CN110101685A - A kind of bionic nano drug, preparation method and application - Google Patents
A kind of bionic nano drug, preparation method and application Download PDFInfo
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Abstract
This application involves field of medicaments, in particular to a kind of bionic nano drug, preparation method and application.Nano medication includes kernel and the shell that is coated on outside kernel；Kernel includes the carrier that the first component, the second component and side chain contain sensitive key；Shell includes cancer cell membrane.The weakly acidic condition of the carrier of sensitive key, carrier Fast-swelling, efficient release anti-cancer medicine TMZ and the second component, cancer cell membrane is made into Nano medication as shell, cancer cell membrane has certain Urine scent and high tumor selectivity targeting " going back to the nest " homologous tumour in vivo, can greatly prolong the circulation time in vivo of Nano medication.As the cancer cell membrane of shell and the carrier high-efficiency release anti-cancer medicine TMZ and the second component of sensitive key, tumour cell is finally killed, achievees the purpose that human glioma targets synergistic treatment.
Description
Technical field
This application involves field of medicaments, in particular to a kind of bionic nano drug, preparation method and application.
Background technique
Malignant glioma is a kind of strongest brain tumor of invasion.Operation is used for tumor resection volume, but normal brain activity is real
Invasive tumor cell in matter cannot completely remove, and remaining tumour cell is by blood-brain barrier (BBB) or blood brain tumor screen
Hinder the protection of (BBTB), which prevent the deliverings of chemotherapeutics, therefore are easy to happen tumor recurrence.Although based on nano particle
Drug delivery system (DDS) shows the ability of the tumor-targeting of enhancing, but these DDS cannot reach postoperative Treatment for Glioma
Whole treatment potentialities, there is a problem of that drug concentration content is lower in tumour.
Summary of the invention
The embodiment of the present application is designed to provide a kind of bionic nano drug, preparation method and application, is intended to change
It is apt to existing tumour medicine lower problem of drug concentration content in tumour.
The application first aspect provides a kind of bionic nano drug, and Nano medication includes kernel and is coated on outer outside kernel
Shell；
Kernel includes the carrier that the first component, the second component and side chain contain sensitive key；
First component includes Temozolomide；Second component includes in cis-platinum, lomustine, vincristine and procarbazine
It is one or more；
Shell includes cancer cell membrane.
Containing Temozolomide (TMZ) and the second component using the carrier containing sensitive key, (cis-platinum, lomustine, Changchun are new
One of alkali and procarbazine are a variety of), TMZ and the second component synergistic treatment glioma are conducive to improve treatment effect
Fruit reduces tumor cell drug resistance.The weakly acidic condition of the carrier of sensitive key, carrier Fast-swelling, efficient release anti-cancer medicine TMZ
With the second component, the carrier of sensitive key is contained into Temozolomide and the second component as kernel, cancer cell membrane is made into as shell
Nano medication, cancer cell membrane have certain Urine scent and high tumor selectivity targeting " going back to the nest " homologous tumour in vivo, energy
Greatly prolong the circulation time in vivo of Nano medication.
As the cancer cell membrane of shell and the carrier high-efficiency release anti-cancer medicine TMZ and the second component of sensitive key, finally kill
Dead tumour cell achievees the purpose that human glioma targets synergistic treatment.
In some embodiments of the application first aspect, above-mentioned sensitivity key includes in acetal bonds, hydrazone bond and amido bond
It is one or more；Preferably, sensitive key is acetal bonds.
Hydrazone bond and amido bond are hydrophobic grouping, can be used as the carrier for loading drug.Acetal bonds are acid sensitive groups, increase contracting
The chemical reaction of aldehyde key is simple, easy to operate, and grafting efficiency is high, can connect more sensitive groups, so that carrier is quicker to acid
Sense.
In some embodiments of the application first aspect, the carrier that above-mentioned side chain contains sensitive key includes that side chain contains contracting
The glucan of aldehyde key.
Characteristic needed for the glucan that side chain contains acetal bonds meets biomaterial is dissolved in organic solvent and fairly insoluble
Yu Shui, the acid-catalyzed hydrolysis of side chain acetal make the acetone and Mathanol regenerating small molecule by-product of natural glucan and harmless amount.
The application second aspect provides a kind of preparation method of bionic nano drug, the preparation method of bionic nano drug
Include:
Carrier, the first component and the second component are mixed, then dialysis removes the first component dissociated and second group
Get kernel；
Cancer cell membrane and kernel are mixed, is then squeezed.
In some embodiments of the application second aspect, carrier, the first component and the second component are mixed into specific packet
It includes:
Carrier is dissolved in tetrahydrofuran obtains the first solution, that the first component and the second component are dissolved in anhydrous dimethyl base is sub-
Sulfone obtains the second solution, then mixes the first solution with the second solution.
The preparation method of bionic nano drug provided by the embodiments of the present application is easy to operate, simple and easy, and preparation process
In mild condition it is not harsh.
In some embodiments of the application second aspect, cancer cell membrane and kernel are mixed, successively passes through 700-
The filter membrane of 800nm, 400-500nm squeeze.
In some embodiments of the application second aspect, cancer cell membrane is mainly made by following steps:
Glioma cell U87 MG cell is digested using EDTA, then is washed using phosphate buffered saline solution, cell membrane is extracted.
In some embodiments of the application second aspect, the glucan that side chain contains acetal bonds mainly passes through following steps
It is made:
Under the conditions of nitrogen protection, glucan is reacted in a solvent with 2- ethoxy propylene, after reaction, with three second
Amine terminates reaction, precipitates, washs in alkaline solution, drying precipitated.
In some embodiments of the application second aspect, glucan and 2- ethoxy propylene are in para-methylbenzenepyridinsulfonate sulfonate
As being reacted under conditions of catalyst.
In some embodiments of the application second aspect, solvent is anhydrous dimethyl sulphoxide.
Glucan synthesizes to obtain linear and annular acetal through single step reaction with 2- ethoxy propylene under conditions of catalysis,
Its graft ratio is 66.72%, wherein linear accounts for 11.28%, annular accounts for 55.44%.Property acetal decomposes in acid condition
The acetone of a molecule and the ethyl alcohol of a molecule are generated, annular acetal in acid condition, only generates the acetone of a molecule.It compares
Example can be calculated by comparing the characteristic peak of ethyl alcohol and the characteristic peak of glucan.
The application third aspect provides a kind of application, and the bionic nano drug that the application first aspect provides is preparing human brain
Application in the target therapeutic agent of glioma.
Bionic nano drug can cross over the protection of blood-brain barrier (BBB), keep being delivered to for drug intracellular, and enhancing is swollen
The ability of tumor targeting, side chain contain sensitive key carrier hydrolysis after carrier Fast-swelling, efficient release anti-cancer medicine TMZ and
CDDP, is conducive to TMZ and CDDP and assembles at tumour, reaches inhibitory effect to tumour, finally kills tumour cell.
Detailed description of the invention
Technical solution in ord to more clearly illustrate embodiments of the present application, below will be to needed in the embodiment attached
Figure is briefly described, it should be understood that the following drawings illustrates only some embodiments of the application, therefore is not construed as pair
The restriction of range for those of ordinary skill in the art without creative efforts, can also be according to this
A little attached drawings obtain other relevant attached drawings.
Fig. 1 shows the nmr spectrum for the glucan that side chain contains acetal bonds；
Fig. 2 shows the nmr spectrums that side chain contains the decomposition of the glucan of acetal bonds.
Fig. 3 shows the partial size and Zeta potential of NP, MNP；
Fig. 4 shows the release in vitro of TMZ difference pH in the case where simulating physiological environment；
Fig. 5 shows the release in vitro of CDDP difference pH in the case where simulating physiological environment；
Fig. 6 shows the experimental result of cytotoxicity and intracellular release experiment；
Fig. 7 shows MNPs-FITC, RNPs-FITC, NPs-FITC and enters U87MG cell situation.
Fig. 8 shows the pharmaceutical concentration-time curve of drug in vivo；
Fig. 9 shows MNPs@TMZ/CDDP for the cylinder therapeutic effect of tumor-bearing mice；
Figure 10 shows different group's mouse tumors position by pretherapy and post-treatment opposite photon amount；
Figure 11 shows different group mouse in the changes of weight of therapeutic process；
Figure 12 shows the life cycle of different group mouse；
Figure 13 shows different group's drugs to the slice of major organs；
Figure 14, which is shown, is loaded with the fluorescence intensity of the MNPs@DiR of DIR in different time points.
Specific embodiment
It, below will be in the embodiment of the present application to keep the purposes, technical schemes and advantages of the embodiment of the present application clearer
Technical solution be clearly and completely described.The person that is not specified actual conditions in embodiment, according to normal conditions or manufacturer builds
The condition of view carries out.Reagents or instruments used without specified manufacturer is the conventional production that can be obtained by commercially available purchase
Product.
The anti-raw Nano medication of the embodiment of the present application, preparation method and application are specifically described below.
Nano medication includes kernel and the shell that is coated on outside kernel；
Kernel includes the carrier that the first component, the second component and side chain contain sensitive key；
First component includes Temozolomide；Second component includes in cis-platinum, lomustine, vincristine or procarbazine
It is one or more.
Shell includes cancer cell membrane.
In embodiments herein, the meaning that each character represents is as follows:
M-dextran-glucan；
Ac-DEX --- side chain contains the glucan of acetal bonds；
BBB-blood-brain barrier；
TMZ-Temozolomide；
CDDP-cis-platinum；
CM-cancer cell membrane；
DiR-IR dyes；
NPs-is using the nanoparticle for not wrapping up cancer cell membrane made of carrier；
The nanoparticle of the loading IR dyes of MNPs@DiR- cancer cell membrane package；
The nanoparticle of MNPs@TMZ/CDDP-cancer cell membrane package loading TMZ and CDDP, i.e. bionic nano drug；
MNPs-cancer cell membrane package airborne nanoparticles, including carrier and cancer cell membrane；
The nanoparticle that MNPs-FITC-cancer cell membrane package label has；
The nanoparticle that RNPs-FITC-erythrocyte membrane package label has；
Free TMZ-free Temozolomide；
Free CDDP-free cis-platinum；
RNPs-erythrocyte membrane wraps up airborne nanoparticles；
Free FITC-free FITC；
The nanoparticle that RNPs-FITC-erythrocyte membrane package label has；
NPs-FITC-is marked with the nanoparticle of FITC；
NPs@TMZ/CDDP-loading TMZ and CDDP nanoparticle.
A kind of Temozolomide (Temozolomide, TMZ), novel imidazoles tetrazine alkylating agent, can run through blood brain screen
Barrier, have both fat-soluble and certain water solubility, be currently used for treat the preferable clinical chemotherapy drug of malignant glioma effect,
Intracellular experience spontaneous hydrolysis is at its active metabolite MITC (3- methyl-(triazine -1- base) imidazoles -4- formamide), alkylation
The position O6 and N7 of guanine, so that accelerating the optimal treatment target of cell therapy is by enhancing tumour-specific to avoid
Invalid treatment results improve the curative effect of chemotherapeutics.But due to there is DNA repair enzyme O6- alkylguanine-DNA into the cell
Alkyl-transferase (MGMT) can repair TMZ alkylation caused by DNA, therefore tumour generates drug resistance, causes therapeutic effect
It is undesirable.
Cis-platinum (cisplatin, CDDP) No. CAS: 15663-27-1；It has been demonstrated that DNA repair enzyme O6- alkyl bird can be reduced
The activity of purine-DNA alkyl-transferase, this enzyme mediate the resistance to TMZ.And cis-platinum (CDDP) is currently as wide spectrum chemotherapy
Drug is widely used in clinic, hurt tumour mechanism mainly can be formed in chain in conjunction with DNA, interchain intersects company
Knot, and then the function of DNA is destroyed, its duplication, transcription are prevented, Apoptosis is eventually led to；Also it can inhibit RNA and egg when high concentration
The synthesis of white matter, but the toxic side effects such as renal toxicity, gastrointestinal toxicity, bone marrow suppression can be also caused to body simultaneously.
Lomustine, No. CAS: 13010-47-4；Molecular formula: C9H16ClN3O2, abbreviation CCNU.
Lip river Mo Siting (CCNU) belongs to chloroethene amido nitrous arteries and veins series antineoplastic medicament, and into after in vivo, molecule is from ammonia first phthalein
Two parts are fractured at amine key, a part is chlorethamin, by chlorinolysis from formation ethylene carbonium ion (CH2=CH+), play alkanisation
Effect makes DNA break, inhibits nucleic acid and protein synthesis；It is cruel that another part is that ammonia first phthalidyl part is then converted to isocyanic acid, or
It is converted into ammonia formic acid, plays the effect of ammonia first phthaleinization, and protein, lysine terminal amino group phase separation especially therein, this
Effect is mainly related with bone marrow suppression, but the effect of ammonia first phthaleinization can also destroy some zymoproteins and play antitumor action.Luo Mosi
Spit of fland (CCNU) is cell cycle nonspecific agent (CCNSA), may act on proliferative cell each phase and non-proliferative cell, is in Gl~S phase side
The cell of boundary or S phase to it is most sensitive, BCNU is better than to G2 phase inhibiting effect.It is viscous to quickly pass through stomach and intestine for the fat-soluble height of this product
Film and blood-brain barrier.
Sting can not damage some zymoproteins while damage dna yet for Lip river, and the MGMT enzyme for repairing Temozolomide can be by
Damage, improves the synergistic therapeutic effect of two kinds of drugs.
Vincristine (Vincristine, Oncovin, VCR), No. CAS: 57-22-7；Molecular formula: C46H56N4O10；
The antitumor action target spot of vincristine is micro-pipe, and main function is to inhibit the polymerization of tubulin and influence spindle
The formation of body micro-pipe.Mitosis is set to stop at metaphase.It may also interfere with protein metabolism and inhibit the work of RNA polymerase
Power, and inhibit the transhipment of the synthesis and amino acid of cell membrane lipoids on cell membrane.Vincristine is non-specific with the cell cycle
Property drug with the use of can also heighten the effect of a treatment.
Procarbazine (Procarbazine, PCZ), No. CAS: 671-16-9；Molecular formula: C12H19N3O；
Procarbazine can inhibit the synthesis of DNA and protein, into human body after autoxidation formed H2O2And OH-based, it can
Cause similar ionising radiation sample to act on, especially makes guanine the 3rd and adenine the 1st upper methylation.There are many biological effect,
Such as inhibit cell mitogen, make Chromosomal arrangement disorder, teratogenesis, carcinogenic, immunosupress, cytotoxicity.PCZ can inhibit
Cell mitogen.Methyl cation is released in vivo, depolymerization is allowed in conjunction with DNA, is non-specific cell cycle medicine
Object mainly acts on the boundary G1/S, and has retarding action to the S phase.It is resistance to without intersecting with alkylating agent, vincristine, cortin
Medicine can significantly improve curative effect when sharing with said medicine.
One of Temozolomide and cis-platinum, lomustine, vincristine and procarbazine are a variety of, synergistic effect.
That there are circulation time in vivo is short for current Temozolomide and cis-platinum, is difficult to across BBB, by tumour cell intake
Low and drug discharges many critical issues such as slow in affected area.
In this application, Temozolomide (TMZ) and the second component are contained using the carrier containing sensitive key (cis-platinum, Lip river is not
Take charge of one of spit of fland, vincristine and procarbazine or a variety of), TMZ and the second component synergistic treatment glioma are conducive to
Therapeutic effect is improved, tumor cell drug resistance is reduced.The weakly acidic condition of the carrier of sensitive key, carrier Fast-swelling efficiently discharge
The carrier of sensitive key is contained Temozolomide (TMZ) and the second component as kernel by anticancer drug TMZ and the second component, and cancer is thin
After birth is made into Nano medication as shell, and cancer cell membrane has certain Urine scent and high tumor selectivity targeting " going back to the nest "
Internal homologous tumour, can greatly prolong the circulation time in vivo of Nano medication.
As the cancer cell membrane of shell and the carrier high-efficiency release anti-cancer medicine TMZ and the second component of sensitive key, finally kill
Dead tumour cell achievees the purpose that human glioma targets synergistic treatment.
Further, in some embodiments of the present application, above-mentioned sensitivity key includes in acetal bonds, hydrazone bond and amido bond
It is one or more；Preferably, sensitive key is acetal bonds.
Hydrazone bond and amido bond are hydrophobic grouping, can be used as the carrier for loading drug.Acetal bonds are acid sensitive groups, increase contracting
The chemical reaction of aldehyde key is simple, easy to operate, and grafting efficiency is high, can connect more sensitive groups, so that carrier is quicker to acid
Sense.
The carrier that side chain contains acetal bonds is degraded under endosome acidic environment, and nanoparticle swelling discharges TMZ and CDDP,
Reach the safe and efficient chemotherapy of human glioma.
Further, in some embodiments of the present application, the carrier that above-mentioned side chain contains sensitive key includes that side chain contains
The glucan (m-dextran) of acetal bonds.
For the glucan for selecting side chain to contain acetal bonds as carrier, the glucan that side chain contains acetal bonds meets biomaterial
Required characteristic is dissolved in organic solvent and completely insoluble in water, and the acid-catalyzed hydrolysis of side chain acetal makes natural glucan and nothing
The acetone and Mathanol regenerating of evil amount are small molecule by-product.
The application also provides a kind of preparation method of bionic nano drug, and the preparation method of bionic nano drug includes:
Carrier, the first component and the second component are mixed, then dialysis removes the first component dissociated and second group
Get kernel；
Cancer cell membrane and kernel are mixed, is then squeezed.
Further, carrier, the first component and the second component are mixed and are specifically included:
Carrier is dissolved in tetrahydrofuran obtains the first solution, that the first component and the second component are dissolved in anhydrous dimethyl base is sub-
Sulfone obtains the second solution, then mixes the first solution with the second solution.
It carrier is first dissolved in tetrahydrofuran, the first component and the second component is dissolved in anhydrous dimethyl sulphoxide and mix again
It closes, is conducive to three and uniformly mixes.
Carrier, the first component and the second component are dissolved in tetrahydrofuran, Temozolomide and the second component are carried on load
Body removes extra Temozolomide and the second component to obtain kernel after dialysis, kernel is mixed with cancer cell membrane laggard
Row co-extrusion obtains core-shell structure.
The preparation method of bionic nano drug provided by the embodiments of the present application is easy to operate, simple and easy, and preparation process
In mild condition it is not harsh.
Further, in the present embodiment, carrier contains the glucan of acetal bonds using side chain, and the second component uses
CDDP is mainly made by following steps:
Under the conditions of nitrogen protection, glucan is reacted in a solvent with 2- ethoxy propylene, after reaction, with three second
Amine terminates reaction, precipitates, washs in alkaline solution, drying precipitated.
Further, glucan and 2- ethoxy propylene are anti-under conditions of para-methylbenzenepyridinsulfonate sulfonate is as catalyst
It answers.
In detail, under the conditions of nitrogen protection, by the glucan (dextran, 10kDa) and 2- ethyoxyl after dry water removal
Propylene normal-temperature reaction 3h in anhydrous dimethyl sulphoxide (DMSO) solvent, and catalytic amount para-methylbenzenepyridinsulfonate sulfonate is added.Reaction
After, it is terminated and is reacted with triethylamine, 3 precipitating, washing prevention acetal bonds degradations, final to produce in the deionized water that pH is 8
Object m-dextran is dried to obtain by the pellet frozen after being centrifuged.Dextran, 2- ethoxy propylene used in synthesis process and
The primary raw materials such as pyridinium p-toluenesulfonic acid are commercially available to be directly obtained.
The synthesis of acetal grafting glucan, acetal bonds are degraded to the reaction of glucan, ethyl alcohol and acetone in acid condition
Formula is as follows:
Target product can be obtained in the method single step reaction of synthesis acetal grafting glucan, and preparation method is simple, final
The product arrived is easily separated, and the purity of product is higher.
Glucan synthesizes to obtain linear and annular acetal through single step reaction with 2- ethoxy propylene under conditions of catalysis,
Its graft ratio is 67.81%, wherein linear accounts for 10.39%, annular accounts for 57.42%.Fig. 1 shows side chain and contains acetal bonds
Glucan nmr spectrum；Fig. 2 shows the nmr spectrums that side chain contains the decomposition of the glucan of acetal bonds.
As shown in Figure 1, linear acetals decompose the ethyl alcohol of the acetone and a molecule that generate a molecule, ratio in acid condition
Example is by comparing the characteristic peak of acetone (2.08ppm, 6H) and ethyl alcohol (0.95ppm, 3H) and the characteristic peak (3.4- of glucan
4.0ppm, 6H) it is calculated.The acetal of annular in acid condition, only generates the acetone of a molecule.Its ratio can be by comparing
The characteristic peak of ethyl alcohol and the characteristic peak of glucan are calculated.
In the present embodiment, cancer cell membrane is mainly made by following steps:
Glioma cell U87 MG cell is digested using EDTA (ethylenediamine tetra-acetic acid), then is washed using phosphate buffered saline solution
It washs, extracts cell membrane.
In detail, glioma cell U87 MG cell is sucked into culture medium after Tissue Culture Dish culture, and clear with PBS
After washing, the EDTA (2mM) that 5mL is added is cleaned after collecting cell with PBS for vitellophag, then uses Membrane protein extraction reagent
Box extracts cell membrane.
Further, in the preparation process of bionic nano drug, successively pass through the filter membrane of 700-800nm, 400-500nm
It repeatedly extrudes 11 times and finally obtains MNPs.
In the other embodiments of the application, glioma cell may be U251 cell, U1261 cell etc..
The application also provides a kind of application, and above-mentioned bionic nano drug is in the targeting synergistic treatment medicine for preparing human glioma
Application in object.
The Urine scent internalization of the excessively external source cancerous cell line of bionic nano drug and high tumor selectivity targeting " going back to the nest "
Internal homologous tumour is identified, is conducive to nanoparticle and is assembled at tumour, to reach inhibitory effect to tumour.
Bionic nano drug can cross over the protection of blood-brain barrier (BBB), keep being delivered to for drug intracellular, and enhancing is swollen
The ability of tumor targeting, side chain contain sensitive key carrier hydrolysis after carrier Fast-swelling, efficient release anti-cancer medicine TMZ and
CDDP, is conducive to TMZ and CDDP and assembles at tumour, reaches inhibitory effect to tumour, finally kills tumour cell.
The feature of the application and performance are described in further detail with reference to embodiments.
Embodiment 1
A kind of anti-raw Nano medication is present embodiments provided, is mainly made by the following method:
Under the conditions of nitrogen protection, the glucan (dextran, 10kDa) after dry water removal is existed with 2- ethoxy propylene
Normal-temperature reaction 3h in anhydrous dimethyl sulphoxide (DMSO) solvent, and catalytic amount para-methylbenzenepyridinsulfonate sulfonate is added.After reaction,
It is terminated and is reacted with triethylamine, 3 precipitating, washing prevention acetal bonds degradations, final product m- in the deionized water that pH is 8
Dextran is dried to obtain by the pellet frozen after being centrifuged.
The extraction of cancer cell membrane (CM): by glioma cell U87 MG cell after Tissue Culture Dish culture, culture is sucked
Base, and after being cleaned with PBS, the EDTA (2mM) that 5mL is added is washed one time after collecting cell with PBS for vitellophag, is then used
Membrane protein extraction kit extracts cell membrane, and being put into -80 DEG C of refrigerators after freeze-drying can long-term preservation.
The formation of acid-sensitive nanoparticle and drug load: m-dextran being dissolved in tetrahydrofuran, corresponding theory is added
The Temozolomide (TMZ) and cis-platinum (CDDP) of drugloading rate, dialysis remove free drug, finally obtain acid-sensitive medicine-carried nano particles
That is kernel.
After kernel is mixed in proportion with CM, MNPs@successively is finally obtained by repeatedly extruding under 800nm, 400nm filter membrane
TMZ/CDDP。
Anti- raw Nano medication provided in this embodiment can be used for preparing the targeting synergistic treatment medicine of human glioma.
Fig. 3 shows the partial size and Zeta potential of NP, MNP；Further, Fig. 3 a shows the partial size of NP, MNP, Fig. 3 b
Show the Zeta potential of NPs, MNPs.
M-dextran can be self-assembly of stable nanoparticle in aqueous solution, wrap up after cell membrane its partial size by
174nm is increased to 185nm (Fig. 3 a), and current potential is -22.7mV (Fig. 3 b) by -44.3mV variation, is tested and is found by DLS, nanoparticle
Diameter distribution is uniform.It is measured by microplate reader and sepectrophotofluorometer, when the theoretical drugloading rate of TMZ is 10%, encapsulation rate is
49.5%.
The research of test example 1-3 is carried out using bionic nano drug made from the present embodiment.
Test example 1
Study the vitro drug release behavior acid response of bionic nano drug: for the drug-loading efficiency of quantitative TMZ and CDDP
(DLE) and drugloading rate (DLC), the UV absorption by drug-carrying nanometer particle directly with multi-function microplate reader detection TMZ at 327nm,
It is 5%HNO that nanoparticle, which is dissolved in volume fraction,3In solution, CDDP content is measured by inductively-coupled plasma spectrometer.Base
DLC and DLE can be calculated in TMZ, CDDP of known concentration standard curve drawn and following formula:
DLC (wt.%)=(total amount of dose/medicine and polymer) × 100
DLE (%)=(measurement dose/theory inventory) × 100
Nano medication is incubated under (simulation) tumour cell endosome weakly acidic condition (pH5~6.5), by DLS in real time with
Quantity, partial size and the particle diameter distribution of track particle.Extracorporeal releasing experiment carries out under the conditions of 37 DEG C, by 600 microlitres of MNPs@TMZ/
CDDP contains in hac buffer in 25mL to dialyse.At the time point of setting, take out 5mL dissolution medium and mending add it is same amount of
Fresh medium.The amount of TMZ and CDDP is surveyed by multi-function microplate reader and inductively-coupled plasma spectrometer respectively in dissolution medium
It is fixed.Releasing result is three Duplicate Samples average values.
Fig. 4 shows the release in vitro of TMZ difference pH in the case where simulating physiological environment, and Fig. 5 shows CDDP in simulation physiology
The release in vitro of difference pH under environment.
By extracorporeal releasing experiment it can be seen from Fig. 4 and Fig. 5 as the result is shown under 37 DEG C, the physiological environment of pH7.4, TMZ
It is lower (24 hours less than 25%) with CDDP burst size.And in acid condition, TMZ is more than 65% in 24 hours burst sizes,
CDDP is more than 75% in 24 hours burst sizes.This is that nanoparticle is swollen causes drug release in acid condition.Explanation
MNPs solves the problems, such as the leakage of traditional biological degradable nano drug simultaneously and discharges slow two into the cell.
Test example 2
Cell experiment
1. cytotoxicity experiment:
Selection human glioma cell U87MG is cell model.U87MG is being contained into 10%FBS, 1% mycillin
It cultivates, is layered on (5 × 10 in 96 orifice plates in the DEME culture medium of the 100 μ L of (100IU/mL)3Cells/well).After 24 hours, siphon away
Culture medium, the airborne nanoparticles (NPs) for not carrying TMZ and CDDP and 10 μ L for changing 90 μ L fresh cultures and 10 μ L do not wrap up cancer
After being incubated for 48h, 10 μ L are added, the 3- (4,5- dimethyl thiazol base)-that concentration is 5mg/mL in the nanoparticle (NPs) of cell membrane
After 2,5- diphenyltetrazolium bromide bromides (MTT) solution is incubated for 4 hours, culture medium is removed, 150 μ L DMSO are added and dissolve living cells
The MTT- first a ceremonial jade-ladle, used in libation of generation.Microplate reader measures each hole in the absorption of 492nm, to have added the culture datum hole of MTT as zero point.Each experiment
Data do five groups (n=5) in parallel.
2. flow cytometer and Laser Scanning Confocal Microscope characterization cell endocytic and intracellular release
Flow cytometer test in, by tri- kinds of U87 MG, A549, Hela cell kinds in 6 porocyte culture plates (1 ×
106Cells/well) after 37 DEG C are cultivated 24 hours, MNPs-FITC, RNPs-FITC, PBS that 500 μ L are added are incubated for 2 hours, are inhaled
Sample is walked, with 500 μ L trypsin digestion cells.Obtained cell suspending liquid is centrifuged 3 minutes in 1000 × g, is washed twice with PBS, then
It is secondary to be dispersed in 500 μ L PBS, flow cytometer (BD FACS Calibur, Becton Dickinson, USA) is carried out in 1 hour
Test takes 10000 cells to obtain with Cell Quest software circle.
Cell endocytic and Intracellular drug release behavior are observed to obtain by CLSM photo.U87MG cell is laid on containing aobvious
(1 × 10 in 24 porocyte culture plates of micro mirror glass slide5Cells/well) after culture 24 hours, the MNPs-FITC of 50 μ L of addition,
RNPs-FITC and NPs-FITC.After being incubated for 4 hours, culture medium is removed and is cleaned twice with PBS.Nucleus 15 is contaminated with DAPI
It is cleaned twice after minute.Fluorescence picture is shot by CLSM (TCS SP5) and is obtained.
Fig. 6 shows the experimental result of cytotoxicity and intracellular release experiment.Wherein: Fig. 6 a shows MNPs and NPs
For detecting the toxicity data for the glucan that side chain contains acetal bonds.Fig. 6 b show different nanoparticles to cancer cell
Mortaility results；It further illustrates TMZ:CDDP in MNPs@TMZ/CDDP and carries medicine mass ratio to kill when 1:1 and 1:2 to cell
Hurt effect.Fig. 6 c shows different cells (U87MG, A549, Hela) respectively to the endocytosis situation of MNPs, RNPs and PBS, with inspection
Survey the homologous Targeting Effect of nanoparticle.
From fig. 6, it can be seen that even if when MNPs and NPs is at concentrations up to 1.0mg/mL, it is still nontoxic to U87 MG cell
(Fig. 6 a), it was confirmed that the good biocompatibility of MNPs and NPs.MNPs goes out significant anti-tumor activity to U87 MG cells show
(Fig. 6 b).Flow cytometry experiments prove that MNPs can be good at by cell endocytic and have preferable homologous Targeting Effect (figure
6c)。
Fig. 7 shows MNPs@FITC, RBCm@NPs@FITC, NPs@FITC and enters U87MG cell situation.
From figure 7 it can be seen that CLSM is observed after MNPs-FITC is incubated for 4 hours, have in U87 MG nucleus very strong
FITC fluorescence, enter effect it is good more than RNPs-FITC and free FITC, illustrate MNPs-FITC in the cell Fast-swelling and
It is released effectively in FITC cytoplasm.The bionic nano drug that embodiment 1 is prepared can more enter U87 MG cell
In, to verify the homologous Targeting Effect of bionic nano drug.
Test example 3
Zoopery
1. pharmacokinetic
In vivo in pharmacokinetic, 6-8 weeks BALB/c mouse is grouped (every group parallel 3) at random, by tail vein
Inject that the MNPs@TMZ/CDDP of 200 μ L, NPs@TMZ/CDDP, (TMZ and CDDP dosage is by free TMZ and free CDDP
5mg/kg), blood is taken in predetermined point of time eye socket.Blood sample goes out drug through organic solvent extraction and separation, and passes through efficient liquid phase
(HPLC) and inductively-coupled plasma spectrometer (ICP).It is compared with the Conventional nano drug of cancer-free cell film package, it can
To conclude the blood stability of bionic nano drug.Fig. 8 shows the pharmaceutical concentration-time curve of drug in vivo.MNPs@
DiR, NPs@DiR and Free DiR are injected in Mice Body, observe nanoparticle in different time points in the accumulation feelings of mouse brain
Condition.
From figure 8, it is seen that the circulation time of targeted nano drug MNPs@TMZ/CDDP in vivo is longer, with NPs@
TMZ/CDDP is suitable, and is longer than Free TMZ or Free CDDP, illustrate the biocompatibility of the film modified nanoparticle of cell compared with
It is good；Bionic nano drug helps the circulation time conducive to chemotherapeutics (TMZ/CDDP) in vivo, and is able to extend in brain
The accumulation of tumour.
2. antitumous effect
The foundation of U87 MG meningeal-colloid cancer model in situ is transplanted in BALB/c nude mice (18-20g, 6-8 week old) brain
Tumor tissues.
Model in situ is established with the human glioma cell (U87 MG-Luc) that luciferase marks, is given by multi-dose
Medicine, by IVIS III is qualitative and quantitative tracking of knub growing state.In therapeutic process layer, is changed by mouse weight and survived
Rate assesses the system toxic side effect and anti-tumor activity of bionic nano drug.After treatment end, organized by H&E and TUNEL etc.
It learns colouring method and analyzes each normal organ health status of mouse and tumor tissues apoptosis situation after bionic nano drug therapy.Pass through
Experiment on therapy, it can be seen that system toxicity and anti-tumor activity of the bionic nano drug to lotus U87 MG-Luc nude mice.
3. bio distribution
In tail vein injection Nano medication to lotus original position U87 MG nude mouse, collect in different time points mouse core, liver,
The Main Tissues such as spleen, lung, kidney, brain and tumour are imaged in vitro with IVIS III.Then, the homogenate of each tissue, organic solvent are extracted
Take, be centrifugated after, sepectrophotofluorometer quantitative analysis drug in different time points vivo biodistribution distribution.Pass through this reality
It tests it is concluded that stability, active targeting performance and the TMZ released and CDDP exist to drug in bionic nano drug body
The influence of tumor locus enrichment, delay and infiltration.
Fig. 9 shows MNPs@TMZ/CDDP for the cylinder therapeutic effect of tumor-bearing mice；
Figure 10 shows different group's mouse tumors position by pretherapy and post-treatment opposite photon amount；Figure 11 shows difference
Changes of weight of the group mouse in therapeutic process；Figure 12 shows the life cycle of different group mouse；Figure 13 shows difference
Sections observation of group's drug to major organs, the hypotoxicity of the results show nanoparticle.
From Figure 10-Figure 13 it can be seen that treatment of the MNPs@TMZ/CDDP in the BALB/c nude mice of lotus U87 MG-luc is real
It tests the results show that it can effectively inhibit tumour to increase by dose dependent fashion, is 5mg/kg in TMZ dosage, CDDP dosage is
When 5mg/kg, tumour growth can be significantly inhibited.When free TMZ and CDDP concentration is 5mg/kg, mouse weight is reduced in 7 days.
Under relatively, the mouse weight variation of MNPs TMZ/CDDP treatment is small, illustrates that bionic nano poisonous side effect of medicine is small.In addition,
Mouse is TMZ 5mg/kg in MNPs TMZ/CDDP dosage, after CDDP 5mg/kg treatment, the survival rate in treatment cycle 22 days
It is 100%.Prove that MNPs@TMZ/CDDP is in TMZ 5mg/kg, CDDP 5mg/ by the Histological results that H&E is dyed
When kgTMZ dosage is administered, very little is endangered to the major organs including the heart, liver, spleen, lung, kidney.As a result illustrate MNPs@TMZ/ again
CDDP has extremely low system toxicity.
4. BBB crosses over effect and targeting
It replaces TMZ and CDDP to be self-assembly of nanoparticle using nir dye DiR, passes through tail vein injection nanometer medicine
In object to lotus original position human glioma U87 MG nude mouse, in vivo by small animal imaging instrument (IVIS III) tracking Nano medication
The distribution situation of different time points, and high spot reviews are in the accumulation and delay at brain tumor position, by being compareed with cancer-free cell film
Group and Free DiR group carry out qualitative and quantitative comparison, investigate BBB and cross over efficiency and Nano medication cancer target ability.
By the distribution situation of small animal imaging instrument (IVIS III) tracking Nano medication different time points in vivo.
Figure 14, which is shown, is loaded with the fluorescence intensity of the MNPs@DiR of DiR in different time points；It is seen from figure 14 that
The fluorescence intensity of MNPs@DiR is apparently higher than control group, illustrates the ability that MNPs has good target tumor.
It in summary it can be seen, bionic nano drug provided by the embodiments of the present application avoids the leakage of drug；Drug is thin
Rate of release intracellular is very fast and forms and is released effectively；And bionic nano drug intracorporal circulation time is longer, biocompatibility
Preferably, there is obvious synergistic therapeutic effect.
The foregoing is merely preferred embodiment of the present application, are not intended to limit this application, for the skill of this field
For art personnel, various changes and changes are possible in this application.Within the spirit and principles of this application, made any to repair
Change, equivalent replacement, improvement etc., should be included within the scope of protection of this application.
Claims (10)
1. a kind of bionic nano drug, which is characterized in that the Nano medication includes kernel and is coated on outer outside the kernel
Shell；
The kernel includes the carrier that the first component, the second component and side chain contain sensitive key；
First component includes Temozolomide；Second component includes cis-platinum, lomustine, vincristine or methyl benzyl
One of hydrazine is a variety of；
The shell includes cancer cell membrane.
2. bionic nano drug according to claim 1, which is characterized in that it is described sensitivity key include acetal bonds, hydrazone bond or
One of person's amido bond is a variety of；Preferably, the sensitive key is acetal bonds.
3. bionic nano drug according to claim 1, which is characterized in that the carrier that the side chain contains sensitive key includes
Side chain contains the glucan of acetal bonds.
4. the preparation method of bionic nano drug as described in any one of claims 1-3, which is characterized in that the bionic nano
The preparation method of drug includes:
The carrier, first component and second component are mixed, then dialysis removes free described first group
Divide and second component obtains the kernel；
The cancer cell membrane and the kernel are mixed, is then squeezed.
5. the preparation method of bionic nano drug according to claim 4, which is characterized in that by the carrier, described
One component and second component mixing specifically include:
By the carrier be dissolved in tetrahydrofuran obtain the first solution, first component and second component are dissolved in it is anhydrous
Dimethyl sulfoxide obtains the second solution, then mixes first solution with second solution.
6. the preparation method of bionic nano drug according to claim 4, which is characterized in that mix the cancer cell membrane with
And the kernel, successively squeezed by the filter membrane of 700-800nm, 400-500nm.
7. the preparation method of bionic nano drug according to claim 4, which is characterized in that the cancer cell membrane mainly leads to
Following steps are crossed to be made:
Glioma cell U87 MG cell is digested using EDTA, then is washed using phosphate buffered saline solution, cell membrane is extracted.
8. the preparation method of bionic nano drug according to claim 4, which is characterized in that side chain contains the Portugal of acetal bonds
Glycan is mainly made by following steps:
Under the conditions of nitrogen protection, glucan is reacted in a solvent with 2- ethoxy propylene, after reaction, with triethylamine end
It only reacts, precipitates, washs in alkaline solution, the dry precipitating.
9. the preparation method of bionic nano drug according to claim 8, which is characterized in that the glucan and the 2-
Ethoxy propylene reacts under conditions of para-methylbenzenepyridinsulfonate sulfonate is as catalyst.
10. the described in any item bionic nano drugs of claim 1-3 are in the target therapeutic agent for preparing human glioma
Using.
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