CN106729746B - To the preparation method and applications of the tumor infiltrating nanosystems of the partial size shrinkage type of FAP- α enzyme, reducing environment sensitive - Google Patents
To the preparation method and applications of the tumor infiltrating nanosystems of the partial size shrinkage type of FAP- α enzyme, reducing environment sensitive Download PDFInfo
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Abstract
The present invention relates to FAP- α enzyme, the preparation method and applications of the tumor infiltrating nanosystems of the partial size shrinkage type of reducing environment sensitive, it is poor that targeting in convenient administration system can effectively be solved, toxic side effect is big, it has a single function, poor permeability, it is difficult to overcome the problems, such as tumor microenvironment biological barrier, its solve technical solution be, adriamycin is connected to form reduction responsive type nanoparticle as linking arm and daiamid by disulfide bond, then this nanoparticle is connected to form by the polypeptide linking arm sensitive to FAP- α to FAP- α, the tumor infiltrating treatment nanosystems of the partial size shrinkage type of reducing environment sensitive, the present invention has good biocompatibility, enzyme and reducing environment dual-sensitivity, high osmosis and the advantages that can effectively overcome tumor microenvironment biological barrier, it is drug system in oncotherapy Innovation in agent.
Description
Technical field
The present invention relates to field of medicaments, especially a kind of pair of FAP- α enzyme, reducing environment sensitive partial size shrinkage type it is swollen
The preparation method and applications of tumor permeability nanosystems.
Background technique
Ascendant trend is presented in the disease incidence of malignant tumour in recent years, and malignant tumour is current global major causes of death
One of, have become the major class disease for seriously endangering human life and health, therefore various novel anti-tumor drugs and nanometer
Drug delivery system comes into being.However, the therapeutic efficiency of many anticancer drugs and drug delivery system always falls flat, this master
If due to the biological barrier effect of tumor microenvironment, so that anticancer drug can not efficient arrival tumor locus performance work
With.Wherein, barrier action is the most significantly exactly the carcinoma-associated fibroblasts for being enclosed in tumour cell periphery.
Carcinoma-associated fibroblasts (carcinoma-associated fibroblasts, CAF) are morphologically a kind of
The irregular big spindle cell of nucleus, is in continuous activation state compared with normal fibroblast, and molecular marker for increased proliferation is often secreted
Some growth factors promote the growth and migration of tumour, also specific expressed some albumen, such as fibroblast activation protein
(Fibroblast activation protein α, FAP- α) etc., and one layer of fine and close fibrosis is formed in tumour cell periphery
Apparent protective barrier, therefore carcinoma-associated fibroblasts (CAF) are expected to become the effect target of most worthy in tumor microenvironment
One of point.
Polypeptide chain Thr-Ser-Gly-Pro-Asn-Gln, AC-Asp-Ala-Thr-Gly-Pro-Ala, Ala-Ser-Gly-
Pro-Asn-Gln and Thr-Gly-Pro-Ala etc. is used as polypeptide linking arm, is specific expressed to carcinoma-associated fibroblasts
Albumen FAP- alpha specific sensitivity, the rapid disconnected of specificity is capable of in the FAP- α for touching carcinoma-associated fibroblasts surface
It splits, shows stronger enzyme sensitive active, be expected to realize the targeting to CAF, to overcome this biological barrier of CAF to provide
Good condition.
Daiamid (polyamidoamine, PAMAM) is used as high dispersion dose and stabilizer, the conjunction for nanoparticle
At there is good application value in terms of nano-complex.PAMAM also has a large amount of end moieties, can carry out different
Functional modification modification, and then well as drug, gene, vaccine carrier, for medicament slow release, targeting drug release, in vitro
Diagnosis, outer-gene transfer and gene therapy etc..As medical carrier, the toxic side effect compared with inorganic carrier is small for it, biofacies
Capacitive is good, safety is higher.PAMAM dendrimer is since its special structure can also be used in NMR imaging, as PAMAM is contained
Gadolinium (Gd) can be used as a kind of very promising paramagnetic resonance imaging (MRI) contrast agent.
Adriamycin (Doxorubicin, DOX) is a kind of antitumor antibiotics, can inhibit the synthesis of RNA and DNA, to RNA
Inhibiting effect it is most strong, antitumor spectra is wider, have effect to kinds of tumors, as breast cancer, lung cancer, soft tissue neoplasm, osteosarcoma,
Bladder cancer etc. belongs to cell cycle nonspecific agent (CCNSA), has killing effect to the tumour cell of various growth cycles.It has listed at present
Many toxic reactions are generated due to lacking targeting when doxorubicin hydrochloride injection clinically uses, such as cardiac toxic inhibits
Hemopoietic function of bone marrow and gastrointestinal reaction etc..
Up to the present, the drug delivery system clinically applied still have lack targeting, toxic side effect are big, have a single function,
It is difficult to overcome the disadvantage of tumor microenvironment biological barrier etc..Because the invention one kind has, targeting is strong, toxic side effect is small, multi-functional
Can effectively overcome biological barrier improve anti-cancer effectiveness drug delivery system be a technical problem to be solved urgently.
Summary of the invention
For above situation, in order to overcome the drawbacks of the prior art, the purpose of the present invention is just to provide a kind of couple of FAP- α
Enzyme, reducing environment sensitive partial size shrinkage type tumor infiltrating nanosystems preparation method and applications, can effectively solve
The targeting that certainly existing anti-tumor drug is used for oncotherapy is poor, toxic side effect is big, has a single function, is difficult to overcome biological barrier etc.
Problem.
The technical solution that the present invention solves is that adriamycin (DOX) is by disulfide bond as linking arm and daiamid
(PAMAM) it is connected to form reduction responsive type nanoparticle (DOX-S-S-PAMAM), is then passed through this nanoparticle sensitive to FAP- α
Polypeptide linking arm be connected to form to the tumor infiltrating nanosystems of the partial size shrinkage type of FAP- α, reducing environment sensitive (i.e.
Nanometer formulation DOX-S-S-PAMAM-peptide-DOX-S-S-PAMAM, abbreviation DSP-pep-DSP), the disulfide bond is 3,
3 '-dithiodipropionic acids or 2,2 '-two thiodiglycolic acids, polypeptide linking arm are threonine-Serine-Glycine-proline-day
Winter amide-glutamine (Thr-Ser-Gly-Pro-Asn-Gln) or AC- Asp-Ala-threonine-glycine-dried meat
Propylhomoserin-alanine (AC-Asp-Ala-Thr-Gly-Pro-Ala) or Alanine-Serine-Gly-Pro-asparagus fern acyl
Amine-glutamine (Ala-Ser-Gly-Pro-Asn-Gln) or threonine-Gly-Pro-alanine (Thr-Gly-
Pro-Ala) etc., it comprises the concrete steps that:
(1) nanoparticle (DOX-S-S-PAMAM) of synthesis reduction responsive type:
1. it weighs as 3, the 3 '-dithiodipropionic acid of disulfide bond of linking arm or 2,2 '-two thiodiglycolic acid 10mg-2g,
It is separately added into 2.0~15.0ml chloroacetic chloride, is placed in flask, flow back 2~6h under 65 DEG C of oil baths, after reactant is concentrated
The ether of 3~4 times of pre-coolings, cooling crystallization is added, vacuum drying obtains 3,3 '-dithio dipropyl acid anhydrides or 2,2 '-two thio diethyls
Acid anhydrides；
2. weigh 0.01~1.0mmolDOX, 0.01~1.0mmol4- dimethylamino naphthyridine (DMAP) and 0.01~
1.0mmol step 1. in acid anhydrides obtained be dissolved separately in 0.5~15.0ml reaction dissolvent, DOX and DMAP solution is mixed,
20~200 μ l triethylamines (TEA) are added, anhydride solution is added in Xiang Shangshu solution, it is protected from light 8 at 25~45 DEG C~for 24 hours,
The ether of 3~4 times of pre-coolings, cooling crystallization is added in reaction after stopping, vacuum drying obtains the adriamycin (DOX-S-S- of carboxylated
COOH)；
3. weighing adriamycin (DOX-S-S-COOH) 20~100mg of carboxylated, 1- ethyl-(3- dimethylaminopropyl)
It is molten that carbodiimide (EDC) 100~250mg and HOSu NHS (NHS) 60~180mg is dissolved separately in 5~25mL reaction
In agent, first DOX-S-S-COOH and EDC solution are mixed, react 0.5~3h, adds NHS solution, 0.5~4h is reacted, obtains work
The carboxylated adriamycin (DOX-S-S-COO-NHS) of change takes daiamid (PAMAM) 10~150mg to be dissolved in 3~12mL reaction
In solvent, add 10~200 μ lTEA, then DOX-S-S-COO-NHS and PAMAM solution is mixed, the nitrogen protection at 20~45 DEG C
6~26h is reacted, is dialysed 2 days with the bag filter of molecular cut off 3500 after reaction, dialyzate is ultrapure water, and every 3~6 is small
When change a water, be freeze-dried, the nanoparticle (DOX-S-S-PAMAM) of responsive type must be restored；
The reaction dissolvent is dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF) it is one or two kinds of
The mixture of the similar solvent such as mixture or formamide and similar solvent；
(2) nanoparticle (DSP-pep-DSP) to FAP- α, reducing environment sensitive is synthesized:
Weigh 2~100mg of polypeptide chain as linking arm, 15~180mg of EDC 20~200mg and NHS is dissolved separately in
In 2~20mL reaction dissolvent, then polypeptide linking arm and EDC solution are mixed, 0.5~2.5h is reacted, adds NHS solution,
0.5~3.5h is reacted, the polypeptide linking arm of activation is obtained, takes the nanoparticle (DOX-S-S- for having loaded the reduction responsive type of adriamycin
PAMAM) 10~200mg is dissolved in 5~25mL reaction dissolvent, then the polypeptide linking arm of activation and above-mentioned nanoparticle solution are mixed
It closes, 8~25h of nitrogen protection at 20~40 DEG C, after reaction with the bag filter dialysis 2 of molecular cut off 3500~8000
It, dialyzate is ultrapure water, and every 3~6h changes a water, and freeze-drying obtains the nanoparticle of FAP- α, reducing environment sensitive
(DSP-pep-DSP)；I.e. to the tumor infiltrating nanosystems of the partial size shrinkage type of FAP- α enzyme, reducing environment sensitive；
The polypeptide linking arm is Thr-Ser-Gly-Pro-Asn-Gln or AC-Asp-Ala-Thr-Gly-Pro-Ala
Or Ala-Ser-Gly-Pro-Asn-Gln or Thr-Gly-Pro-Ala, reaction dissolvent are dimethyl sulfoxide (DMSO), N, N- bis-
The mixture of the similar solvent such as one or two kinds of mixture or formamide of methylformamide (DMF) and similar solvent.
The tumor infiltrating nanosystems of partial size shrinkage type prepared by the present invention to FAP- α enzyme, reducing environment sensitive
The biological barrier of tumor microenvironment can effectively be overcome, and then curative effect is played to tumour cell, realization is preparing new antitumoral medicine
Application in object.
Synthesis technology of the present invention is simple and convenient, has good biocompatibility, high targeting, reduction responsive type, enzyme quick
Perception, hypotoxicity and the advantages that can effectively overcome tumor microenvironment biological barrier, are the wounds treated on tumour pharmaceutical formulations
Newly.
Specific embodiment
It elaborates with reference to embodiments to a specific embodiment of the invention.
Embodiment 1
The present invention in specific implementation, can be realized by following steps:
(1) nanoparticle (DOX-S-S-PAMAM) of synthesis reduction responsive type:
1. weighing 2 as linking arm, 2 '-two thiodiglycolic acid 109mg and chloroacetic chloride 3ml are placed in flask, at 65 DEG C
Flow back 2h under oil bath, and the ether of 3 times of pre-coolings, cooling crystallization are added after reactant is concentrated, and vacuum drying obtains 2,2 '-two
Thiodiglycolic acid acid anhydride；
2. weighing 0.3mmolDOX, 0.3mmol4- dimethylamino naphthyridine (DMAP) and 0.3mmol2,2 '-two thio diethyls
Acid anhydrides is dissolved separately in 5mlN, in dinethylformamide (DMF)；DOX and DMAP solution is mixed, 20 μ l triethylamines are added
(TEA), 2,2 '-two thiodiglycolic acid anhydride solutions are added in Xiang Shangshu solution, 8h is protected from light at 35 DEG C, reaction adds after stopping
Enter the ether of 3 times of pre-coolings, cooling crystallization, vacuum drying obtains the adriamycin (DOX-S-S-COOH) of carboxylated；
3. weighing adriamycin (DOX-S-S-COOH) 20mg, 1- ethyl-(3- dimethylaminopropyl) carbon two of carboxylated
Imines (EDC) 100mg and HOSu NHS (NHS) 80mg are dissolved separately in 6mL dimethyl sulfoxide (DMSO), then will
DOX-S-S-COOH solution and EDC solution react 0.5h, add NHS solution reaction 1h, obtain the carboxylated adriamycin of activation
(DOX-S-S-COO-NHS), it takes daiamid (PAMAM) 30mg to be dissolved in 3mL DMSO, adds 20 μ lTEA, then by DOX-S-
The mixing of S-COO-NHS and PAMAM solution, is protected from light 8h at 25 DEG C, uses the dialysis of molecular cut off 3500 after reaction
Bag dialysis 2 days, dialyzate is ultrapure water, changes within every 4 hours a water, is freeze-dried, must restore the nanoparticle (DOX-S- of responsive type
S-PAMAM)；
(2) nanoparticle (DSP-pep-DSP) to FAP- α, reducing environment sensitive is synthesized:
Weigh polypeptide chain Thr-Ser-Gly-Pro-Asn-Gln5mg, EDC 30mg and NHS 25mg points as linking arm
It is not dissolved in 4mL n,N-Dimethylformamide (DMF), polypeptide linking arm solution and EDC solution is then reacted into 0.5h, then
NHS solution reaction 1h is added, obtains the polypeptide linking arm of activation, takes nanoparticle (DOX-S-S-PAMAM) 30mg of reduction responsive type
It is dissolved in 7mL DMF, then the polypeptide linking arm of activation and above-mentioned nanoparticle solution is mixed, be protected from light 12h at 20 DEG C,
It is dialysed 2 days with the bag filter of molecular cut off 3500 after reaction, dialyzate is ultrapure water, changes within every 4 hours a water, is freezed
It is dry, obtain FAP- α enzyme, reducing environment sensitive partial size shrinkage type tumor infiltrating nanosystems (DSP-pep-DSP).
Embodiment 2
The present invention in specific implementation, can also be realized by following steps:
(1) nanoparticle (DOX-S-S-PAMAM) of synthesis reduction responsive type:
1. weighing 3 as linking arm, 3 '-dithiodipropionic acid 252mg and chloroacetic chloride 6.0ml are placed in flask, 65
Flow back 4h under DEG C oil bath, and the ether of 3.5 times of pre-coolings, cooling crystallization are added after reactant is concentrated, and vacuum drying obtains 3,
3 '-dithio dipropyl acid anhydrides；
2. weighing 0.6mmolDOX, 0.6mmol4- dimethylamino naphthyridine (DMAP) and 0.6mmol3,3 '-dithio dipropyls
Acid anhydrides is dissolved separately in 9mlN, in dinethylformamide (DMF)；Then DOX solution and DMAP solution are mixed, adds 60
μ l triethylamine (TEA) solution, is eventually adding 3,3 '-dithio dipropyl anhydride solutions, 12h is protected from light at 40 DEG C, reaction stops
The ether of 3.5 times of pre-coolings, cooling crystallization are added after only, vacuum drying obtains the adriamycin (DOX-S-S-COOH) of carboxylated；
3. weighing adriamycin (DOX-S-S-COOH) 40mg, 1- ethyl-(3- dimethylaminopropyl) carbon two of carboxylated
Imines (EDC) 180mg and HOSu NHS (NHS) 120mg are dissolved separately in 12mL N,N-dimethylformamide (DMF)
In, DOX-S-S-COOH solution and EDC solution are then reacted into 1h, add NHS solution reaction 2h, obtain activation carboxylated Ah
Mycin (DOX-S-S-COO-NHS)；It takes daiamid (PAMAM) 60mg to be dissolved in 6mL DMF, adds 60 μ lTEA, then by DOX-
The mixing of S-S-COO-NHS and PAMAM solution, nitrogen protection reacts 12h at 30 DEG C, uses molecular cut off 3500 after reaction
Bag filter dialyse 2 days, dialyzate is ultrapure water, change within every 5 hours a water, be freeze-dried, the nanoparticle of responsive type must be restored
(DOX-S-S-PAMAM)；
(2) nanoparticle (DSP-pep-DSP) to FAP- α, reducing environment sensitive is synthesized:
Weigh polypeptide chain AC-Asp-Ala-Thr-Gly-Pro-Ala20mg, EDC 100mg and the NHS as linking arm
80mg is dissolved separately in 6mL dimethyl sulfoxide (DMSO), then by polypeptide linking arm solution and EDC solution reaction 1h, then plus
Enter NHS solution reaction 2h, obtains the polypeptide linking arm of activation；Take nanoparticle (DOX-S-S-PAMAM) 100mg of reduction responsive type molten
Solution mixes in 15mL DMSO, then by the polypeptide linking arm of activation and above-mentioned nanoparticle solution, reacts at 25 DEG C for 24 hours, reaction
After dialysed 2 days with the bag filter of molecular cut off 3500, dialyzate is ultrapure water, changes within every 5 hours a water, and freezing is dry
It is dry, obtain FAP- α enzyme, reducing environment sensitive partial size shrinkage type tumor infiltrating nanosystems (DSP-pep-DSP).
Embodiment 3
The present invention in specific implementation, can also be realized by following steps:
(1) nanoparticle (DOX-S-S-PAMAM) of synthesis reduction responsive type:
1. weighing 3 as linking arm, 3 '-dithiodipropionic acid 420mg and chloroacetic chloride 9ml are placed in flask, at 65 DEG C
Flow back 5h under oil bath, and the ether of 4 times of pre-coolings, cooling crystallization are added after reactant is concentrated, and vacuum drying obtains 3,3 '-two
Thio-2 acid acid anhydride；
2. weighing 0.9mmolDOX, 0.9mmol4- dimethylamino naphthyridine (DMAP) and 0.9mmol3,3 '-dithio dipropyls
Acid anhydrides is dissolved separately in 14ml dimethyl sulfoxide (DMSO)；DOX solution and DMAP solution are mixed, 80 μ l triethylamines are added
(TEA), 3,3 '-dithio dipropyl anhydride solutions are added in Xiang Shangshu solution, are protected from light at 45 DEG C for 24 hours, after reaction stops
The ether of 4 times of pre-coolings, cooling crystallization is added, vacuum drying obtains the adriamycin (DOX-S-S-COOH) of carboxylated；
3. weighing adriamycin (DOX-S-S-COOH) 70mg, 1- ethyl-(3- dimethylaminopropyl) carbon two of carboxylated
Imines (EDC) 250mg and HOSu NHS (NHS) 180mg are dissolved separately in 18mL dimethyl sulfoxide (DMSO), then
DOX-S-S-COOH solution and EDC solution are reacted into 2h, NHS solution reaction 1.5h is added, obtains the carboxylated adriamycin of activation
(DOX-S-S-COO-NHS), it takes daiamid (PAMAM) 80mg to be dissolved in 9mL DMSO, adds 80 μ lTEA, then by DOX-S-
The mixing of S-COO-NHS and PAMAM solution, is protected from light for 24 hours at 35 DEG C, uses the dialysis of molecular cut off 3500 after reaction
Bag dialysis 2 days, dialyzate is ultrapure water, changes within every 6 hours a water, is freeze-dried, must restore the nanoparticle (DOX-S- of responsive type
S-PAMAM)；
(2) nanoparticle (DSP-pep-DSP) to FAP- α, reducing environment sensitive is synthesized:
It weighs molten as polypeptide chain Thr-Gly-Pro-Ala30mg, EDC 180mg and NHS the 150mg difference of linking arm
Polypeptide linking arm solution and EDC solution are then reacted 1.5h, added by solution in 9mL n,N-Dimethylformamide (DMF)
NHS solution reaction 3h obtains the polypeptide linking arm of activation, takes nanoparticle (DOX-S-S-PAMAM) the 160mg dissolution of reduction responsive type
It mixes, is protected from light at 30 DEG C for 24 hours, instead in 20mL DMF, then by the polypeptide linking arm of activation and above-mentioned nanoparticle solution
It is dialysed 2 days after answering with the bag filter of molecular cut off 7000, dialyzate is ultrapure water, changes within every 6 hours a water, and freezing is dry
It is dry, obtain FAP- α enzyme, reducing environment sensitive partial size shrinkage type tumor infiltrating nanosystems (DSP-pep-DSP).
It can be seen from the above, present invention selection 3,3 '-dithiodipropionic acids (or 2, the analogs such as 2 '-two thiodiglycolic acids) is
Linking arm connects adriamycin (DOX) and daiamid (PAMAM) containing amino, forms reduction responsive type nanoparticle (DOX-S-
S-PAMAM), partial size is between 25~40nm.Again with the polypeptide of the FAP- α sensitivity to the surface carcinoma-associated fibroblasts (CAF)
Linking arm gets up the reduction responsive type nanoparticle crosslinking of these small particles, forms nanometer of the partial size between 100~200nm
Grain (DSP-pep-DSP).Polypeptide linking arm has the enzyme sensibility sensitive to the FAP- α on the surface CAF, is encountering outside tumour cell
Week CAF when can specific cleavage, so that large-sized nanoparticle DSP-pep-DSP is cracked into the small particle of many carrying medicaments
Reduction responsive type nanoparticle DOX-S-S-PAMAM, and then can destroy or pass through biological barrier, into inside tumor cells send out
The effect of waving effectively overcomes biological barrier, improves anti-cancer effectiveness；After DOX-S-S-PAMAM enters inside tumor, disulfide bond
To restore response type chemical bond, by the effect of glutathione highly expressed in tumour cell, it is broken rapidly, so that antineoplastic
Object adriamycin efficiently discharges.The present invention is that one kind has both reduction responsive type, enzyme sensibility, carcinoma-associated fibroblasts targeting advantage
Can effectively overcome tumor microenvironment biological barrier, improve the newtype drug system of anti-cancer effectiveness.And it is achieved through test non-
Often satisfied advantageous effects, related testing data are as follows:
1, to the tumor infiltrating nanosystems of the partial size shrinkage type of FAP- α enzyme, reducing environment sensitive (to FAP- α enzyme,
The tumor infiltrating nanosystems of the partial size shrinkage type of reducing environment sensitive are also known as DSP-pep-DSP nanometer formulation) in DOX
Assay:
Using the content of uv analysis method measurement DOX, the drugloading rate of sample is calculated with formula (1), drugloading rate reaches
32.5% or more.
(1)
2, the partial size of DSP-pep-DSP nanometer formulation and current potential characterization:
After taking appropriate preparation to be diluted with water to suitable concentration, it is measured with Nano-ZS90 type laser nano Particle Size Analyzer
Partial size and current potential are respectively 156.2nm and -21.3 ± 0.30mv.
3, DSP-pep-DSP nanometer formulation tests the Proliferation Ability of cell:
Cell culture processes: the method that test is co-cultured using 2 kinds of cells, be by carcinoma-associated fibroblasts (CAF) and
MCF-7 cell co-incubation (hereinafter referred to as CAF-MCF7) and is used as following cell experiment in Tissue Culture Flask.
The step of passing on according to cell is by CAF-MCF7 cell processing to single cell suspension, every hole inoculation 5 × 10 after counting3
A cell on 96 orifice plates, incubator culture (37 DEG C, 5%CO2) for 24 hours, add after former culture medium is discarded after cell is adherent completely
Medicine, DSP-pep-DSP group, DOX-S-S-PAMAM group and DOX group, added drug concentration are in one with adriamycin (DOX) concentration
Graded series are formulated with the culture medium without serum, and the concentration gradient of DOX is followed successively by 0,0.039,0.078,0.156,
0.313,0.625,1.25,2.5,5,10 μ g/ml, and continue to take out culture plate after cultivating 48h after dosing, 50 μ l are added in every hole
50% trichloroacetic acid of pre-cooling, final concentration of 10%, stand 5min；It moves in 4 DEG C of refrigerators and stands 1h, take out, with ultrapure washing 5
Time, in air at room temperature after drying completely, the SRB50 μ l of 1% peracetic acid formulation is added in every hole, dyes 20min at room temperature, outwells dye
Liquid is washed 5 times with 1% acetic acid, removes the dyestuff being not associated in hole, the 10mmol/lTris alkali of pH10.5 is used after air at room temperature is dry
150 μ l of liquid dissolution shakes 10min in air heating shaking table, in measuring light of each hole at 515nm on enzyme-linked immunosorbent assay instrument
Absorb angle value.Calculate inhibiting rate (%)=(1- experimental group A/ control group A) × 100%, it follows that the half of above-mentioned sample presses down
Concentration (IC50) processed is successively are as follows: 0.5158,1.0016,1.5108 μ g/ml.
4, DSP-pep-DSP nanometer formulation absorbs cell streaming and tests:
Cell culture processes: the method that test is co-cultured using 2 kinds of cells, be by carcinoma-associated fibroblasts (CAF) and
MCF-7 cell co-incubation (hereinafter referred to as CAF-MCF7) and is used as following cell experiment in Tissue Culture Flask.
Experiment is divided into DSP-pep-DSP group, DOX-S-S-PAMAM group, DOX group is additionally provided with blanc cell group.Take logarithm
The step of CAF-MCF7 cell in growth period is passed on according to cell is processed into single cell suspension, spreads six orifice plates after counting, often
Hole cell number is 3 × 105A/hole, and incubator (37 DEG C, 5%CO2) in culture for 24 hours, it is adherent completely after, discard culture medium, be added
0.5h, 1h, 2h is respectively set in the drug prepared with the culture medium without serum, and the period of 4h, 6h carry out post-processing, medicine
Liquid sucks in corresponding EP pipe, is washed 2 times with PBS, then uses the pancreatin digestion process 1min without EDTA of 0.5ml, culture is added
Base 1ml sucks corresponding EP pipe and discards supernatant after 1000rpm/10min centrifugation, 2mlPBS piping and druming is added in precipitating uniformly,
It after 1000rpm/10min centrifugation, discards supernatant, in precipitating, is transferred in 1.5mlEP pipe after 0.5mlPBS piping and druming uniformly is added
It is placed in ice chest, machine testing in streaming is waited, measures the streaming intake of time point 6h successively are as follows: 90.1%, 73.8%,
57.6%.
5, the pharmacodynamics test of DSP-pep-DSP nanometer formulation:
Prepare 10 female mices and carry out the ascites culture of S-180 sarcoma, ascites is extracted after two weeks, for mouse entity tumor
Plantation, when the volume of tumour reaches 100mm3When above, tumor model is inoculated with successfully, tumor-bearing mice is randomly divided into four groups, often
Group eight, grouping situation are as follows: (1) blank group；(2) DOX group；(3) DOX-S-S-PAMAM group；(4) DSP-pep-DSP group.So
The next day of carrying out afterwards administration, dosage are 4mg/kg, tail vein injection administration by people mouse dose lonvestion.The life of observation mouse daily
Deposit situation and the amount of weighing knurl product (gross tumor volume V=A × B2/ 2), then pass through opposite knurl product R=V/V0Variation
(V0For the size of administration the previous day knurl product) evaluation Antitumor Activity of Drugs.Record statistics indicate that, at the end of administration and give
It is compared before medicine, each group knurl product inhibiting rate is followed successively by 0.03%, 46.58%, 67.86%, 85.38%, swollen with significantly inhibiting
The effect of knurl product can be used for preparing anti-tumor drug.
Experiment show compared with prior art, the present invention have it is following prominent the utility model has the advantages that
1, the present invention is based on the stronger carcinoma-associated fibroblasts CAF of biological barrier effect in tumor microenvironment, selections
The polypeptide chain sensitive to the FAP- α of its surface specific expression is as linking arm, by the reproducibility nanoparticle DOX-S- of small particle
S-PAMAM crosslinking gets up to form nanometer formulation DSP-pep-DSP.Nanometer formulation being capable of specificity when encountering the FAP- α on CAF
Fracture makes big grain diameter nano grain be cracked into the small particle reduction responsive type nanoparticle of carrying medicament, and then can destroy or pass through
Biological barrier plays reduction sensitization into inside tumor cells and discharges drug, improves anti-cancer effectiveness；
2, the present invention is based on the bioreductive glutathione of high concentration to provide tumor tissues reproducibility microenvironment, selection
Linking arm connection antineoplastic adriamycin and daiamid containing disulfide bond, may be implemented antineoplastic using this trigger mechanism
Object in vivo quickly, Targeting delivery drug, reduce the toxic side effect of anti-tumor drug；
3, daiamid PAMAM can be that a kind of biocompatibility is good at the dendrimer of nanoparticle as itself
Pharmaceutical carrier greatly reduces toxic side effect compared with traditional inorganic carrier, also has that long circulating, tumor-targeting are good, carry medicine
The advantages that various informative, is advantageous to the treatment of tumour, and it is in tumor that effective percentage, which can be improved to 80% or more,
One big innovation, economic and social benefit are huge.
Claims (5)
1. the preparation method of the tumor infiltrating nanosystems of the partial size shrinkage type of a kind of pair of FAP- α enzyme, reducing environment sensitive,
It is characterized in that, adriamycin is connected to form reduction responsive type nanoparticle as linking arm and daiamid by disulfide bond, then
This nanoparticle is connected to form by the polypeptide linking arm sensitive to FAP- α, the partial size of FAP- α, reducing environment sensitive are shunk
The tumor infiltrating nanosystems of type, the disulfide bond are 3,3 '-dithiodipropionic acids or 2, and 2 '-two thiodiglycolic acids are more
Peptide linking arm is threonine-Serine-Glycine-Proline-Asparagine-glutamine or AC- Asp-Ala-
Threonine-Gly-Pro-alanine or Alanine-Serine-Gly-Pro-asparagine-glutamin or
Threonine-Gly-Pro-alanine；Specifically includes the following steps:
(1) nanoparticle of synthesis reduction responsive type:
1. weighing as 3, the 3 '-dithiodipropionic acid of disulfide bond of linking arm or 2,2 '-two thiodiglycolic acid 10mg-2g, respectively
Be added 2.0 ~ 15.0ml chloroacetic chloride, be placed in flask, under 65 DEG C of oil baths flow back 2 ~ 6h, after reactant is concentrated be added 3 ~
The ether of 4 times of pre-coolings, cooling crystallization, vacuum drying obtain 3,3 '-dithio dipropyl acid anhydrides or 2,2 '-two thiodiglycolic acid acid anhydrides；
2. weigh 0.01 ~ 1.0mmol adriamycin, 0.01 ~ 1.0mmol4- dimethylamino naphthyridine and 0.01 ~ 1.0mmol step 1. in
Acid anhydrides obtained is dissolved separately in 0.5 ~ 15.0ml reaction solvent A, and adriamycin and 4-dimethylaminopyridine solution are mixed, added
Enter 20 ~ 200 μ l triethylamines, anhydride solution is added in Xiang Shangshu solution, it is protected from light 8 at 25 ~ 45 DEG C ~ for 24 hours, after reaction stops
The ether of 3 ~ 4 times of pre-coolings, cooling crystallization is added, vacuum drying obtains the adriamycin of carboxylated；
3. weigh 20 ~ 100mg of adriamycin of carboxylated, 1- ethyl-(3- dimethylaminopropyl) 100 ~ 250mg of carbodiimide and
60 ~ 180mg of HOSu NHS is dissolved separately in 5 ~ 25mL reaction solvent A, first by the adriamycin of carboxylated and 1- ethyl-
The mixing of (3- dimethylaminopropyl) Carbodiimide solution, reacts 0.5 ~ 3h, adds HOSu NHS solution, reacts
0.5 ~ 4h obtains the carboxylated adriamycin of activation, 10 ~ 150mg of daiamid is taken to be dissolved in 3 ~ 12mL reaction solvent A, add 10 ~
200 μ l triethylamines, then the carboxylated adriamycin of activation and daiamid solution are mixed, the nitrogen protection reaction 6 at 20 ~ 45 DEG C
~ 26h is dialysed 2 days with the bag filter of molecular cut off 3500 after reaction, and dialyzate is ultrapure water, is changed within every 3 ~ 6 hours primary
Water, freeze-drying, must restore the nanoparticle of responsive type；
The reaction solvent A is one or two kinds of mixtures of dimethyl sulfoxide, N,N-dimethylformamide；
(2) nanoparticle to FAP- α, reducing environment sensitive is synthesized:
Weigh 2 ~ 100mg of polypeptide chain as linking arm, 1- ethyl-(3- dimethylaminopropyl) 20 ~ 200mg of carbodiimide
It is dissolved separately in 2 ~ 20mL reaction dissolvent B with 15 ~ 180mg of HOSu NHS, then by polypeptide linking arm and 1- second
The mixing of base-(3- dimethylaminopropyl) Carbodiimide solution, reacts 0.5 ~ 2.5h, adds HOSu NHS solution,
0.5 ~ 3.5h is reacted, the polypeptide linking arm of activation is obtained, takes the 10 ~ 200mg of nanoparticle for having loaded the reduction responsive type of adriamycin molten
Solution mixes in 5 ~ 25mL reaction dissolvent B, then by the polypeptide linking arm of activation and above-mentioned nanoparticle solution, the nitrogen at 20 ~ 40 DEG C
8 ~ 25h of gas shielded is dialysed 2 days with the bag filter of molecular cut off 3500 ~ 8000 after reaction, and dialyzate is ultrapure water, and every 3
~ 6h changes a water, and freeze-drying obtains the nanoparticle of FAP- α, reducing environment sensitive；I.e. to FAP- α enzyme, reducing environment Lazer
The tumor infiltrating nanosystems of the partial size shrinkage type of sense；
The reaction dissolvent B is one or two kinds of mixtures of dimethyl sulfoxide, N,N-dimethylformamide.
2. the tumor infiltrating nanometer of the partial size shrinkage type according to claim 1 to FAP- α enzyme, reducing environment sensitive
The preparation method of system, which comprises the following steps:
(1) nanoparticle of synthesis reduction responsive type:
1. weighing 2 as linking arm, 2 '-two thiodiglycolic acid 109mg and chloroacetic chloride 3ml are placed in flask, in 65 DEG C of oil baths
Lower reflux 2h, is added the ether of 3 times of pre-coolings, cooling crystallization after reactant is concentrated, vacuum drying obtains 2,2 '-two is thio
Diethyl acid anhydrides；
2. weighing 0.3mmol adriamycin, 0.3mmol4- dimethylamino naphthyridine and 0.3mmol2,2 '-two thiodiglycolic acid acid anhydrides difference
5mlN is dissolved in, in dinethylformamide；Adriamycin and 4-dimethylaminopyridine solution are mixed, 20 μ l triethylamines are added,
2,2 '-two thiodiglycolic acid anhydride solutions are added into above-mentioned solution, 8h is protected from light at 35 DEG C, reaction is added 3 times after stopping
The ether of pre-cooling, cooling crystallization, vacuum drying obtain the adriamycin of carboxylated；
3. weighing adriamycin 20mg, 1- ethyl-(3- dimethylaminopropyl) the carbodiimide 100mg and hydroxysuccinimidyl of carboxylated
Acid imide 80mg is dissolved separately in 6mL dimethyl sulfoxide, then by the Doxorubicin solution of carboxylated and 1- ethyl-(3- diformazan
Base aminopropyl) Carbodiimide solution reaction 0.5h, HOSu NHS solution reaction 1h is added, the carboxylated of activation is obtained
Adriamycin takes daiamid 30mg to be dissolved in 3mL dimethyl sulfoxide, adds 20 μ l triethylamines, then by carboxylated Ah mould of activation
Element and the mixing of daiamid solution, are protected from light 8h at 25 DEG C, saturating with the bag filter of molecular cut off 3500 after reaction
Analysis 2 days, dialyzate is ultrapure water, changes within every 4 hours a water, is freeze-dried, must restore the nanoparticle of responsive type；
(2) nanoparticle to FAP- α, reducing environment sensitive is synthesized:
Weigh polypeptide chain threonine-Serine-Glycine-Proline-Asparagine-glutamine 5mg, 1- as linking arm
Ethyl-(3- dimethylaminopropyl) carbodiimide 30mg and HOSu NHS 25mg is dissolved separately in 4mL N, N- bis-
In methylformamide, then polypeptide linking arm solution and 1- ethyl-(3- dimethylaminopropyl) Carbodiimide solution are reacted
0.5h adds HOSu NHS solution reaction 1h, obtains the polypeptide linking arm of activation, takes the nanoparticle of reduction responsive type
30mg is dissolved in 7mL n,N-Dimethylformamide, then the polypeptide linking arm of activation and above-mentioned nanoparticle solution is mixed, In
It is protected from light 12h at 20 DEG C, is dialysed 2 days with the bag filter of molecular cut off 3500 after reaction, dialyzate is ultrapure water, often
Change within 4 hours a water, be freeze-dried, obtain FAP- α enzyme, reducing environment sensitive partial size shrinkage type tumor infiltrating nanometer system
System.
3. the tumor infiltrating nanometer of the partial size shrinkage type according to claim 1 to FAP- α enzyme, reducing environment sensitive
The preparation method of system, which comprises the following steps:
(1) nanoparticle of synthesis reduction responsive type:
1. weighing 3 as linking arm, 3 '-dithiodipropionic acid 252mg and chloroacetic chloride 6.0ml are placed in flask, in 65 DEG C of oil
The lower 4h that flows back of bath, is added the ether of 3.5 times of pre-coolings, cooling crystallization, vacuum drying obtains 3,3 '-two after reactant is concentrated
Thio-2 acid acid anhydride；
2. weighing 0.6mmol adriamycin, 0.6mmol4- dimethylamino naphthyridine and 0.6mmol3,3 '-dithio dipropyl acid anhydrides difference
9mlN is dissolved in, in dinethylformamide；Then Doxorubicin solution and 4-dimethylaminopyridine solution are mixed, adds 60
μ l triethylamine solution is eventually adding 3,3 '-dithio dipropyl anhydride solutions, and 12h is protected from light at 40 DEG C, and reaction adds after stopping
Enter the ether of 3.5 times of pre-coolings, cooling crystallization, vacuum drying obtains the adriamycin of carboxylated；
3. weighing adriamycin 40mg, 1- ethyl-(3- dimethylaminopropyl) the carbodiimide 180mg and hydroxysuccinimidyl of carboxylated
Acid imide 120mg is dissolved separately in 12mL n,N-Dimethylformamide, then by the Doxorubicin solution of carboxylated and 1- second
Base-(3- dimethylaminopropyl) Carbodiimide solution reacts 1h, adds HOSu NHS solution reaction 2h, must activate
Carboxylated adriamycin；It takes daiamid 60mg to be dissolved in 6mL n,N-Dimethylformamide, adds 60 μ l triethylamines, then will live
The carboxylated adriamycin and daiamid solution of change mix, and nitrogen protection reacts 12h at 30 DEG C, after reaction with retention point
The bag filter of son amount 3500 is dialysed 2 days, and dialyzate is ultrapure water, changes within every 5 hours a water, is freeze-dried, is obtained reduction responsive type
Nanoparticle；
(2) nanoparticle to FAP- α, reducing environment sensitive is synthesized:
Weigh polypeptide chain AC- Asp-Ala-threonine-Gly-Pro-alanine 20mg as linking arm,
1- ethyl-(3- dimethylaminopropyl) carbodiimide 100mg and HOSu NHS 80mg is dissolved separately in 6mL diformazan
In base sulfoxide, polypeptide linking arm solution and 1- ethyl-(3- dimethylaminopropyl) Carbodiimide solution are then reacted into 1h, then
HOSu NHS solution reaction 2h is added, obtains the polypeptide linking arm of activation；Take the nanoparticle 100mg dissolution of reduction responsive type
It mixes, is reacted at 25 DEG C for 24 hours in 15mL dimethyl sulfoxide, then by the polypeptide linking arm of activation and above-mentioned nanoparticle solution,
It is dialysed 2 days with the bag filter of molecular cut off 3500 after reaction, dialyzate is ultrapure water, changes within every 5 hours a water, is freezed
It is dry, obtain FAP- α enzyme, reducing environment sensitive partial size shrinkage type tumor infiltrating nanosystems.
4. the tumor infiltrating nanometer of the partial size shrinkage type according to claim 1 to FAP- α enzyme, reducing environment sensitive
The preparation method of system, which comprises the following steps:
(1) nanoparticle of synthesis reduction responsive type:
1. weighing 3 as linking arm, 3 '-dithiodipropionic acid 420mg and chloroacetic chloride 9ml are placed in flask, in 65 DEG C of oil baths
Lower reflux 5h, is added the ether of 4 times of pre-coolings, cooling crystallization after reactant is concentrated, vacuum drying obtains 3,3 '-two is thio
Dipropyl acid anhydrides；
2. weighing 0.9mmol adriamycin, 0.9mmol4- dimethylamino naphthyridine and 0.9mmol3,3 '-dithio dipropyl acid anhydrides difference
It is dissolved in 14ml dimethyl sulfoxide；Doxorubicin solution and 4-dimethylaminopyridine solution are mixed, 80 μ l triethylamines are added, to
3,3 '-dithio dipropyl anhydride solutions are added in above-mentioned solution, are protected from light at 45 DEG C for 24 hours, reaction is added 4 times in advance after stopping
Cold ether, cooling crystallization, vacuum drying obtain the adriamycin of carboxylated；
3. weighing adriamycin 70mg, 1- ethyl-(3- dimethylaminopropyl) the carbodiimide 250mg and hydroxysuccinimidyl of carboxylated
Acid imide 180mg is dissolved separately in 18mL dimethyl sulfoxide, then by the Doxorubicin solution of carboxylated and 1- ethyl-(3- bis-
Dimethylaminopropyl) Carbodiimide solution reaction 2h, HOSu NHS solution reaction 1.5h is added, the carboxyl of activation is obtained
Change adriamycin, daiamid 80mg taken to be dissolved in 9mL dimethyl sulfoxide, add 80 μ l triethylamines, then by activation carboxylated Ah
Mycin and the mixing of daiamid solution, are protected from light for 24 hours at 35 DEG C, use the bag filter of molecular cut off 3500 after reaction
Dialysis 2 days, dialyzate is ultrapure water, changes within every 6 hours a water, is freeze-dried, must restore the nanoparticle of responsive type；
(2) nanoparticle to FAP- α, reducing environment sensitive is synthesized:
Weigh polypeptide chain threonine-Gly-Pro-alanine 30mg, 1- ethyl-(3- dimethylamino as linking arm
Base propyl) carbodiimide 180mg and HOSu NHS 150mg be dissolved separately in 9mL n,N-Dimethylformamide,
Then polypeptide linking arm solution and 1- ethyl-(3- dimethylaminopropyl) Carbodiimide solution are reacted into 1.5h, adds hydroxyl
Base succinimide solution reaction 3h, obtains the polypeptide linking arm of activation, and the nanoparticle 160mg of reduction responsive type is taken to be dissolved in 20mL
In n,N-Dimethylformamide, then by the polypeptide linking arm of activation and the mixing of above-mentioned nanoparticle solution, it is protected from light at 30 DEG C
For 24 hours, it is dialysed 2 days with the bag filter of molecular cut off 7000 after reaction, dialyzate is ultrapure water, change a water within every 6 hours,
Freeze-drying, obtain FAP- α enzyme, reducing environment sensitive partial size shrinkage type tumor infiltrating nanosystems.
5. the partial size to FAP- α enzyme, reducing environment sensitive of the described in any item preparation method preparations of claim 1-4 is shunk
The tumor infiltrating nanosystems application in preparation of anti-tumor drugs of type.
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| CN105524141A (en) * | 2015-11-12 | 2016-04-27 | 中山大学 | Preparation and application of FAPalpha activated polypeptide magnetic nanosphere compound used for diagnosis of tumors |
| CN105727309A (en) * | 2016-03-31 | 2016-07-06 | 中国药科大学 | Preparation and application of dual-sensitivity amphiphilic polysaccharide-doxorubicin conjugate and pharmaceutical composition thereof |
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| CN105524141A (en) * | 2015-11-12 | 2016-04-27 | 中山大学 | Preparation and application of FAPalpha activated polypeptide magnetic nanosphere compound used for diagnosis of tumors |
| CN105727309A (en) * | 2016-03-31 | 2016-07-06 | 中国药科大学 | Preparation and application of dual-sensitivity amphiphilic polysaccharide-doxorubicin conjugate and pharmaceutical composition thereof |
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