriamycin release is relied on exposed to the disulfide bond between mesoporous silicon and cyclodextrin, is wrapped in than what 6-MP release relied on
Disulfide bond in beta-schardinger dextrin is more easily accessible to GSH, so adriamycin first discharges than mercaptopurine, after consuming certain GSH,
GSH concentration reduces, and the disulfide bond being wrapped in cyclodextrin cavity is because GSH concentration reduces, and fracture amount is reduced, so DMP drug release
Amount is affected, and is reduced with burst size when individually carrying DMP.Two kinds of medicines of 6-MP and adriamycin are under the conditions of 1mM GSH
There is certain release, and with accumulation.
The system of this experimental design is can be seen that according to the drug release profiles of three groups of samples, there is GSH stimulating responsives, and
And DOX@MSN-SS-CD@DMP systems can keep " zero release " before tumour cell is reached, and can be by two kinds of medicines
Different spaces are stored in, avoid mixing in advance, are released the drug rapidly after reaching tumour cell.
2nd, the double medicament-carried nano intelligent medicine releasing system cytotoxicities of warehouse separated type
This experiment determines the toxicity of three kinds of different materials using CKK-8 methods, and specific method is as follows:By A20 cells with 5 ×
104Individual/hole is inoculated on the glass cover-slip of 12 orifice plates, and each hole adds the DMEM culture medium 1.5mL containing 10% hyclone,
37 DEG C are placed in, 5%CO2Cultivated in constant incubator.8h is cultivated, 10 microlitres is separately added into and contains DOX@MSN-SS-CD, MSN-
SS-CD@DMP, DOX@MSN-SS-CD@DMP solution, and the nutrient solution containing nano particle MSN-SH (prepared by embodiment 1)
(10 microlitres) totally four groups of materials, wherein the nutrient solution containing nano particle MSN-SH is negative control group.Four groups of materials are placed in
48h is incubated in incubator altogether.The CKK-8 of 10 micrograms is added, is co-cultured 24 hours, methanol is added, with 90% glycerine mounting, is placed in
Observed under cytotoxic cell instrument.
Four groups of materials are as shown in Figure 4 to the cytotoxicity curve of A20 cells.It can be seen that carefully by Fig. 4-middle MSN-SH curves
For born of the same parents' survival rate 85% or so, it is hypotoxicity in itself to illustrate mesoporous silicon sphere nano-particle, is a kind of good pharmaceutical carrier,
There is good biocompatibility in organism.As seen from Figure 4, collaboration carries the DOX@MSN-SS-CD@DMP of medicine half
Lethal dose is 0.8 μ g/mL, than the DOX@MSN-SS-CD for individually carrying medicine the μ g/mL of median lethal dose 3.2 and individually load medicine
The MSN-SS-CD@DMP μ g/mL of median lethal dose 5.7 are much low, illustrate the system of collaboration load medicine and can not only smoothly discharge
Medicine poisons tumour cell with poison, moreover it is possible to which the system than individually carrying medicine more efficiently poisons tumour cell with poison.The double medicament-carried nanos of warehouse separated type
Particle has the ability of stronger antitumor cell, can make two kinds of medicines while play effect, reach the purpose of synergistic treatment.
In summary, there is the material redox stimuli responsive and point storehouse to carry medicine intelligence targeting drug release function, to tumour
Treatment have a clear superiority.
Claims (9)
1. with stimuli responsive and the nanometer particle for dividing storehouse intelligently to carry medicine drug release feature, it is characterised in that:It is described mesoporous
Silicon nano is that surface modification is had stimuli responsive group and carried using the cyclodextrin of alkynyl modification as " nano-valve " point storehouse
The nanometer particle of medicine, its particle diameter are 80-190nm.
2. nanometer particle according to claim 1, it is characterised in that:The stimuli responsive group is disulfide bond.
3. targeted drug prepared by a kind of nanometer particle according to claim 1 or 2, it is characterised in that described
Targeted drug loads 2 some drugs by nanometer particle and obtained, and is separated between 2 some drugs by cyclodextrin
Open.
4. the preparation method of the targeted drug described in a kind of claim 3, it is characterised in that step is as follows:
1) the nanometer particle with surfactant is prepared:By CTAB and NaOH in mass ratio 100:3-7 is dissolved in
In ionized water, it is then heated to 70-100 DEG C and is stirred vigorously, is uniformly mixing to obtain mixed solution, then TEOS is slowly added dropwise
Into the mixed solution, the TEOS and CTAB mass ratioes are 5-7:1, drop speed is 8-25d/min, is stirred vigorously reaction 2h,
Centrifugation obtains white solid thing, is cleaned respectively with secondary water and methanol, obtains carrying Surfactant CTAB after vacuum drying
MCM-41 types nanometer particle CTAB@MSN;
2) the nanometer particle of the sulfhydrylation containing surfactant is prepared:CTAB@MSN obtained by step 1) are scattered in first
In alcohol, ultrasound makes it be uniformly dispersed, and then adds 3-mercaptopropyi trimethoxy silane, at 20-35 DEG C, rotating speed 4000-
24h is stirred vigorously under 1000r/min, centrifuges and is cleaned with secondary water and methanol, obtained after vacuum drying containing surfactant
Sulfhydrylation nanometer particle CTAB@MSN-SH;
3) the nanometer particle of sulfhydrylation is prepared:CTAB@MSN-SH obtained by step 2) are scattered in methanol, are uniformly dispersed
Afterwards, concentrated hydrochloric acid is added, after vigorous stirring overnight, reaction is placed at 40-60 DEG C the 24-48h that flows back, by centrifuging, cleaning, vacuum
Surfactant CTAB can be effectively extracted after drying, obtains the nanometer particle MSN-SH of sulfhydrylation;
4) the nanometer particle of double sulfur functionalizations is prepared:MSN-SH obtained by step 3) is scattered in methanol, ultrasound makes it
It is uniformly dispersed, then adds S- (2-aminoethylthio) -2-thiopyridine hydrochloride, be stirred vigorously
Under the conditions of in room temperature reaction 24h, centrifuge and simultaneously cleaned with secondary water and methanol, the mesoporous silicon of pair sulfur functionalizations is obtained after vacuum drying
Nano particle MSN-SS-NH2;
5) alkynyl-modified double sulfur functionalization nanometer particles are prepared:By MSN-SS-NH obtained by step 4)2It is scattered in methanol
In, ultrasound makes it be uniformly dispersed, and then adds propine bromine and triethylamine and is stirred vigorously, react 24h at room temperature, centrifuges and be used in combination
Secondary water and methanol cleaning, obtain alkynyl-modified double sulfur functionalization nanometer particle MSN-SS- after vacuum drying
alkyne;
6) the reduction response type mesoporous silicon controlled drug delivery system A@MSN-SS-CD of carrying medicament A cyclodextrin closure are prepared:Keeping away
Under optical condition, MSN-SS-alkyne obtained by step 5) is scattered in mixed solution of the methanol with pH value for 7.0 PBS
In, after ultrasonic disperse is uniform, medicine A salt is added, and reactant mixture is vigorously mixed at room temperature for 24h, then add folded
Nitrogenize cyclodextrin mono-6-azido- β-CD, the CuSO of modification4·5H2O, sodium ascorbate, in room under nitrogen atmosphere protection
Temperature reaction 3 days, by centrifuging and being cleaned with secondary water and methanol, carrying medicament A cyclodextrin closure is obtained after vacuum drying
Stimuli responsive type mesoporous silicon controlled drug delivery system A@MSN-SS-CD;
7) prepare with stimuli responsive and the nanometer particle for dividing storehouse intelligently to carry medicine drug release feature:By A@obtained by step 6)
MSN-SS-CD is scattered in methanol and in the mixed solution for the PBS that pH value is 7.0, ultrasonic disperse uniformly adds medicine afterwards
B, 24h being reacted at room temperature, centrifuging 10min, gained solid is cleaned with secondary water and methanol respectively, is dried in vacuo, product is negative
It is loaded with the double medicines of medicine A and medicine B structure warehouse separated types and carries delivery system A MSN-SS-CD B altogether, i.e., with stimuli responsive and Fen Cang
Intelligence carries the nanometer particle of medicine drug release feature.
5. preparation method according to claim 4, it is characterised in that:Step 2) the 3-mercaptopropyi trimethoxy silane
It is 1 with CTAB@MSN mass ratioes:1-2.
6. preparation method according to claim 4, it is characterised in that:Step 4) the S- (2-aminoethylthio)-
2-thiopyridine hydrochloride are 1 with MSN-SH mass ratioes:1-2.
7. preparation method according to claim 4, it is characterised in that:Step 6) medicine A salt and MSN-SS-
Alkyne mass ratioes are 100:3-5.
8. preparation method according to claim 4, it is characterised in that:Step 6) mono-6-azido- β-the CD,
CuSO4·5H2O, the mass ratio of sodium ascorbate is 1-2:1:2.
9. preparation method according to claim 4, it is characterised in that:Step 6) and step 7) the medicine A and B difference are only
Vertical one kind in adriamycin, camptothecine, 6-MP dimer.
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