CN105477645A - Nano-carrier capable of realizing co-delivery of genes and medicines and preparation method of nano-carrier - Google Patents
Nano-carrier capable of realizing co-delivery of genes and medicines and preparation method of nano-carrier Download PDFInfo
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- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
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Abstract
The invention discloses a nano-carrier capable of realizing co-delivery of genes and medicines and a preparation method of the nano-carrier, and in particular relates to a nano-carrier capable of realizing co-loading and co-delivery of genes and medicines. The medicine delivery system is formed through self-assembly of a cation prodrug polymer and the genes through the electrostatic interaction between the cation prodrug polymer and the genes, wherein the cation prodrug polymer can release active medicines through the hydrolysis by esterases in the cells, after entering into the cells under the phagocytosis, the nano-composition escapes from an endosome under the effect of the buffer capacity of polyamines on a polymer, and releases the medicines ad the genes in the cytoplasm, so that the medicines and the genes can inhibit the tumor proliferation together.
Description
Technical field
The present invention relates to a kind of nano-carrier of delivering drugs and gene altogether, the targeting drug delivery system of load genomic medicine and medicine while of being specifically related to a kind of, the present invention altogether delivery system can by discharging gene while hydrolysis release medicine in tumor cell, the propagation of the two collaborative inhibition tumor cell, the migration of common inhibition tumor cell, belongs to nano-drug preparation technical field simultaneously.
Background technology
Tumor has become one of disease of serious threat people life.At present, the first-selected Therapeutic Method of tumor is operative treatment, but not all patient is applicable to operation.Only have tissue physiology's function better, tumor is more concentrated, and does not have the patient shifted just to be suitable for operation.The patient of the clinical overwhelming majority can not perform the operation because of a variety of causes.So chemotherapy is still one of conventional strategy for the treatment of tumor.Heterogeneity due to tumor is one of feature of malignant tumor, and therefore, single chemotherapy means are difficult to reach good therapeutic effect.
At present, gene therapy is as one of means with potentiality Therapeutic cancer.But easily degraded and removing after in uncorrected gene expression input body, and the problem such as very difficult permeate through cell membranes, limit it and be used alone.Therefore, efficient gene transmission system becomes the key of gene therapy technology success or not.Comparatively extensive in clinical experiment of current viral vector.But immunogenicity and some toxic and side effects of viral vector impel research worker to develop a large amount of non-virus carrier.Because non-virus carrier is more easily prepared, good biocompatibility, does not limit the size of contained gene, therefore gets more and more people's extensive concerning.But although have these advantages, compared with viral vector, still there is the shortcomings such as transfection efficiency is low in existing non-viral gene vector.
Polymine (polyethylenimine, PEI) is one of non-viral gene vector commonly used in research, is called as non-viral gene vector " goldstandard ".But the transfection of the PEI of macromolecule is better, but cytotoxicity is comparatively large, and the transfection of the PEI of small-molecular-weight is lower, and cytotoxicity is less.Therefore, be necessary that the polyamines with small-molecular-weight connects into the cationic polymer of certain molecular weight.
Cantharidin is a kind of effective antitumor medicine extracted from Mylabris, due to the toxicity that it is stronger, limits its application clinically.Norcantharidin be the cantharidin of China's independent research seemingly, there is stronger antitumor action equally, and be unique antitumor drug with function of increasing leukocyte, can at cytotoxicity, anti-stick multiple link performance antitumaous effects such as transfer, apoptosis-induced, Tumor suppression angiogenesis, be applied to clinical.But it is facile hydrolysis in water, cause it more difficult through cell.Therefore, be necessary that being transformed into polymer carrys out delivery of gene, realizes therapeutic alliance tumor.
In recent years, the research that medicine and gene are sent by some bibliographical information altogether, these medicine carryings are by grafting after medicine to polymer substantially, or parcel is in the polymer, and this mode drug loading is lower, and troublesome poeration.Also some document is by the research of medicine carrying thing after pharmaceutical synthesis polymer, but it can not discharge proto-drug very well, therefore norcantharidin class medicine with ester bond form synthetic cationic polymers simultaneously transfer gene realize sending altogether of medicine and gene.
Summary of the invention
Object: the nano-carrier that the invention provides a kind of delivering drugs and gene altogether, this delivery system is the object realizing Synergistic treatment tumor, relate to a kind of cationic polymer compress simultaneously gene self assembly formed send nano-carrier altogether, chemotherapeutics and gene can be delivered in target cell by nano-delivery system of the present invention simultaneously, discharge medicine under the effect of target cell lactonase while, gene is also discharged, make them in born of the same parents, play collaborative antitumor action.
Technical scheme: for solving the problems of the technologies described above, the technical solution used in the present invention is:
The nano-carrier that gene and medicine are sent altogether, the nano-complex formed by cation prodrug polymer and gene; The chemical structural formula of prodrug polymer is as follows:
Wherein, m, n are positive integer.
The nano-carrier that described gene and medicine are sent altogether, preparation method comprises the following steps: joined by cdna solution in isopyknic prodrug polymer solution under vortex, vortex 10-30s, room temperature leaves standstill 15-30min, to obtain final product.Preferably, the nano-carrier that described gene and medicine are sent altogether, is characterized in that: described gene is shAkt1, P53 or PDCD4.
The chemical structural formula of prodrug polymer is as follows:
Wherein, m, n are positive integer.
Preparation method is as follows: be dissolved in appropriate ethanol by cantharidin medicine acrylate, add polyamine molecule, cantharidin medicine acrylate and polyamine molecule molar ratio are 1.0:(1.0-2.0), at 30-90 DEG C and stirred under nitrogen atmosphere reaction 1-5d; Products therefrom is dissolved in the deionized water of 4 DEG C, and then to dialyse at 4 DEG C 2d with the bag filter of molecular cut off 3500, lyophilizing, to obtain final product.
Preferably, described prodrug polymer, is characterized in that: polyamine molecule comprises spermine, spermidine, diethylenetriamine, triethylene tetramine, TEPA tetraethylene pentamine, five ethylene hexamine and PEI300, PEI423, PEI600, PEI1200, PEI1800.
Described prodrug polymer, is characterized in that: described cantharidin medicine acrylate is norcantharidin diacrylate or cantharidin diacrylate.
Present invention also offers above-mentioned prodrug polymer, as the application of polymeric prodrugs or genophore.
The nano-carrier that above-mentioned gene and medicine are sent altogether is preparing the application in Hepatoma therapy, pulmonary carcinoma or breast cancer medicines.
The nano-carrier that above-mentioned gene and medicine are sent altogether, by pulmonary's suction or by injection system administration.
Beneficial effect: the present invention, with cation prodrug polymer, mixes with elecrtonegativity gene, forms the nano-carrier of delivering drugs and gene altogether.This nanometer altogether delivery of particles, by after cellular uptake, under the effect of polyamines buffer capacity, escapes out from lysosome, and under cytosolic esterases effect, hydrolysis discharges active medicine, also can promote the release of gene simultaneously.Gene and medicine Synergistic treatment tumor, reach higher therapeutic effect.
Accompanying drawing explanation
Fig. 1 is hydrogen spectrum and the molecular weight characterization of the PEI-alt-DAN polymer that the present invention synthesizes according to embodiment 1;
Fig. 2 is the sign of the PEI-alt-DAN/DNA complex that the present invention is prepared according to embodiment 5: (A) PEI-alt-DAN, PEI423 and DNA is with the complex gel electrophoresis figure of different quality than preparation; (B) PEI-alt-DAN is to the gel electrophoresis figure of DNA protective capability; (C) PEI-alt-DAN and DNA forms the TEM figure of nanoparticle; (D) PEI-alt-DAN is self-assembled into the grain-size graph of nanoparticle to DNA;
Fig. 3 is the outer-gene transfection of PEI-alt-DAN/DNA nano-complex in SMMC7721 cell that the present invention is prepared according to embodiment 5;
Fig. 4 PEI-alt-DAN/shAkt1 nano-complex that to be the present invention prepare according to embodiment 5 is at the toxicity detection of SMMC7721 cell;
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further described.
The present invention is realized by following technical scheme, and concrete steps are as follows:
When R is H, prodrug polymer P EI-alt-DAN chemical structural formula is as follows:
Synthetic schemes is specific as follows: first by norcantharidin and 2-(Acryloyloxy)ethanol Reactive Synthesis norcantharidin diacrylate, then norcantharidin diacrylate and small-molecular-weight polyamines polyreaction generate polymer P EI-alt-DAN, through dialysis, precipitation, vacuum drying, obtains sterling for subsequent use.
When R is methyl CH
3, adopt cantharidin diacrylate to replace norcantharidin diacrylate, in like manner synthesize and get final product.R is H or CH
3, the common delivering drugs of prodrug polymer and preparation and the nano-carrier of gene, compound property is similar with effect, illustrates no longer one by one, sets forth in embodiment for PEI-alt-DAN.
Sending nano-carrier is altogether all fresh preparations, and preparation scheme is specific as follows: joined under vortex by cdna solution in isopyknic prodrug polymer solution, vortex 30s, room temperature leaves standstill 30min, obtains and sends nano-carrier altogether.
Common delivering drugs prepared by above-mentioned preparation method and the nano-carrier of gene, described nano-carrier particle size range is 100nm-400nm.
The nano-carrier of above-mentioned delivering drugs and gene is altogether preparing the application in Therapeutic cancer (particularly hepatocarcinoma, pulmonary carcinoma, breast carcinoma etc.) medicine.
Embodiment 1
The synthesis of norcantharidin diacrylate: norcantharidin, DMAP, 2-(Acryloyloxy)ethanol and dicyclohexylcarbodiimide feed intake with certain proportion mol ratio (1.0:0.02:2.0:2.1), be dissolved in dichloromethane, reaction 36h, crosses silicagel column and obtains norcantharidin diacrylate; Polymer P EI-alt-DAN synthesizes: get appropriate norcantharidin diacrylate, with dissolve with ethanol, add PEI423, feed intake with certain proportion mol ratio (1.0:1.0), the lower 60 DEG C of stirring reaction 5d of nitrogen protection, dialysis (MWCO=3500), by solution in lyophilization, obtains final polymeric articles;
Embodiment 2
The synthesis of cantharidin diacrylate: cantharidin, DMAP, 2-(Acryloyloxy)ethanol and dicyclohexylcarbodiimide feed intake with certain proportion mol ratio (1.0:0.02:2.0:2.1), be dissolved in dichloromethane, reaction 36h, crosses silicagel column and obtains norcantharidin diacrylate; Macroscopic single crystal: get appropriate cantharidin diacrylate, dissolve with ethanol, add PEI300, feed intake with certain proportion mol ratio (1.0:1.0), the lower 60 DEG C of stirring reaction 5d of nitrogen protection, dialysis (MWCO=3500), by solution in lyophilization, obtains final polymeric articles;
Embodiment 3
PEI-alt-PEG Macroscopic single crystal: get appropriate polyethylene glycol acrylate; dissolve with ethanol; add PEI423; feed intake with certain proportion mol ratio (1.0:1.0); the lower 60 DEG C of stirring reaction 5d of nitrogen protection; dialysis (MWCO=3500), by solution in lyophilization, obtains comparison polymer material.
Embodiment 4
The Structural Identification of PEI-alt-DAN polymer and molecular weight characterization
PEI-alt-DAN polymer identifies structure by hydrogen nuclear magnetic resonance.Fig. 1 (A), on the hydrogen spectrum spectrogram of hydrogen spectrum result display: PA, chemical displacement value 2.5-3.3ppm is the characteristic peak of the hydrogen in PEI-alt-DAN on PEI, chemical displacement value is 4.41-4.55ppm, 3.0-3.29ppm and 1.22-1.49ppm is the characteristic peak of the hydrogen of methylene on norcantharidin medium ring, above-mentioned characteristic peak all has display, and the synthesis success of polymer P EI-alt-DAN is described.
Molecular weight is detected by gel permeation chromatography, and column temperature is 30 DEG C, flow velocity 1.0mL/min, and mobile phase is 0.5M metabisulfite solution.
Embodiment 5
The preparation of PEI-alt-DAN/DNA complex
All PEI-alt-DAN/DNA complex are all fresh preparations, and concrete grammar is, are added to by DNA solution in the polymer solution under equal-volume, lightly vortex 30s, keep 30min under room temperature.
Embodiment 6
Polymer P EI-alt-DAN is to DNA compression and the investigation of protective capability
Polymer P EI-alt-DAN is characterized by electrophoresis DNA compression and protective capability.The mass ratio of polymer P EI-alt-DAN/DNA is 0.1 to 20, adds loading pigment, and last volume is 12 μ L.In order to evaluate the protective capability of polymer P EI-alt-DAN to DNA, DNaseI is as digestive enzyme.Complex is added in 1% agarose gel, with TAE buffer as electrolyte, runs 40min under 50V.
Embodiment 7
The sign of complex
The size of complex and surface charge use Dynamic Light Scattering Determination.Each sample is 2mL, and wherein DNA concentration is 50ug/mL.
Embodiment 8
In-vitro transfection
The transfection efficiency in vitro of the PEI-alt-DAN adopting SMMC7721 cell line evaluate root to synthesize according to embodiment 1.SMMC7721 cell is human liver cancer cell.At 37 DEG C, at 5%CO
2cell is maintained in the DMEM culture medium of incubator (ThermoScientific).Concerning transfection experiment, by two kinds of cells 10 × 10
4the amount of individual cells/well is seeded in 24 hole flat undersides, after hatching 18h, replaces, then hatch 4h by the culture medium of PEI-alt-DAN/pGL3 complex at serum-free.Replace by fresh culture medium afterwards, then hatch 24h at 37 DEG C.Uciferase activity measures the method according to manufacturer.BCA protein assay reagent kit for extracting albumen, its concentration Chemiluminometer (Autolumat, LB953; EG & GBerthold, Germany) measure.
Embodiment 9
The detection of PEI-alt-DAN/shAkt1 drug effect
Cytotoxicity after the PEI-alt-DAN complex gene adopting SMMC7721 cell line evaluate root to synthesize according to embodiment 1.SMMC7721 cell is human liver cancer cell.At 37 DEG C, at 5%CO
2cell is maintained in the DMEM culture medium of incubator (ThermoScientific).By two kinds of cells 1 × 10
4the amount of individual cells/well is seeded in 96 hole flat undersides, after hatching 18h, add containing PEI-alt-DAN/shAkt1 nanoparticle, PEI-alt-DAN/scrshRNA nanoparticle, PEI-alt-PEG/shAkt1 nanoparticle, PEI-alt-PEG/scrshRNA nanoparticle, PEI25K/shAkt1 nanoparticle, PEI25K/scrshRNA nanoparticle, shAkt1 solution, NCTD solution etc.For making each processed group above-mentioned have comparability, fix N CTD concentration is 10 μ g/mL, and shAkt1 concentration is 1 μ g/well, process 24 or 72h.Use 20 μ L5mg/mlMTT afterwards, lucifuge 37 DEG C of jolting 4h, microplate reader 490nm tests.
The above is only the preferred embodiment of the present invention; be noted that for those skilled in the art; under the premise without departing from the principles of the invention, can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. the nano-carrier sent altogether of gene and medicine, the nano-complex formed by cation prodrug polymer and gene; The chemical structural formula of prodrug polymer is as follows:
Wherein, m, n are positive integer.
2. the nano-carrier sent altogether of gene according to claim 1 and medicine, preparation method comprises the following steps: joined by cdna solution in isopyknic prodrug polymer solution under vortex, vortex 10-30s, room temperature leaves standstill 15-30min, to obtain final product.
3. the nano-carrier sent altogether of gene according to claim 1 and 2 and medicine, is characterized in that: described gene is shAkt1, P53 or PDCD4.
4. a prodrug polymer, is characterized in that: the chemical structural formula of prodrug polymer is as follows:
Wherein, m, n are positive integer.
5. prodrug polymer according to claim 4, preparation method is as follows: be dissolved in appropriate ethanol by cantharidin medicine acrylate, add polyamine molecule, cantharidin medicine acrylate and polyamine molecule molar ratio are 1.0:(1.0-2.0), at 30-90 DEG C and stirred under nitrogen atmosphere reaction 1-5d; Products therefrom is dissolved in the deionized water of 4 DEG C, and then to dialyse at 4 DEG C 2d with the bag filter of molecular cut off 3500, lyophilizing, to obtain final product.
6. prodrug polymer according to claim 5, is characterized in that: polyamine molecule comprises spermine, spermidine, diethylenetriamine, triethylene tetramine, TEPA tetraethylene pentamine, five ethylene hexamine and PEI300, PEI423, PEI600, PEI1200, PEI1800.
7. prodrug polymer according to claim 5, is characterized in that: described cantharidin medicine acrylate is norcantharidin diacrylate or cantharidin diacrylate.
8. prodrug polymer according to claim 4, as the application of polymeric prodrugs or genophore.
9. the nano-carrier that the gene according to any one of claim 1-3 and medicine are sent altogether is preparing the application in Hepatoma therapy, pulmonary carcinoma or breast cancer medicines.
10. the nano-carrier that the gene according to any one of claim 1-3 and medicine are sent altogether, by pulmonary's suction or by injection system administration.
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Cited By (2)
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| CN112300187A (en) * | 2019-07-25 | 2021-02-02 | 贵州柏强制药有限公司 | Cantharidin derivative, pharmaceutical composition and application thereof |
| CN113082054A (en) * | 2021-03-15 | 2021-07-09 | 中国药科大学 | Gene delivery vector transfected by stem cells and preparation method and application thereof |
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| CN101437544A (en) * | 2006-01-23 | 2009-05-20 | 艾博特公司 | Chemically modified polycation polymer for siRNA delivery |
| CN101367850A (en) * | 2008-10-15 | 2009-02-18 | 苏州大学 | Norabieta cantharidin derivant and synthesis thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112300187A (en) * | 2019-07-25 | 2021-02-02 | 贵州柏强制药有限公司 | Cantharidin derivative, pharmaceutical composition and application thereof |
| CN113082054A (en) * | 2021-03-15 | 2021-07-09 | 中国药科大学 | Gene delivery vector transfected by stem cells and preparation method and application thereof |
| CN113082054B (en) * | 2021-03-15 | 2023-09-26 | 中国药科大学 | Stem cell transfected gene delivery vector and preparation method and application thereof |
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