CN104983716A - Tumor cell membrane/nuclear membrane double-targeting tumor nano-drug slow-release system and preparation and application thereof - Google Patents
Tumor cell membrane/nuclear membrane double-targeting tumor nano-drug slow-release system and preparation and application thereof Download PDFInfo
- Publication number
- CN104983716A CN104983716A CN201510428283.4A CN201510428283A CN104983716A CN 104983716 A CN104983716 A CN 104983716A CN 201510428283 A CN201510428283 A CN 201510428283A CN 104983716 A CN104983716 A CN 104983716A
- Authority
- CN
- China
- Prior art keywords
- msn
- tatp
- tls11a
- dox
- tumor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses a tumor cell membrane/nuclear membrane double-targeting tumor nano-drug slow-release system and preparation and application thereof. The tumor cell membrane/nuclear membrane double-targeting tumor nano-drug slow-release system is a nano particle composed of a nucleus and a shell, wherein the shell is composed of an aptamer, PEG and nano liposomes, and the aptamer is connected with the nano liposome through the PEG and capable of specifically recognizing a tumor cell; the nucleus is composed of a nano material modified by polypeptide and an antineoplastic drug carried by the nano material modified by the polypeptide, and the polypeptide is capable of penetrating through a cell nucleus nuclear membrane. It is proved through experiments that the tumor cell membrane/nuclear membrane double-targeting tumor nano-drug slow-release system can inhibit tumor growth and prolong the survival time of a tumor-bearing animal and can be used for treating a tumor.
Description
Technical field
The present invention relates to the two target tumor Nano medication slow-released system of tumor cell membrane/nuclear membrane in biomedical sector and preparation and application thereof.
Background technology
Hepatocarcinoma is one of modal tumor clinically, and its sickness rate rises year by year, and the healthy of the mankind in serious threat.Guangxi Zhuang Autonomous Region is China High Phc Incidence Area, and its mortality rate is the twice in the whole nation.Hepatocarcinoma often grade malignancy is high, and treatment difficulty is large, and transfer time early, manyly during discovery arrives middle and advanced stage, loses the chance of operative treatment.Although new treatment technology is constantly updated, operation, chemotherapy, radiotherapy remain the mainstay of oncotherapy.Chemotherapeutics directly can kill thin cancer born of the same parents, is the most desirable and one of the most obvious treatment means of effect.
Amycin (Doxorubicin, DOX) is one of the most frequently used clinically anti-chemotherapy of hepatocellular carcinoma medicine, effectively can suppress the synthesis of RNA and DNA, thus reach antineoplastic action.But, because of its serious cardiac toxicity and suppression hemopoietic function of bone marrow, cause it to be in the position of clinical two wires medication for a long time.Liposomal doxorubicin certain limit can reduce drug side effect, but because it can not targets neoplastic cells specifically, this causes serious impact to the normal physiological function of human body after causing it to enter body circulation, greatly reduces the ability to bear of patient to drug dose and the resistivity to disease.
Aptamers (aptamer) screens by the phyletic evolution technology (systematic evolution ofligands by exponential enrichment, SELEX) of index concentration aglucon single stranded DNA, the RNA that the class that obtains can be combined with specific target molecule.
The Liposome nanaparticle (lipid bilayer, LB) of about the 100nm modified through Polyethylene Glycol (PEG) nowadays studies one of the most popular nano-medicament carrier.But LB sphere of action primary limitation is in tumor endochylema, and act on nuclear medicine for some, it is limited in one's ability, and after it is engulfed by endosome, stability reduces greatly, thus limits its ability as the many targeted therapies of tumor and drug release.
Mesoporous silicon dioxide nano particle (Mesoporous Silica Nanoparticle, MSN) has good biocompatibility, specific surface area is large, pore volume aperture is large, mesoporous pore size (2 ~ 50nm) is controlled and Stability Analysis of Structures.
Nuclear membrane high penetrating power peptide TATp (transactivator of transcription peptide, TATp) is the TATp albumen the preceding paragraph small-molecular peptides (Tyr – Gly – Arg – Lys – Lys – Arg – Arg – Gln – Arg – Arg-Arg) deriving from HIV.
Although the treatment of hepatocarcinoma makes some progress in recent years, the therapeutic effect of hepatocarcinoma is still unsatisfactory.Therefore, in the urgent need to researching and developing new treatment technology means and strategy to improve therapeutic efficacy for hepatic carcinoma.
Summary of the invention
Technical problem to be solved by this invention how to improve tumour medicine to the targeting of tumor and lethality and how to extend tumour medicine circulation time in vivo.
For solving the problems of the technologies described above, the present invention provide firstly Nano medication slow-released system.
The nanoparticle that Nano medication slow-released system provided by the present invention is made up of core and shell, described shell is made up of aptamers, PEG and nanometer liposome, described aptamers is connected with described nanometer liposome by described PEG, described adaptive physical ability specially recognizing tumor cells; Described core is made up of peptide modified nano material and the antitumor drug be carried in described peptide modified nano material, described polypeptide energy penetration cell core nuclear membrane.
In said system, the aminoacid sequence of described polypeptide can be SEQ ID No.1 in sequence table, and its name is called transactivator of transcription peptide (TATp).
In said system, described nano material can be mesopore silicon dioxide nano material.Described mesoporous aperture can be 2-10nm.
In said system, described nano material can be amido modified.
In said system, the particle diameter of described nano material can be 30-70nm.The particle diameter of described nano material specifically can be 50nm.
In said system, the particle diameter of described nanometer liposome can be 60-200nm.The particle diameter of described nanometer liposome specifically can be 80nm.
In said system, described tumor cell can be solid tumor cell.
In said system, described tumor cell can be hepatoma carcinoma cell.Described hepatoma carcinoma cell specifically can be H22 tumor cell.
In said system, the nucleotide sequence of described aptamers can be SEQ ID No.2 in sequence table, and its name is called TLS11a.
In said system, described tumour medicine can be amycin.Described amycin specifically can be Sigma Products, and article No. is D1515.
For solving the problems of the technologies described above, present invention also offers the preparation method of described Nano medication slow-released system.
The preparation method of described Nano medication slow-released system provided by the present invention, to comprise with described shell bag by described core, obtains described system.
In said method, described method also can comprise the preparation of described shell and/or the preparation of described core;
The preparation of described shell can comprise: the nanometer liposome that preparation PEG modifies; The nanometer liposome modifying described PEG modification by described aptamers obtains described shell;
The preparation of described core can comprise: load described antitumor drug by described peptide modified nano material and obtain described core.
In said method, the preparation method of the nanometer liposome that described PEG modifies can comprise: the nanometer liposome preparing described PEG modification with POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), cholesterol, PEG2000-DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethyleneglycol)-2000]), PHOSPHATIDYL ETHANOLAMINE-Macrogol 2000-maleimide (MAL-PEG2000-DSPE) and α-tocopherol.The mol ratio of described POPC, described cholesterol, described PEG2000-DSPE, described MAL-PEG2000-DSPE and described α-tocopherol can be 52.26:41.97:5.255:0.315:0.2.
In said method, the preparation of described peptide modified nano material can comprise: obtain described peptide modified nano material by the nano material that described peptide modified amination is modified.
In said method, describedly can to comprise by described peptide modified described nano material: amido modified described nano material obtains the nano material that amination is modified; Described peptide modified nano material is obtained by the nano material that described peptide modified described amination is modified.
In said method, described nano material can be hexadecyltrimethylammonium chloride and triethanolamine is obtained by reacting material.Described reaction temperature can be 95-100 DEG C, as 98 DEG C.The mass ratio of described hexadecyltrimethylammonium chloride and described triethanolamine can be 100:4.
In said method, the aminoacid sequence of described polypeptide can be SEQ ID No.1 in sequence table.
In said method, described nano material can be mesopore silicon dioxide nano material.Described mesoporous aperture can be 2-10nm.
In said method, the particle diameter of described nano material can be 30-70nm.The particle diameter of described nano material specifically can be 50nm.
In said method, the particle diameter of described nanometer liposome can be 60-200nm.The particle diameter of described nanometer liposome specifically can be 80nm.
In said method, described tumor can be entity tumor.
In said method, described tumor can be hepatocarcinoma.Described tumor specifically can be the tumor that H22 tumor cell causes.
In said method, the nucleotide sequence of described aptamers can be SEQ ID No.2 in sequence table.
In said method, described tumour medicine can be amycin.Described amycin specifically can be Sigma Products, and article No. is D1515.
For solving the problems of the technologies described above, present invention also offers the reagent set for the preparation of described Nano medication slow-released system.
Reagent set for the preparation of described Nano medication slow-released system provided by the present invention, for four kinds in described aptamers, described tumour medicine, described polypeptide and described nano material these four kinds, wantonly three kinds or any two.
For solving the problems of the technologies described above, present invention also offers described Nano medication slow-released system or described reagent set and preparing the application treated and/or prevented in tumour medicine; Or described reagent set is preparing the application in liposome.
For solving the problems of the technologies described above, present invention also offers and treat and/or prevent tumour medicine.
The active component treating and/or preventing tumour medicine provided by the present invention is described Nano medication slow-released system.
In the present invention, described Nano medication slow-released system is prepared according to the preparation method of described Nano medication slow-released system.
In the present invention, described PEG can be distearyl acid phosphatidyl amine derivative or other PEG derivants of PEG.Described PEG specifically can be described PEG2000-DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethyleneglycol)-2000]) or described PHOSPHATIDYL ETHANOLAMINE-Macrogol 2000-maleimide (MAL-PEG2000-DSPE).
Experiment proves, the volume of the tumor after the growth of Nano medication slow-released system (TLS11a-LB-TATp-MSN/DOX) Tumor suppression of the present invention: TLS11a-LB-TATp-MSN/DOX treats is respectively 0.0615 times, 0.1507 times, 0.1034 times, 0.4214 times, 0.0791 times, 0.2274 times of PBS, DOX, TATp-MSN/DOX, TLS11a-LB-MSN/DOX, TLS11a-LB-TATp-MSN, LB-TATp-MSN/DOX.
Experiment proves, Nano medication slow-released system (TLS11a-LB-TATp-MSN/DOX) of the present invention obviously can extend the life span of lotus tumor BalB/c nude mice: the time when the lotus tumor BalB/c nude mice survival rate of TLS11a-LB-TATp-MSN/DOX treatment is 50% apart from the 1st treatment is respectively PBS, DOX injection, TATp-MSN/DOX injection, TLS11a-LB-MSN/DOX injection, apart from 2.47 times of the time of the 1st treatment when the lotus tumor BalB/c nude mice survival rate of TLS11a-LB-TATp-MSN injection and LB-TATp-MSN/DOX injection for treating is 50%, 1.45 doubly, 1.91 doubly, 1.11 doubly, 2.34 doubly, 1.42 doubly.
Experiment proves, the Nano medication slow-released system that TLS11a of the present invention modifies
(TLS11a-LB-TATp-MSN/DOX) have targeting to tumor: the lotus tumor BalB/c nude mice of fluorescently-labeled TLS11a-LB-TATp-MSN/DOX process in the fluorescence intensity of tumor site apparently higher than the lotus tumor BalB/c nude mice of fluorescently-labeled LB-TATp-MSN/DOX process in the fluorescence intensity of tumor site.
Experiment proves, the Nano medication slow-released system (TLS11a-LB-TATp-MSN/DOX) that TATp of the present invention modifies has targeting to nucleus, and can nucleus be entered: hatch 24 constantly little, not by TATp modify and the TLS11a-LB-FITC-MSN be fluorescently labeled mainly concentrate among endochylema, the TATp-MSN of green fluorescence FITC labelling that TATp modifies mainly concentrates in nucleus.
Nano medication slow-released system of the present invention has following characteristics: two targeted moleculars---the single-chain nucleic acid aptamers TLS11a and short chain high penetrating power peptide section TATp used in the preparation of (1) Nano medication slow-released system, synthesize with low cost, method is simple; (2) liposome used in the preparation of Nano medication slow-released system and mesoporous silicon oxide technology of preparing maturation, can prepare on a large scale; (3) Nano medication slow-released system circulation time is in vivo long; (4) Nano medication slow-released system can realize the targeting to tumor; (5) Nano medication slow-released system can realize the targeting to neoplastic cell nuclei, improves the drug-rich amount of neoplastic cell nuclei, thus improves antitumous effect.Experiment proves, the growth of Nano medication slow-released system energy Tumor suppression of the present invention, and can extend the time-to-live of tumor animal, can be used to treat tumor.
Accompanying drawing explanation
Fig. 1 is the schematic diagram of the two target tumor Nano medication slow-released system of tumor cell membrane/nuclear membrane.Wherein, MAL-DSPE-PEG
2000for MAL-PEG
2000-DSPE.
Fig. 2 is the preparation process schematic diagram of TLS11a-LB-TATp-MSN/DOX.
Fig. 3 is the transmission electron microscope picture of the intermediate product in TLS11a-LB-TATp-MSN/DOX and preparation process thereof.Wherein, A is the transmission electron microscope picture of MSN; B is the transmission electron microscope picture of TLS11a-LB-TATp-MSN.
Fig. 4 is the particle diameter of the intermediate product in TLS11a-LB-TATp-MSN/DOX and preparation process thereof.
Fig. 5 is the volume of the tumor of the lotus tumor BalB/c nude mice of different disposal.
Fig. 6 is the time that the lotus tumor BalB/c nude mice of different disposal is treated apart from the 1st time when different survival rates.Wherein, TLS11a-LB@TATp-MSN/DOX is TLS11a-LB-TATp-MSN/DOX, TLS11a-LB@MSN/DOX is TLS11a-LB-MSN/DOX, TLS11a-LB@TATp-MSN be TLS11a-LB-TATp-MSN, LB@TATp-MSN/DOX is LB-TATp-MSN/DOX.
Fig. 7 is the tumor of the lotus tumor BalB/c nude mice of different disposal.Wherein, 1,2,3 and 4 represent respectively first time, for the second time, for the third time and four time inject, Free DOX represents DOX.
Fig. 8 is the impact of TATp on the targeting of TLS11a-LB-TATp-MSN/DOX.A is FITC-TATp-MSN; B is DiI-TLS11a-LB; C is DiI-TLS11a-LB-FITC-TATp-MSN; D is the tumor cell of DiI-TLS11a-LB-FITC-MSN process; E is the tumor cell of DiI-TLS11a-LB-FITC-TATp-MSN process.
Fig. 9 is the impact of TLS11a on the targeting of TLS11a-LB-TATp-MSN/DOX.Wherein, TLS11a-LB-TATp-MSN represents the lotus tumor BalB/c nude mice of DiR-TLS11a-LB-TATp-MSN/DOX process; LB-TATp-MSN represents the lotus tumor BalB/c nude mice of DiR-LB-TATp-MSN/DOX process; DiR is contrast.
Detailed description of the invention
Below in conjunction with detailed description of the invention, the present invention is further described in detail, the embodiment provided only in order to illustrate the present invention, instead of in order to limit the scope of the invention.
Experimental technique in following embodiment, if no special instructions, is conventional method.
Material used in following embodiment, reagent etc., if no special instructions, all can obtain from commercial channels.
Ethyl orthosilicate (TEOS, tetraethyl orthosilicate) in following embodiment is Sigma Products, and article No. is 131903;
EDC is Sigma Products, and article No. is E6383;
NHS is Sigma Products, and article No. is 130672;
POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) for U.S. AVANTI Products, article No. be 850457;
Cholesterol (cholesterol) is Beijing Suo Laibao Science and Technology Ltd. product, and article No. is C8280;
PEG
2000-DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethyleneglycol)-2000]) is AVANTI company of U.S. Products, and article No. is 880128;
MAL-PEG
2000-DSPE is U.S. AVANTI Products, and article No. is 880150; α-tocopherol is Beijing Suo Laibao Science and Technology Ltd. of U.S. product, and article No. is V8010.
Amycin in following embodiment is Sigma Products, and article No. is D1515.
TATp in following embodiment is Chinese Peptide Company Products, and article No. is the aminoacid sequence of 828608, TATp is SEQ ID No.1 in sequence table.
Aptamers TLS11a in following embodiment makes a living work biological engineering (Shanghai) limited company product, and article No. is that the nucleotides sequence of hc-447806, TLS11a is classified as SEQ ID No.2 in sequence table.Inbred line Female nude mice (BALB/c Nude Mice) in following embodiment is Shanghai Bang Yao Bioisystech Co., Ltd product.
H22 tumor cell in following embodiment is Wuhan University's preservation hub products.
The preparation of the two target tumor Nano medication slow-released system of embodiment 1, tumor cell membrane/nuclear membrane
Nano medication slow-released system provided by the present invention is the two target tumor Nano medication slow-released system of tumor cell membrane/nuclear membrane, and as shown in Figure 1, its name is called TLS11a-LB-TATp-MSN/DOX.
TLS11a-LB-TATp-MSN/DOX, the nanoparticle be made up of core (TATp-MSN/DOX) and shell (TLS11a-LB), shell is made up of aptamers (TLS11a), PEG and nanometer liposome, TLS11a is connected with nanometer liposome by PEG, TLS11a energy specific recognition hepatoma carcinoma cell, the nucleotides sequence of aptamers TLS11a is classified as SEQ ID No.2 in sequence table; Nano material (the mesopore silicon dioxide nano material that TATp-MSN/DOX is modified by polypeptide (TATp), MSN) and be carried in peptide modified nano material antitumor drug (DOX) composition, TATp energy penetration cell core nuclear membrane, the aminoacid sequence of peptide T ATp is SEQ ID No.1 in sequence table.
As shown in Figure 2, concrete preparation method is as follows for the preparation process of TLS11a-LB-TATp-MSN/DOX:
The preparation of S1, mesopore silicon dioxide nano material (MSN):
Get 10g hexadecyltrimethylammonium chloride (CTAC) and 0.4g triethanolamine (TEA) is dissolved in 100ml deionized water, obtain CTAC-TEA aqueous solution; CTAC-TEA aqueous solution is placed in round-bottomed flask, oil bath in trimethyl silicone oil condensing reflux, oil bath condensing reflux carries out under vigorous magnetic stirs, after vigorous magnetic stirs 1h, 15000rpm (28500g) obtains liquid A 1 in centrifugal 30 minutes, the abundant temperature of trimethyl silicone oil oil is 98 DEG C, and the rotating speed of condensing reflux magnetic agitation is 250rpm;
By 8ml ethyl orthosilicate (TEOS, tetraethyl orthosilicate) dropwise join in aforesaid liquid A1, continue oil bath in trimethyl silicone oil and condensing reflux, oil bath condensing reflux carries out under vigorous magnetic stirs, vigorous magnetic stirs 1h, obtains liquid A 2; Liquid A 2 is naturally cooled to room temperature, and under 15000rpm (28500g), high speed centrifugation collects solid product C1; Remove Residual reactants 3 times with dehydrated alcohol ultrasonic cleaning solid product in ultrasonic washing unit, obtain solid product C2, ultrasound condition is: 250W, water bath sonicator under room temperature (20-25 DEG C);
By solid product C2, at ethanol solution hydrochloride, (ethanol solution hydrochloride is made up of hydrochloric acid and dehydrated alcohol, in ethanol solution hydrochloride, the concentration of volume percent of hydrochloric acid is 5%) middle condensing reflux extraction 6h removal template CTAC, extraction repetition 3 times, remove completely to CTAC, be extracted rear material, extraction temperature is 75-80 DEG C, and extraction time is 6-12h;
In ultrasonic washing unit, material dehydrated alcohol ultrasonic disperse after extraction is cleaned 3 times, 3 times are cleaned again with deionized water ultrasonic disperse, obtain mesopore silicon dioxide nano material (MSN), ultrasound condition is: 250W, water bath sonicator under room temperature (20-25 DEG C).The aperture of mesopore silicon dioxide nano material is 2-10nm, and particle diameter is 30-70nm.
Mesopore silicon dioxide nano material (MSN-NH is modified in S2, amination
2) preparation
Getting the MSN that 100mg step S1 obtains is dispersed in 20ml deionized water, add 100 μ l glacial acetic acids and 50 μ l APTES, stirred at ambient temperature 24 hours, washes 3-4 time with deionized water, vacuum lyophilization 24 hours, mesopore silicon dioxide nano material (MSN-NH is modified in amination
2).
The preparation of the mesopore silicon dioxide nano material (TATp-MSN) that S3, TATp modify
In 20ml PBS solution (pH 7.2-7.4), add 3.12mg TATp, 38.4mg EDC and 56mg NHS, room temperature vigorous stirring 1.5 hours, obtains liquid B 1; By the MSN-NH that 20mg step S2 obtains
2add in liquid B 1, room temperature vigorous stirring 24 hours, obtains liquid B 2; Liquid B 2 is centrifugal under 15000rpm (28500g), abandon supernatant, be precipitated D1; Centrifugal under washing precipitation D1,15000rpm (28500g) with deionized water, obtain the mesopore silicon dioxide nano material (TATp-MSN) that TATp modifies.
The preparation of the core material (TATp-MSN/DOX) of S4, load amycin
(solution M adds the solution that amycin obtains in PBS (pH 7.0) TATp-MSN that 10mg step S3 obtains to be dispersed in 5ml solution M, in solution M, the concentration of amycin is 0.5mg/ml) in, room temperature magnetic agitation is after 24 hours, centrifugal under 15000rpm (28500g), abandon supernatant, be precipitated E1, centrifugal under precipitation E1 PBS being cleaned 15000rpm_ (28500g), obtain the core material of load amycin, by its called after TATp-MSN/DOX, every gram of TATp-MSN/DOX loads the amycin of 833mg.
According to the method described above, the TATp-MSN that step S3 obtains is replaced with the MSN-NH that step S2 obtains
2, other steps are all constant, obtain the MSN-NH of load amycin
2, by its called after MSN/DOX.
Utilize document (Pan et al., Overcoming multidrug resistance of cancer cells bydirect intranuclear drug delivery using TAT-conjugated mesoporous silicananoparticles, Biomaterials, 34 (2013) 2719-2730) in method measure the envelop rate of amycin, TATp-MSN is 83.3% to amycin envelop rate.
The preparation of the lipid bilayer (LB) that S5, PEG modify
By POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), cholesterol, PEG2000-DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethyleneglycol)-2000]), MAL-PEG2000-DSPE, α-tocopherol be in molar ratio 52.26:41.97:5.255:0.315:0.2 ratio mixing, obtain mix reagent N1; Getting 1ml mix reagent N1 adds in the round-bottomed flask of 5ml, the round-bottomed flask this being filled above-mentioned each reagent is received on Rotary Evaporators, Rotary Evaporators is that 200rpm/min rotates and opens vacuum pump evacuation with rotating speed, after round-bottomed flask surface produces one deck steam, body is down to water-bath at 35 DEG C in water-bath, can vacuum pump be closed after rotating 10min and stop the rotation, obtaining the round-bottomed flask filling the rear reagent of reaction; After filling the round bottom flask of reagent after reaction dry 2h remove organic solvent to vacuum drying oven, add the hepes buffer (pH6.5 of 1ml, 10mmol/l) (preparation method of hepes buffer is: the list that accurate weighing 2.383gHEPES is dissolved in 800ml steams water, use the hydrochloric acid of 1M that pH is adjusted to 6.5, then volumetric flask standardize solution is used to 1L), obtain mixed liquor N2; By mixed liquor N2 water bath sonicator (ultrasound condition is 250W, water bath sonicator under room temperature (20-25 DEG C)) 5min in ultrasonic washing unit, obtain white suspension; Added by white suspension in the glass syringe of liposome extruder, mistake 200nm polycarbonate membrane 20 times, 100nm polycarbonate membrane 20 times and 50nm polycarbonate membrane 21 times, obtains the lipid bilayer (LB) that PEG modifies successively.
The preparation of the lipid bilayer (TLS11a-LB) that S6, aptamers TLS11a modify
Be the ratio mixing of 1:10 according to mol ratio by aptamers TLS11a and MAL-PEG2000-DSPE, obtain mix reagent P1; Get 50 μ l mix reagent P1 to add to after in the amine-modified lipid bilayer (LB) of maleimide that S5 obtains; under nitrogen protection environment, react 24h, the lipid bilayer (TLS11a-LB) that unreacted aptamers TLS11a obtains aptamers TLS11a modification is removed in dialysis.Dialysis time is 4 hours, within 2 hours, change a dialysis solution, the molecular cut off of bag filter is 10000, dialysis solution is the liquid be made up of deionized water, sodium chloride and Tris hydrochloric acid, in dialysis solution, the concentration of sodium chloride is 140mmol/L, the concentration of Tris hydrochloric acid (Tris-HCl) is 25mmol/L, and the pH of dialysis solution is 7.0).
The preparation of the two target tumor Nano medication slow-released system (TLS11a-LB-TATp-MSN/DOX) of S7, tumor cell membrane/nuclear membrane
The TATp-MSN/DOX that 10mg step S4 obtains is added in the lipid bilayer (TLS11a-LB) of the aptamers TLS11a modification that 100 μ l step S6 obtain, by liquid-transfering gun mixed number 30 times, 4 weeks are left standstill at 4 DEG C, obtain mixed liquor R1, by mixed liquor R1 under 15000rpm (28500g) centrifugal 3 minutes, its supernatant, is precipitated Q1; Q1 PBS (pH7.2-7.4) will be precipitated wash, obtain being mounted with in TLS11a-LB the two target tumor Nano medication slow-released system (TLS11a-LB-TATp-MSN/DOX) of system-tumor cell membrane/nuclear membrane of TATp-MSN/DOX, containing a TATp-MSN/DOX in each TLS11a-LB-TATp-MSN/DOX.
Utilize document (Pan et al., Overcoming multidrug resistance of cancer cells bydirect intranuclear drug delivery using TAT-conjugated mesoporous silicananoparticles, Biomaterials, 34 (2013) 2719-2730) in method measure the envelop rate of amycin, TATp-MSN is 83.3% to amycin envelop rate.
According to the method described above, the TATp-MSN/DOX obtained by step S4 replaces with the MSN/DOX that step S4 obtains, and other steps are all constant, obtains the system being mounted with MSN/DOX in TLS11a-LB, by its called after TLS11a-LB-MSN/DOX.
According to the method described above, the TATp-MSN/DOX obtained by step S4 replaces with the TATp-MSN that step S3 obtains, and other steps are all constant, obtains the system being mounted with TATp-MSN in TLS11a-LB, by its called after TLS11a-LB-TATp-MSN.
According to the method described above, the TATp-MSN/DOX that step S4 obtains is replaced with the MSN-NH that step S2 obtains
2, other steps are all constant, obtain being mounted with MSN-NH in TLS11a-LB
2system, by its called after TLS11a-LB-MSN-NH
2.
According to the method described above, the TATp-MSN/DOX obtained by step S4 replaces with TATp, and other steps are all constant, obtains the system being mounted with TATp in TLS11a-LB, by its called after TLS11a-LB-TATp.
According to the method described above, the TATp-MSN/DOX obtained by step S4 replaces with DOX, and other steps are all constant, obtains the system being mounted with DOX in TLS11a-LB, by its called after TLS11a-LB-DOX.
According to the method described above, the lipid bilayer (TLS11a-LB) that the aptamers TLS11a that obtained by step S6 modifies replaces with the amine-modified lipid bilayer (LB) of maleimide that step S5 obtains, other steps are all constant, obtain the system being mounted with TATp-MSN/DOX in LB, by its called after LB-TATp-MSN/DOX.
According to the method described above, the TATp-MSN/DOX obtained by step S4 replaces with the MSN/DOX that step S4 obtains, and the lipid bilayer (TLS11a-LB) that the aptamers TLS11a obtained by step S6 modifies replaces with the amine-modified lipid bilayer (LB) of maleimide that step S5 obtains, other steps are all constant, obtain the system being mounted with MSN/DOX in LB, by its called after LB-MSN/DOX.
According to the method described above, the TATp-MSN/DOX obtained by step S4 replaces with the TATp-MSN that step S3 obtains, and the lipid bilayer (TLS11a-LB) that the aptamers TLS11a obtained by step S6 modifies replaces with the amine-modified lipid bilayer (LB) of maleimide that step S5 obtains, other steps are all constant, obtain the system being mounted with TATp-MSN in LB, by its called after LB-TATp-MSN.
According to the method described above, the TATp-MSN/DOX that step S4 obtains is replaced with the MSN-NH that step S2 obtains
2and the lipid bilayer (TLS11a-LB) that the aptamers TLS11a obtained by step S6 modifies replaces with the amine-modified lipid bilayer (LB) of maleimide that step S5 obtains, other steps are all constant, obtain being mounted with MSN-NH in LB
2system, by its called after LB-MSN-NH
2.
According to the method described above, the TATp-MSN/DOX obtained by step S4 replaces with TATp, and the lipid bilayer (TLS11a-LB) that the aptamers TLS11a obtained by step S6 modifies replaces with the amine-modified lipid bilayer (LB) of maleimide that step S5 obtains, other steps are all constant, obtain the system being mounted with TATp in LB, by its called after LB-TATp.
According to the method described above, the TATp-MSN/DOX obtained by step S4 replaces with DOX, and the lipid bilayer (TLS11a-LB) that the aptamers TLS11a obtained by step S6 modifies replaces with the amine-modified lipid bilayer (LB) of maleimide that step S5 obtains, other steps are all constant, obtain the system being mounted with DOX in LB, by its called after LB-DOX.
Observe above-mentioned each system under transmission electron microscope, result as shown in Figure 3.In Fig. 3, A is the transmission electron microscope picture of MSN, and MSN is uniformly dispersed, smooth surface, and in Fig. 3, B is the transmission electron microscope picture of TLS11a-LB-TATp-MSN, and TLS11a-LB-TATp-MSN size is even, the dense material of surface parcel one deck.
MSN, MSN-NH
2, TATp-MSN, LB-TATp-MSN and TLS11a-LB-TATp-MSN particle diameter as shown in Figure 4.Result shows, and without the particle diameter of the MSN of any modification at about 50nm, modifies through TATp, after lipid bilayer packaging, TLS11a modify, the particle diameter of the TLS11a-LB-TATp-MSN/DOX finally obtained is about 80nm.
The TLS11a-LB-TATp-MSN/DOX of embodiment 2, embodiment 1 is to the therapeutical effect of tumor
Respectively TLS11a-LB-TATp-MSN/DOX, TATp-MSN/DOX, TLS11a-LB-MSN/DOX, TLS11a-LB-TATp-MSN and LB-TATp-MSN/DOX PBS of embodiment 1 is suspended, obtain doxorubicin content respectively and be the TLS11a-LB-TATp-MSN/DOX injection of 6 μ g/ μ L, TATp-MSN/DOX injection, TLS11a-LB-MSN/DOX injection, TLS11a-LB-TATp-MSN injection and LB-TATp-MSN/DOX injection.DOX is dissolved in PBS, obtains the DOX injection that doxorubicin content is 6 μ g/ μ L.
Get 6-8 inbred line Female nude mice in age in week (BALB/c Nude Mice), every only in left fore axillary fossa subcutaneous vaccination 2 × 10
6individual H22 tumor cell.Measure tumor major diameter and minor axis, according to formula TV=1/2 × a × b twice weekly
2calculate gross tumor volume.Treat that tumor average volume grows to about 10mm
3time, obtain lotus tumor BalB/c nude mice.Inject the above-mentioned TLS11a-LB-TATp-MSN/DOX injection of 200 μ L in tail vein to every lotus tumor BalB/c nude mice to treat, first time injection is designated as treatment the 0th day, the above-mentioned TLS11a-LB-TATp-MSN/DOX injection of 200 μ L within 9th day, is all injected, coprocessing 26 lotus tumor BalB/c nude mices respectively in treatment the 3rd day, treatment the 6th day and treatment.
According to the method described above, TLS11a-LB-TATp-MSN/DOX injection is replaced with respectively PBS, DOX injection, TATp-MSN/DOX injection, TLS11a-LB-MSN/DOX injection, TLS11a-LB-TATp-MSN injection and LB-TATp-MSN/DOX injection, other steps are all constant, obtain the lotus tumor BalB/c nude mice of PBS and each injection process, each process is 26 lotus tumor BalB/c nude mices.
The gross tumor volume (Fig. 5 and table 1) of 20 lotus tumor BalB/c nude mices in each process within 12nd day, is measured respectively in treatment the 2nd day, treatment the 4th day, treatment the 6th day, treatment the 8th day, treatment the 10th day and treatment, the time-to-live of 20 lotus tumor BalB/c nude mices in each process is recorded 1st day, statistics survival rate (Fig. 6 and table 2) from treatment.
Volume (the mm of tumor after table 1, different injection for treating lotus tumor BalB/c nude mice
3)
Result shows, TLS11a-LB-TATp-MSN/DOX, DOX, TATp-MSN/DOX, TLS11a-LB-MSN/DOX, with the growth of LB-TATp-MSN/DOX equal energy Tumor suppression, treatment the 12nd day, the volume of the tumor after TLS11a-LB-TATp-MSN/DOX injection for treating is respectively PBS, DOX injection, TATp-MSN/DOX injection, TLS11a-LB-MSN/DOX injection, TLS11a-LB-TATp-MSN injection, 0.0615 times of LB-TATp-MSN/DOX injection, 0.1507 times, 0.1034 times, 0.4214 times, 0.0791 times, 0.2274 times, show that the inhibitory action of TLS11a-LB-TATp-MSN/DOX to tumor growth is maximum, illustrate that TLS11a-LB-TATp-MSN/DOX can be used for treating tumor.
Table 2, the lotus tumor BalB/c nude mice time that distance is treated for the 1st time when different survival rates (my god)
Result shows, TLS11a-LB-TATp-MSN/DOX obviously can extend the life span of lotus tumor BalB/c nude mice: the time when the lotus tumor BalB/c nude mice survival rate of TLS11a-LB-TATp-MSN/DOX treatment is 50% apart from the 1st treatment is respectively PBS, DOX injection, TATp-MSN/DOX injection, TLS11a-LB-MSN/DOX injection, apart from 2.47 times of the time of the 1st treatment when the lotus tumor BalB/c nude mice survival rate of TLS11a-LB-TATp-MSN injection and LB-TATp-MSN/DOX injection for treating is 50%, 1.45 doubly, 1.91 doubly, 1.11 doubly, 2.34 doubly, 1.42 doubly.
Remaining for each process 6 lotus tumor BalB/c nude mices are respectively got respectively the tumor (Fig. 7) of a nude mice the 12nd day this every day of six days in treatment the 2nd day, treatment the 4th day, treatment the 6th day, treatment the 8th day, treatment the 10th day and treatment.Result shows, and the volume of the tumor of the lotus tumor BalB/c nude mice of TLS11a-LB-TATp-MSN/DOX process is significantly less than the volume of the tumor of the lotus tumor BalB/c nude mice of other process.
Above-mentioned experimental result shows, TLS11a-LB-TATp-MSN/DOX of the present invention has good antitumous effect, obviously can grow by Tumor suppression, extend the life span of lotus tumor BalB/c nude mice.
Embodiment 3, TLS11a and TATp are on the impact of the targeting of TLS11a-LB-TATp-MSN/DOX
1, TATp is on the impact of the targeting of TLS11a-LB-TATp-MSN/DOX
A kind of fat-soluble red fluorescence dyestuff Di I of labelling on the TLS11a-LB that embodiment 1 step S6 obtains, obtain by the TLS11a-LB of red fluorescence dyestuff DiI labelling (DiI-TLS11a-LB), labelling green fluorescence FITC on the TATp-MSN that the MSN obtained at embodiment 1 step S1 and step S2 obtains, obtains by the MSN of green fluorescence FITC labelling (FITC-MSN) with by the TATp-MSN of green fluorescence FITC labelling (FITC-TATp-MSN).
According to the preparation method of the TLS11a-LB-TATp-MSN/DOX of embodiment 1, the TATp-MSN/DOX obtained by step S4 replaces with above-mentioned FITC-MSN, and the lipid bilayer (TLS11a-LB) that the aptamers TLS11a obtained by step S6 modifies replaces with above-mentioned Di I-TLS11a-LB, other steps are all constant, obtain the system being mounted with FITC-MSN in DiI-TLS11a-LB, by its called after DiI-TLS11a-LB-FITC-MSN.
According to the preparation method of the TLS11a-LB-TATp-MSN/DOX of embodiment 1, the TATp-MSN/DOX obtained by step S4 replaces with above-mentioned FITC-TATp-MSN, and the lipid bilayer (TLS11a-LB) that the aptamers TLS11a obtained by step S6 modifies replaces with above-mentioned DiI-TLS11a-LB, other steps are all constant, obtain the system being mounted with FITC-TATp-MSN in DiI-TLS11a-LB, by its called after DiI-TLS11a-LB-FITC-TATp-MSN.
The fluorescent dye DAPI labelling blue by the nucleus of H22 tumor cell, obtains the H22 tumor cell DAPI-H22 of fluorescent dye DAPI labelling.
By DAPI-H22 and DiI-TLS11a-LB-FITC-MSN in DMEM complete medium in 37 DEG C, 5%CO
2cell culture incubator in hatch, hatching 4 little constantly little up to 24, DiI-TLS11a-LB-FITC-MSN mainly concentrates on (Fig. 8) among endochylema; By DAPI-H22 and DiI-TLS11a-LB-FITC-TATp-MSN in DMEM complete medium in 37 DEG C, 5%CO
2cell culture incubator in hatch, hatch 4 constantly little, DiI-TLS11a-LB-FITC-TATp-MSN mainly concentrates on (Fig. 8) among endochylema, and hatching 24 constantly little, the TATp-MSN being marked with green fluorescence FITC mainly concentrates on (Fig. 8) in nucleus.Show, mesopore silicon dioxide nano material (TATp-MSN) active targeting being mounted with TATp modification prepared in the present invention can synthesize to cell by the TATp used in the present invention.
2, TLS11a is on the impact of the targeting of TLS11a-LB-TATp-MSN/DOX
The fat-soluble fluorescent dye DiR of labelling on the TLS11a-LB that embodiment 1 step S6 obtains, obtain by the TLS11a-LB (DiR-TLS11a-LB) of fat-soluble fluorescent dye DiR labelling, the fat-soluble fluorescent dye DiR of labelling on the LB that embodiment 1 step S5 obtains, obtains by the LB (DiR-LB) of fat-soluble fluorescent dye DiR labelling.
According to the preparation method of the TLS11a-LB-TATp-MSN/DOX of embodiment 1, the lipid bilayer (TLS11a-LB) that the aptamers TLS11a obtained by step S6 modifies replaces with above-mentioned DiR-TLS11a-LB, other steps are all constant, obtain the system being mounted with TATp-MSN/DOX in DiI-TLS11a-LB, by its called after DiR-TLS11a-LB-TATp-MSN/DOX.
According to the preparation method of the TLS11a-LB-TATp-MSN/DOX of embodiment 1, the lipid bilayer (TLS11a-LB) that the aptamers TLS11a obtained by step S6 modifies replaces with above-mentioned DiR-LB, other steps are all constant, obtain the system being mounted with TATp-MSN/DOX in DiI-LB, by its called after DiR-LB-TATp-MSN/DOX.
The lotus tumor BalB/c nude mice of Example 2, DiR-TLS11a-LB-TATp-MSN/DOX is injected in the tail vein of lotus tumor BalB/c nude mice, injection is designated as 0h at that time, under U.S. Carestream small animal living body imaging (Bruker imaging system), observes DiR-TLS11a-LB-TATp-MSN/DOX metabolic condition in vivo (Fig. 9) at 0h, 6h, 12h, 24h, 48h, 72h, 96h and 120h respectively.DiR-LB-TATp-MSN/DOX is injected in the tail vein of lotus tumor BalB/c nude mice, injection was designated as 0h at that time, under U.S. Carestream small animal living body imaging (Bruker imaging system), observe DiR-TLS11a-LB-TATp-MSN/DOX metabolic condition in vivo (Fig. 9) at 0h, 6h, 12h, 24h, 48h, 72h, 96h and 120h respectively, inject DiR in contrast in the tail vein of lotus tumor BalB/c nude mice.
Result shows, the lotus tumor BalB/c nude mice of DiR-TLS11a-LB-TATp-MSN/DOX process in the fluorescence intensity of tumor site apparently higher than the lotus tumor BalB/c nude mice of DiR-LB-TATp-MSN/DOX process in the fluorescence intensity of tumor site, show that aptamers TLS11a can improve the targeting of TLS11a-LB-TATp-MSN/DOX to tumor.
Claims (10)
1. Nano medication slow-released system, the nanoparticle be made up of core and shell, described shell is made up of aptamers, PEG and nanometer liposome, and described aptamers is connected with described nanometer liposome by described PEG, described adaptive physical ability specially recognizing tumor cells; Described core is made up of peptide modified nano material and the antitumor drug be carried in described peptide modified nano material, described polypeptide energy penetration cell core nuclear membrane.
2. system according to claim 1, is characterized in that: the aminoacid sequence of described polypeptide is SEQ ID No.1 in sequence table;
And/or,
Described nano material is mesopore silicon dioxide nano material.
3. system according to claim 1 and 2, is characterized in that: the particle diameter of described nano material is 30-70nm;
And/or,
The particle diameter of described nanometer liposome is 60-200nm.
4., according to described system arbitrary in claim 1-3, it is characterized in that: described tumor cell is hepatoma carcinoma cell;
And/or,
The nucleotides sequence of described aptamers is classified as SEQ ID No.2 in sequence table.
5., according to described system arbitrary in claim 1-4, described system is according to the method preparation described in claim 6 or 7.
6. the preparation method of arbitrary described system in claim 1-5, to comprise with described shell bag by described core, obtains described system.
7. method according to claim 6, is characterized in that: described method also comprises the preparation of described shell and/or the preparation of described core;
The preparation of described shell comprises: modify with PEG the nanometer liposome that described nanometer liposome obtains PEG modification; The nanometer liposome modifying described PEG modification by described aptamers obtains described shell;
The preparation of described core comprises: load described antitumor drug by described peptide modified nano material and obtain described core.
8. for the preparation of the reagent set of described Nano medication slow-released system arbitrary in claim 1-5, for four kinds in described aptamers arbitrary in claim 1-5, described tumour medicine, described polypeptide and described nano material these four kinds, wantonly three kinds or any two.
9. in claim 1-5, reagent set described in arbitrary described system or claim 8 is preparing the application treated and/or prevented in tumour medicine; Or the application of reagent set described in claim 8 in preparation claim 1-5 in arbitrary described system.
10. treat and/or prevent tumour medicine, it is characterized in that: described in treat and/or prevent tumour medicine active component be arbitrary described system in claim 1-5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510428283.4A CN104983716B (en) | 2015-07-20 | 2015-07-20 | The double target tumor Nano medication slow-released systems of tumor cell membrane/nuclear membrane and its preparation and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510428283.4A CN104983716B (en) | 2015-07-20 | 2015-07-20 | The double target tumor Nano medication slow-released systems of tumor cell membrane/nuclear membrane and its preparation and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104983716A true CN104983716A (en) | 2015-10-21 |
| CN104983716B CN104983716B (en) | 2018-04-27 |
Family
ID=54295707
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510428283.4A Expired - Fee Related CN104983716B (en) | 2015-07-20 | 2015-07-20 | The double target tumor Nano medication slow-released systems of tumor cell membrane/nuclear membrane and its preparation and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104983716B (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105496961A (en) * | 2015-12-25 | 2016-04-20 | 广西医科大学 | Targeted lipidosome drug-loading system containing aptamers, preparation method and application |
| CN105997881A (en) * | 2016-07-26 | 2016-10-12 | 上海应用技术学院 | Tumor cell targeting mesoporous silicon nanometer assembly and preparation method for same |
| CN106265624A (en) * | 2016-08-08 | 2017-01-04 | 中国农业大学 | The treatment pharmaceutical composition of breast carcinoma, drug delivery system and preparation method thereof |
| CN106924755A (en) * | 2015-12-31 | 2017-07-07 | 复旦大学 | The bionic nano particle and preparation method of a kind of Polymorphonuclear Leukocytes Membrane cladding of activation |
| CN109044993A (en) * | 2018-09-18 | 2018-12-21 | 华南理工大学 | It is a kind of to target polyethyleneglycol modified mesoporous silicon dioxide nano particle and preparation method thereof with aptamer |
| CN109045304A (en) * | 2018-04-13 | 2018-12-21 | 中山大学 | A kind of kernel targeted nano carrier and its preparation method and application carrying Polymerase I inhibitor |
| CN111068066A (en) * | 2019-12-31 | 2020-04-28 | 福州大学 | Biological nano material and application and preparation thereof |
| CN113876964A (en) * | 2020-07-02 | 2022-01-04 | 中国科学院苏州纳米技术与纳米仿生研究所 | Tumor cell membrane drug-loading system and construction method and application thereof |
| CN114958748A (en) * | 2022-04-24 | 2022-08-30 | 东北大学 | Nano magnetic affinity material for efficiently capturing and nondestructively releasing circulating tumor cells |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014138278A1 (en) * | 2013-03-05 | 2014-09-12 | The Regents Of The University Of California | Lipid bilayer coated mesoporous silica nanoparticles with a high loading capacity for one or more anticancer agents |
| CN104174027A (en) * | 2014-09-15 | 2014-12-03 | 中国科学院上海硅酸盐研究所 | Tumor vessel-tumor cell membrane-cell nucleus continuous targeted drug delivery system, as well as preparation method and application thereof |
| CN104434801A (en) * | 2014-11-19 | 2015-03-25 | 上海纳米技术及应用国家工程研究中心有限公司 | Adriamycin-carried targeted lipid and silicon dioxide complex as well as preparation method and application thereof |
-
2015
- 2015-07-20 CN CN201510428283.4A patent/CN104983716B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014138278A1 (en) * | 2013-03-05 | 2014-09-12 | The Regents Of The University Of California | Lipid bilayer coated mesoporous silica nanoparticles with a high loading capacity for one or more anticancer agents |
| CN104174027A (en) * | 2014-09-15 | 2014-12-03 | 中国科学院上海硅酸盐研究所 | Tumor vessel-tumor cell membrane-cell nucleus continuous targeted drug delivery system, as well as preparation method and application thereof |
| CN104434801A (en) * | 2014-11-19 | 2015-03-25 | 上海纳米技术及应用国家工程研究中心有限公司 | Adriamycin-carried targeted lipid and silicon dioxide complex as well as preparation method and application thereof |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105496961A (en) * | 2015-12-25 | 2016-04-20 | 广西医科大学 | Targeted lipidosome drug-loading system containing aptamers, preparation method and application |
| CN106924755B (en) * | 2015-12-31 | 2020-06-09 | 复旦大学 | Activated neutral particle cell membrane coated bionic nano particle and preparation method thereof |
| CN106924755A (en) * | 2015-12-31 | 2017-07-07 | 复旦大学 | The bionic nano particle and preparation method of a kind of Polymorphonuclear Leukocytes Membrane cladding of activation |
| CN105997881A (en) * | 2016-07-26 | 2016-10-12 | 上海应用技术学院 | Tumor cell targeting mesoporous silicon nanometer assembly and preparation method for same |
| CN106265624B (en) * | 2016-08-08 | 2019-12-13 | 中国农业大学 | Pharmaceutical composition for treating breast cancer, drug delivery system and preparation method thereof |
| CN106265624A (en) * | 2016-08-08 | 2017-01-04 | 中国农业大学 | The treatment pharmaceutical composition of breast carcinoma, drug delivery system and preparation method thereof |
| CN109045304A (en) * | 2018-04-13 | 2018-12-21 | 中山大学 | A kind of kernel targeted nano carrier and its preparation method and application carrying Polymerase I inhibitor |
| CN109045304B (en) * | 2018-04-13 | 2022-04-05 | 中山大学 | Nucleolar targeting nano-carrier carrying Polymerase I inhibitor and preparation method and application thereof |
| CN109044993A (en) * | 2018-09-18 | 2018-12-21 | 华南理工大学 | It is a kind of to target polyethyleneglycol modified mesoporous silicon dioxide nano particle and preparation method thereof with aptamer |
| CN111068066A (en) * | 2019-12-31 | 2020-04-28 | 福州大学 | Biological nano material and application and preparation thereof |
| CN113876964A (en) * | 2020-07-02 | 2022-01-04 | 中国科学院苏州纳米技术与纳米仿生研究所 | Tumor cell membrane drug-loading system and construction method and application thereof |
| CN113876964B (en) * | 2020-07-02 | 2023-07-21 | 中国科学院苏州纳米技术与纳米仿生研究所 | Tumor cell membrane drug-carrying system and construction method and application thereof |
| CN114958748A (en) * | 2022-04-24 | 2022-08-30 | 东北大学 | Nano magnetic affinity material for efficiently capturing and nondestructively releasing circulating tumor cells |
| CN114958748B (en) * | 2022-04-24 | 2024-02-13 | 东北大学 | Nanometer magnetic affinity material for efficiently capturing and nondestructively releasing circulating tumor cells |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104983716B (en) | 2018-04-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104983716A (en) | Tumor cell membrane/nuclear membrane double-targeting tumor nano-drug slow-release system and preparation and application thereof | |
| Wang et al. | Mitoxantrone-preloaded water-responsive phospholipid-amorphous calcium carbonate hybrid nanoparticles for targeted and effective cancer therapy | |
| Rychahou et al. | Delivery of RNA nanoparticles into colorectal cancer metastases following systemic administration | |
| Zhang et al. | Redox-and light-responsive alginate nanoparticles as effective drug carriers for combinational anticancer therapy | |
| CA3016655C (en) | Ovarian cancer specifically targeted biodegradable amphiphilic polymer, polymer vesicle prepared thereby and use thereof | |
| CN105056233A (en) | Multifunctional mesoporous silica nanoparticles having near-infrared photothermal and in-vivo fluorescence imaging characteristics as well as preparation method and application of mesoporous silica nanoparticles | |
| CN104434806B (en) | Lipid-mixed poly (lactic-co-glycolic acid) (PLGA) nanoparticle having high drug loading amount and active targeting effect | |
| Zhang et al. | Biocompatible iron oxide nanoparticles for targeted cancer gene therapy: A review | |
| CN107913289A (en) | Application of the water-soluble fullerene structure in the medicine for preparing treatment tumour | |
| CN107875384A (en) | A kind of neoplasm targeted therapy drug delivery system for containing sensitising agent | |
| CN111632153A (en) | Chemical gene drug co-loaded targeting nano drug delivery system and preparation method thereof | |
| CN104606127A (en) | Targeted EGFR (epidermal growth factor receptor) modified platinum drug supported albumin nanoparticle as well as preparation and application thereof | |
| CN103720658A (en) | Heparin-modified adriamycin liposome preparation and preparation method thereof | |
| CN108126210A (en) | A kind of application of single targeting reduction response vesica Nano medication in treatment of brain tumor drug is prepared | |
| CN109464676B (en) | Preparation method and product of chitosan oligosaccharide photosensitive targeting nanoparticles | |
| CN101337076A (en) | Functional dendritic polymer gene vector system of targeted malignant cerebroma | |
| CN107007550B (en) | Redox-responsive amphiphilic copolymer and preparation method and application thereof | |
| CN111743861B (en) | Targeted triple-negative breast cancer hypoxia response chiral drug micelle and preparation method thereof | |
| Huang et al. | Albumin-embellished arsenic trioxide-loaded polymeric nanoparticles enhance tumor accumulation and anticancer efficacy via transcytosis for hepatocellular carcinoma therapy | |
| CN109893662B (en) | Preparation method and application of prodrug-carrying brain metastasis targeted drug delivery system for inhibiting Mfsd2a | |
| CN105030730B (en) | Multiple targeting anti-tumor compound formulation and preparation method thereof | |
| CN102631678A (en) | Triblock polymer carrier containing polyarginine as well as preparation method and application thereof | |
| CN108186564B (en) | Tumor microenvironment responsive gene nano micelle and preparation method and application thereof | |
| CN104771382A (en) | Polymersome with hydrophilic lumen carrying anthracene ring medicines as well as preparation method and application | |
| CN105168230A (en) | Tumor targeted prodrug having endosome escaping function as well as nano preparation and preparation method of tumor targeted prodrug |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180427 Termination date: 20190720 |