CN115990144A - Adriamycin and tanshinone IIA combined anti-tumor nano-delivery system and preparation method thereof - Google Patents
Adriamycin and tanshinone IIA combined anti-tumor nano-delivery system and preparation method thereof Download PDFInfo
- Publication number
- CN115990144A CN115990144A CN202211487041.9A CN202211487041A CN115990144A CN 115990144 A CN115990144 A CN 115990144A CN 202211487041 A CN202211487041 A CN 202211487041A CN 115990144 A CN115990144 A CN 115990144A
- Authority
- CN
- China
- Prior art keywords
- cmcs
- tanshinone iia
- azo
- doxorubicin
- solution
- 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.)
- Pending
Links
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 title claims abstract description 145
- AIGAZQPHXLWMOJ-UHFFFAOYSA-N tanshinone IIA Natural products C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)=CO1 AIGAZQPHXLWMOJ-UHFFFAOYSA-N 0.000 title claims abstract description 93
- HYXITZLLTYIPOF-UHFFFAOYSA-N Tanshinone II Natural products O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1C(C)=CO2 HYXITZLLTYIPOF-UHFFFAOYSA-N 0.000 title claims abstract description 77
- AZEZEAABTDXEHR-UHFFFAOYSA-M sodium;1,6,6-trimethyl-10,11-dioxo-8,9-dihydro-7h-naphtho[1,2-g][1]benzofuran-2-sulfonate Chemical compound [Na+].C12=CC=C(C(CCC3)(C)C)C3=C2C(=O)C(=O)C2=C1OC(S([O-])(=O)=O)=C2C AZEZEAABTDXEHR-UHFFFAOYSA-M 0.000 title claims abstract description 77
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 229940009456 adriamycin Drugs 0.000 title claims abstract description 11
- 229960004679 doxorubicin Drugs 0.000 claims abstract description 60
- 239000003814 drug Substances 0.000 claims abstract description 48
- 239000002105 nanoparticle Substances 0.000 claims abstract description 44
- 229940079593 drug Drugs 0.000 claims abstract description 41
- 229940002612 prodrug Drugs 0.000 claims abstract description 27
- 239000000651 prodrug Substances 0.000 claims abstract description 27
- 229920000642 polymer Polymers 0.000 claims abstract description 15
- 206010021143 Hypoxia Diseases 0.000 claims abstract description 13
- 230000007954 hypoxia Effects 0.000 claims abstract description 12
- 239000004480 active ingredient Substances 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 28
- 239000008367 deionised water Substances 0.000 claims description 28
- 229910021641 deionized water Inorganic materials 0.000 claims description 28
- 238000000502 dialysis Methods 0.000 claims description 15
- 238000011068 loading method Methods 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- NWHZQELJCLSKNV-UHFFFAOYSA-N 4-[(4-carboxyphenyl)diazenyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1N=NC1=CC=C(C(O)=O)C=C1 NWHZQELJCLSKNV-UHFFFAOYSA-N 0.000 claims description 13
- 239000002245 particle Substances 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 239000000843 powder Substances 0.000 claims description 12
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 10
- 238000005538 encapsulation Methods 0.000 claims description 10
- 238000004108 freeze drying Methods 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 6
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 239000006228 supernatant Substances 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 5
- 229920001661 Chitosan Polymers 0.000 claims description 4
- 238000002296 dynamic light scattering Methods 0.000 claims description 4
- 238000000227 grinding Methods 0.000 claims description 4
- 238000003760 magnetic stirring Methods 0.000 claims description 4
- 230000004043 responsiveness Effects 0.000 claims description 4
- 239000012535 impurity Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000000523 sample Substances 0.000 claims description 3
- 238000009210 therapy by ultrasound Methods 0.000 claims description 3
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000000385 dialysis solution Substances 0.000 claims description 2
- 238000004806 packaging method and process Methods 0.000 claims description 2
- 238000001338 self-assembly Methods 0.000 claims description 2
- 238000002798 spectrophotometry method Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 238000012546 transfer Methods 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 16
- 206010028980 Neoplasm Diseases 0.000 abstract description 15
- 230000008901 benefit Effects 0.000 abstract description 7
- 231100000331 toxic Toxicity 0.000 abstract description 7
- 230000002588 toxic effect Effects 0.000 abstract description 7
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 230000002195 synergetic effect Effects 0.000 abstract description 3
- 206010059866 Drug resistance Diseases 0.000 abstract description 2
- 229940044683 chemotherapy drug Drugs 0.000 abstract description 2
- 229940126680 traditional chinese medicines Drugs 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 11
- 229930183118 Tanshinone Natural products 0.000 description 8
- 230000006872 improvement Effects 0.000 description 7
- 238000005457 optimization Methods 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 229920002521 macromolecule Polymers 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- -1 nitro, quinolyl Chemical group 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- DMLAVOWQYNRWNQ-UHFFFAOYSA-N azobenzene Chemical class C1=CC=CC=C1N=NC1=CC=CC=C1 DMLAVOWQYNRWNQ-UHFFFAOYSA-N 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
- AZQWKYJCGOJGHM-UHFFFAOYSA-N para-benzoquinone Natural products O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses an adriamycin and tanshinone IIA combined anti-tumor nano-delivery system and a preparation method thereof. Further, the tanshinone IIA and the hypoxia-responsive polymer prodrug are autonomously assembled to form double-drug nanoparticles, the chemotherapeutic drugs and the active ingredients of the traditional Chinese medicines are simultaneously delivered to the tumor part, the synergistic advantage of the tanshinone IIA and the doxorubicin is utilized, the anti-tumor curative effect is enhanced, the pharmacokinetic property is improved, the drug resistance is overcome to the greatest extent, the toxic and side effects are minimized, and the application value is very high.
Description
Technical Field
The invention relates to the technical field of nano material preparation and drug controlled release, in particular to a preparation method of an adriamycin and tanshinone IIA combined anti-tumor nano system.
Background
Malignant tumors are a common public health problem, and have biological characteristics such as abnormal cell differentiation, proliferation, metastasis and the like, so that the malignant tumors become a worldwide difficult problem and seriously threaten human health and life. Chemotherapy is still the main means for treating tumors, can overcome the limitations of surgical treatment and radiotherapy, has obvious curative effects on diffuse and metastatic tumors, but is accompanied by multiple adverse reactions such as pain, recurrence, poor cell selectivity, large toxic and side effects, immunity destruction and the like, is difficult to exert the optimal curative effects, and fails to improve the pain of patients to a great extent. Therefore, a proper nano drug delivery response system is designed according to the characteristics of tumor microenvironment, and targeted drug delivery has become important content for treating tumors.
Hypoxia is a large feature of many solid tumors, and design of drug delivery systems based on tumor microenvironment hypoxia has become an option for tumor targeted therapy. At present, several types of biological reducing molecules such as azobenzene derivatives, nitro, quinolyl and the like are widely applied to the design of an anoxic response system, and small molecules react under the anoxic condition or the stimulation of endogenous reductase, so that the loaded medicine can be further released to play an anti-tumor role.
Doxorubicin belongs to antibiotics, has a broad antitumor spectrum, and is often used in combination with other anticancer drugs. It can be inserted directly between nucleobases of DNA, affect transcription of corresponding genes in cells, and prevent formation of mRNA, thereby inhibiting synthesis of DNA and RNA. Despite these beneficial aspects, there are still serious limitations to the use of doxorubicin, particularly its resultant cardiotoxicity, due to the lack of specificity and tumor resistance during chemotherapy. Tanshinone IIA is a quinone compound extracted from Saviae Miltiorrhizae radix, and is mainly used for treating tumor and cardiovascular diseases clinically. In vitro studies have now demonstrated that the combined use of tanshinone and doxorubicin can effectively enhance the antitumor effect. Because doxorubicin and tanshinone IIA have the defects of poor water solubility, low bioavailability and the like, and the clinical use of the two medicines is seriously influenced, a simple and efficient solution for medicine transmission is urgently needed, so that the doxorubicin and tanshinone IIA can simultaneously exert the optimal curative effect, improve the bioavailability and reduce the toxic and side effects of the medicines.
Disclosure of Invention
Based on the defects of the prior art, a preparation method of an adriamycin and tanshinone IIA combined anti-tumor nano-delivery system. The high molecular material carboxymethyl chitosan with good biocompatibility and low toxicity is used as a carrier, and the azo bond is used as a bridge, so that the doxorubicin is grafted to prepare the high molecular prodrug with hypoxia response, and the drug can be delivered to a tumor site in a targeted manner for release, so that the toxic and side effects on normal tissues are reduced. Further, the tanshinone IIA and the hypoxia-responsive polymer prodrug are autonomously assembled to form double-drug nanoparticles, the chemotherapeutic drugs and the active ingredients of the traditional Chinese medicines are simultaneously delivered to the tumor part, the synergistic advantage of the tanshinone IIA and the doxorubicin is utilized, the anti-tumor curative effect is enhanced, the pharmacokinetic property is improved, the drug resistance is overcome to the greatest extent, the toxic and side effects are minimized, and the application value is very high.
In order to solve the technical problems, the invention provides a preparation method of an adriamycin and tanshinone IIA combined anti-tumor nano-delivery system, which comprises the following steps:
(1) Dissolving a proper amount of azobenzene-4, 4' -dicarboxylic Acid (AZO) in pyridine, ultrasonically dissolving, adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC), N-hydroxysuccinimide (NHS) and 4-DMAP accounting for 10% of the azobenzene-4, 4' -dicarboxylic acid which are equimolar with the azobenzene-4, 4' -dicarboxylic acid, and catalyzing for two hours; dissolving a proper amount of CMCS in deionized water, adjusting the pH value to 7.4, and performing ultrasonic treatment for 5min to obtain CMCS solution; dropwise adding the CMCS solution into the catalyzed AZO solution, magnetically stirring overnight at room temperature, dialyzing, removing pyridine, centrifuging at 5000rpm, and freeze-drying the supernatant to obtain CMCS-AZO intermediate freeze-dried powder;
(2) Dissolving CMCS-AZO freeze-dried powder in deionized water, regulating the pH value to be 6-7, adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC), N-hydroxysuccinimide (NHS) and 4-DMAP accounting for 10% of CMCS-AZO which are equimolar with CMCS-AZO, and regulating the pH value to be 7.5-8.0 after catalyzing for two hours; dissolving Doxorubicin (DOX) in DMSO to obtain DOX solution; dropwise adding DOX solution into CMCS-AZO solution, magnetically stirring at room temperature in the absence of light overnight, dialyzing with mixed solution of DMSO and deionized water, removing organic solvent and other impurities, centrifuging at 5000rpm, and freeze-drying supernatant to obtain CMCS-AZO-DOX polymer prodrug powder;
(3) Dissolving tanshinone IIA (TSIIA) in a proper amount of DMSO to prepare a TSIIA solution, dissolving CMCS-AZO-DOX in a proper amount of deionized water to prepare a prodrug solution, dropwise adding the TSIIA solution into the prodrug solution under magnetic stirring at room temperature, magnetically stirring for 4-8 hours at room temperature in the dark, performing ultrasonic grinding at low temperature to obtain a CMCS-AZO-DOX nanoparticle solution coated with the TSIIA, dialyzing in the deionized water, and performing freeze drying to obtain nanoparticle freeze-dried powder, namely the doxorubicin and tanshinone IIA combined anti-tumor nano delivery system.
As the optimization of the technical scheme, the preparation method of the doxorubicin and tanshinone IA combined anti-tumor nano-delivery system further comprises part or all of the following technical characteristics:
as an improvement of the technical scheme, the ratio of AZO to pyridine in the step (1) is 3-3.2 mg: 1.8-2 mL; the molar ratio of AZO to CMCS was 1:1, the molar mass of CMCS was 1 x 104, and the degree of carboxymethyl substitution was 85%; the reaction solution is transferred into a 3.5kDa dialysis bag for packaging, deionized water is used as dialysis medium, and the reaction solution is dialyzed for 36-48h, and medium is changed once in the period of 4 h.
As the optimization of the technical scheme, the doxorubicin and tanshinone IA combined anti-tumor nano-delivery system and the preparation method thereof further comprise part or all of the following technical characteristics:
as an improvement of the technical scheme, the mass ratio of CMCS-AZO to DOX in the step (2) is 3-4.5 mg/1 mg; the dialysis is to pack the reaction solution into a 3.5kDa dialysis bag, dialyze for 12 hours by taking a mixed solution of dimethyl sulfoxide and deionized water as a dialysis medium in a ratio of 3:7, and dialyze for 48 hours by deionized water, wherein the dialysis solution is changed every 4-6 hours.
As the optimization of the technical scheme, the doxorubicin and tanshinone IA combined anti-tumor nano-delivery system and the preparation method thereof further comprise part or all of the following technical characteristics:
as an improvement of the technical scheme, the drug loading rate of the CMCS-AZO-DOX polymer prodrug obtained in the step (2) is 10.10% -14.45%. Wherein the drug loading is measured by ultraviolet spectrophotometry.
As the optimization of the technical scheme, the doxorubicin and tanshinone IA combined anti-tumor nano-delivery system and the preparation method thereof further comprise part or all of the following technical characteristics:
as an improvement of the technical scheme, the mass ratio of the CMCS-AZO-DOX polymer prodrug to the traditional Chinese medicine active ingredient TSIIA in the step (3) is 2:1-10:1.
As the optimization of the technical scheme, the doxorubicin and tanshinone IA combined anti-tumor nano-delivery system and the preparation method thereof further comprise part or all of the following technical characteristics:
as an improvement of the technical scheme, the low-temperature ultrasonic crushing in the step (3) is performed by using an ultrasonic cell crusher, probe ice bath protection, ultrasonic waves at low temperature for 3.0s and intermittent 2.0s, and the ultrasonic cell crusher works in a pulse mode with power of 90w for 10min.
As the optimization of the technical scheme, the doxorubicin and tanshinone IA combined anti-tumor nano-delivery system and the preparation method thereof further comprise part or all of the following technical characteristics:
as an improvement of the technical scheme, the grain diameter range of the doxorubicin and tanshinone IIA combined anti-tumor nanoparticle obtained in the step (3) is 180-220nm, the drug loading rate of the tanshinone IIA is 6.21% -17.87%, and the encapsulation rate is 51.76% -73.59%. Wherein, the particle size of the nano particles is measured by a dynamic light scattering instrument (DLS); the drug-loading rate and encapsulation efficiency of tanshinone IIA are both determined by high performance liquid chromatography.
The transmission system is characterized in that carboxymethyl chitosan and the doxorubicin are connected through amide reaction to form an amphiphilic polymer prodrug with hypoxia responsiveness, tanshinone IIA is continuously added into an aqueous solution containing CMCS-AZO-DOX polymer prodrug through a dripping method, and after uniform stirring and mixing, the combined anti-tumor nanoparticle loaded with the doxorubicin and the tanshinone IIA simultaneously is obtained through ultrasonic crushing and dialysis self-assembly, namely the nano transmission system.
As the optimization of the technical scheme, the doxorubicin and tanshinone IA combined anti-tumor nano-delivery system provided by the invention further comprises part or all of the following technical characteristics:
as an improvement of the above technical solution, the transfer system is manufactured by any method as described above.
Compared with the prior art, the technical scheme of the invention has the following beneficial effects:
1. the invention creatively packages the doxorubicin and tanshinone IIA in the nano dosage form for the first time, and has the advantages of small particle size, good nanoparticle stability, high drug-loading encapsulation rate and the like.
2. The carrier used in the invention is carboxymethyl chitosan, has the advantages of low toxicity, good biocompatibility and degradability, and is grafted with doxorubicin through amidation to form the amphiphilic polymer prodrug with hypoxia responsiveness, so that the systemic stability can be improved, and the characteristic of intelligently controlling and releasing the drug can be achieved.
3. According to the method, the macromolecule prodrug grafted with the doxorubicin is independently packaged and loaded with the tanshinone IIA to form the combined administration nanoparticle, the nanoparticle is spherical, good in uniformity and moderate in particle size, and can directly enter the tumor tissue in a targeted manner under the mediation of the EPR effect, so that toxic and side effects caused by leakage at normal parts are avoided.
4. The doxorubicin and tanshinone IIA combined administration nano system has good synergistic anti-tumor advantage, and can not only regulate a plurality of signal paths of abnormal cells to obviously enhance the anti-tumor effect of the therapies, but also achieve the purpose of killing tumor cells in different periods and stages of tumor; the optimal treatment effect is achieved, the dosage of single medicine is reduced to the maximum, the defect of multi-medicine resistance of organisms can be overcome effectively, and simultaneously, toxic and side effects and complications generated by the single medicine can be inhibited.
The foregoing description is only an overview of the present invention, and is intended to be implemented in accordance with the teachings of the present invention in order that the same may be more clearly understood and appreciated, as well as the other objects, features and advantages of the present invention, as described in detail below in connection with the preferred embodiments.
Drawings
In order to more clearly illustrate the technical solution of the embodiments of the present invention, the drawings of the embodiments will be briefly described below.
FIG. 1 is a graph showing the particle size distribution of a nano-delivery system for combined administration of doxorubicin and tanshinone IIA prepared in example 1 of the present invention;
FIGS. 2 (A) and 2 (B) are graphs showing the release of doxorubicin and tanshinone IIA in combination with a nano-delivery system prepared in example 1 according to the present invention under normoxic and anoxic conditions, respectively;
FIGS. 3 (A) and 3 (B) are graphs showing stability of a nano-delivery system for combined administration of doxorubicin and tanshinone IIA prepared in example 1 of the present invention;
fig. 4 is a graph showing cytotoxicity results (mean±sd, n=6) (< 0.05 vs;: <0.01 vs;: < p < 0.01) after 24h of administration of doxorubicin and tanshinone IIA in combination with a nanodelivery system prepared in example 1 of the present invention to 4T1 breast cancer cells under normoxic and hypoxic conditions.
Detailed Description
The following detailed description of the invention, which is a part of this specification, illustrates the principles of the invention by way of example, and other aspects, features, and advantages of the invention will become apparent from the detailed description.
Example 1
(1) 30mg of azobenzene-4, 4' -dicarboxylic Acid (AZO) was weighed and dissolved in 18mL of pyridine, dissolved by ultrasonic, and 26mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC), 14mg of N-hydroxysuccinimide (NHS) and 10% of 4-DMAP were added for two hours of catalysis; dissolving 40mg of CMCS in 20mL of deionized water, adjusting the pH value to 7.4, and performing ultrasonic treatment for 5min to obtain CMCS solution; and (3) dropwise adding the CMCS solution into the catalyzed AZO solution, magnetically stirring for 24 hours at room temperature, dialyzing, removing pyridine, centrifuging at 5000rpm, and freeze-drying the supernatant to obtain CMCS-AZO intermediate freeze-dried powder.
(2) Weighing 50mg of CMCS-AZO freeze-dried powder, dissolving in 30mL of deionized water, regulating the pH value to be 6-7, adding 26mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC), 14mg of N-hydroxysuccinimide (NHS) and 10% of 4-DMAP, and regulating the pH value to be 7.5-8.0 after two hours of catalysis; weighing 30mg of Doxorubicin (DOX) and dissolving in 10mL of DMSO to obtain DOX solution; dropwise adding DOX solution into CMCS-AZO solution, magnetically stirring at room temperature in the absence of light for 24 hours, dialyzing with a mixed solution of DMSO and deionized water at a ratio of 3:7 for 24 hours, dialyzing with deionized water for 48 hours, removing organic solvent and other impurities, centrifuging at 5000rpm, and freeze-drying supernatant to obtain CMCS-AZO-DOX polymer prodrug powder.
(3) 5mg of tanshinone IIA (TSIIA) is weighed and dissolved in 5mL of LDMSO, TSIIA solution is prepared, 30mg of CMCS-AZO-DOX macromolecule prodrug is weighed and dissolved in 30mL of deionized water, prodrug solution is prepared, TSIIA solution is dropwise added into prodrug solution under magnetic stirring at room temperature, light is avoided, magnetic stirring is carried out for 4 hours at room temperature, the mixture is transferred to an ultrasonic cell grinder, a probe is subjected to ultrasonic grinding for 10 minutes at low temperature for 3.0s, intermittent 2.0s and pulse mode with power of 90w, ultrasonic grinding is carried out for 5 minutes, so that nanoparticle solution of CMCS-AZO-DOX for coating the TSIIA is obtained, the nanoparticle solution is split into dialysis bags with molecular weight of 3500Da, deionized water is used as dialysis medium, and freeze drying is carried out after 24 hours of dialysis, and nanoparticle freeze-dried powder is obtained.
The drug loading of the dual-drug nanoparticle prepared in the example is 9.08% by high performance liquid chromatography, and the encapsulation efficiency is 73.59%.
Example 2
This embodiment differs from embodiment 1 in that: in the embodiment, in the step (3), 5mg of tanshinone IIA (TSIIA) is weighed and dissolved in 5mLDMSO to prepare TSIIA solution; 10mgCMCS-AZO-DOX macromolecule prodrug is weighed and dissolved in 10mL of deionized water, other preparation raw material compositions and a preparation process of an adriamycin and tanshinone IIA combined anti-tumor nano-delivery system are the same as in example 1.
The drug loading rate of the dual-drug nano-particles prepared in the example is 17.87% by high performance liquid chromatography, and the encapsulation rate is 51.76%.
Example 3
This embodiment differs from embodiment 1 in that: in the embodiment, in the step (3), 5mg of tanshinone IIA (TSIIA) is weighed and dissolved in 5mLDMSO to prepare TSIIA solution; the preparation process of weighing 20mgCMCS-AZO-DOX macromolecule prodrug in 20mL deionized water, other preparation raw material composition and a combined anti-tumor nano-delivery system of doxorubicin and tanshinone IIA is the same as in example 1.
The drug loading of the dual-drug nanoparticle prepared in the example is 9.33% by high performance liquid chromatography, and the encapsulation efficiency is 53.19%.
Example 4
This embodiment differs from embodiment 1 in that: in the embodiment, in the step (3), 5mg of tanshinone IIA (TSIIA) is weighed and dissolved in 5mLDMSO to prepare TSIIA solution; 40mg CMCS-AZO-DOX polymer prodrug is weighed and dissolved in 40mL deionized water, other preparation raw material compositions and a preparation process of an adriamycin and tanshinone IIA combined anti-tumor nano-delivery system are the same as in example 1.
The drug loading rate of the dual-drug nano-particles prepared in the example is 6.37% by high performance liquid chromatography, and the encapsulation rate is 63.07%.
Example 5
This embodiment differs from embodiment 1 in that: in the embodiment, in the step (3), 5mg of tanshinone IIA (TSIIA) is weighed and dissolved in 5mLDMSO to prepare TSIIA solution; 50mgCMCS-AZO-DOX macromolecule prodrug is weighed and dissolved in 50mL of deionized water, other preparation raw material compositions and a preparation process of an adriamycin and tanshinone IIA combined anti-tumor nano-delivery system are the same as in example 1.
The drug loading rate of the dual-drug nano-particles prepared in the example is 6.21% by high performance liquid chromatography, and the encapsulation efficiency is 60.16%.
Example 6
Particle size distribution experiment of nanoparticle combination administration of doxorubicin and tanshinone IIA:
the doxorubicin and tanshinone IIA double-drug nanoparticles prepared in example 1 are ultrasonically dissolved by deionized water to prepare a solution of 1mg/mL, the obtained particle size distribution is shown in figure 1 by measurement of a Markov particle size analyzer, the average particle size of the double-drug nanoparticles is 216.7nm, and the double-drug nanoparticles are mainly distributed between 180 and 230nm and uniformly dispersed and are in normal distribution, so that the nanoparticles are more easily aggregated at tumor sites under the mediation of EPR effect.
Example 7
In vitro release experiment of nanoparticle of doxorubicin and tanshinone IIA combined administration
The in vitro release of the nanoparticle prepared in the embodiment 1 is studied, the obtained in vitro release curve is shown in figure 2, the doxorubicin and tanshinone IIA have good slow release characteristics and hypoxia sensitivity, the release of the two drugs is faster under the conditions of pH 5.0 and hypoxia, and the release is slower under the conditions of pH 7.4 and normoxic, and the data show that the prepared double-drug nanoparticle has good hypoxia responsiveness and has good application prospect for administration in tumor microenvironment.
Example 8
Stability study of nanoparticle of combination administration of Adriamycin and tanshinone IIA
The double-drug nanoparticle prepared in the example 1 is placed at a low temperature of 4 ℃ for one week, sampling is carried out every day within one week, and the particle size and the PDI value of the double-drug nanoparticle are respectively measured, and the result is shown as a figure 3 (A), wherein the particle size and the PDI value of the double-drug nanoparticle are not obvious, so that the double-drug nanoparticle has good stability and dispersibility; the dual-drug nanoparticle prepared in example 1 was dissolved in deionized water, PBS, physiological saline, DMEM medium, and the particle size and PDI value thereof were measured, and the results were as shown in fig. 3 (B), and the dual-drug nanoparticle was stable in particle size in different solvents, free from obvious differences, and also good in dispersibility.
Example 9
Cytotoxicity study after doxorubicin and tanshinone IIA administration nanoparticles acted on 4T1 breast cancer cells for 24h under normoxic and hypoxia conditions
The free doxorubicin crude drug, free tanshinone IIA crude drug, doxorubicin single drug nanoparticle and the double drug nanoparticle prepared in example 1 as controls were used for 4T1 cytotoxicity experimental study, and the specific steps were as follows: taking 4T1 cells in logarithmic growth phase, using trypsin to digest, diluting with a culture medium, adding 5000 cells/hole into a 96-well plate, incubating for 24 hours, then respectively replacing the original culture solution with free doxorubicin crude drug, free tanshinone IIA crude drug, single doxorubicin nanoparticle and double drug nanoparticle prepared in example 1, wherein the concentration of all solutions is calculated to be 0.25-2.0umol/L based on the concentration of doxorubicin, 6 complex holes are arranged at each concentration, incubating for 24 hours, replacing each hole with 100uL of culture solution containing 10% of CCK-8, and incubating for 2 hours. Cytotoxicity results are shown in FIG. 4 (A) and FIG. 4 (B) below. As shown in fig. 4, the prepared nanoparticle has the strongest inhibition effect on 4T1 cells, has a significant difference compared with two free raw materials, and has a good application prospect in clinical treatment of breast cancer.
The present invention can be realized by the respective raw materials listed in the present invention, and the upper and lower limits and interval values of the respective raw materials, and the upper and lower limits and interval values of the process parameters (such as temperature, time, etc.), and examples are not listed here.
While the invention has been described with respect to the preferred embodiments, it will be understood that the invention is not limited thereto, but is capable of modification and variation without departing from the spirit of the invention, as will be apparent to those skilled in the art.
Claims (9)
1. The preparation method of the doxorubicin and tanshinone IIA combined anti-tumor nano delivery system is characterized by comprising the following steps of:
(1) Dissolving a proper amount of azobenzene-4, 4' -dicarboxylic acid in pyridine, ultrasonically dissolving, adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide which are equimolar with the azobenzene-4, 4' -dicarboxylic acid and 4-DMAP accounting for 10% of the azobenzene-4, 4' -dicarboxylic acid, and catalyzing for two hours; dissolving a proper amount of CMCS in deionized water, adjusting the pH value to 7.4, and performing ultrasonic treatment for 5min to obtain CMCS solution; dropwise adding the CMCS solution into the catalyzed AZO solution, magnetically stirring overnight at room temperature, dialyzing, removing pyridine, centrifuging at 5000rpm, and freeze-drying the supernatant to obtain CMCS-AZO intermediate freeze-dried powder;
(2) Dissolving CMCS-AZO freeze-dried powder in deionized water, regulating the pH value to be 6-7, adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide, N-hydroxysuccinimide and 4-DMAP accounting for 10% of CMCS-AZO which are equimolar with CMCS-AZO, and regulating the pH value to be 7.5-8.0 after catalyzing for two hours; dissolving doxorubicin in DMSO to obtain DOX solution; dropwise adding DOX solution into CMCS-AZO solution, magnetically stirring at room temperature in the absence of light overnight, dialyzing with mixed solution of DMSO and deionized water, removing organic solvent and other impurities, centrifuging at 5000rpm, and freeze-drying supernatant to obtain CMCS-AZO-DOX polymer prodrug powder;
(3) Dissolving tanshinone IIA in a proper amount of DMSO to prepare a TSIIA solution, dissolving CMCS-AZO-DOX in a proper amount of deionized water to prepare a prodrug solution, dropwise adding the TSIIA solution into the prodrug solution under magnetic stirring at room temperature, avoiding light, magnetically stirring for 4-8 hours at room temperature, performing ultrasonic grinding at low temperature to obtain a CMCS-AZO-DOX nanoparticle solution coated with the TSIIA, dialyzing in deionized water, and freeze-drying to obtain nanoparticle freeze-dried powder, namely the doxorubicin and tanshinone IIA combined anti-tumor nano transfer system.
2. The method for preparing the doxorubicin and tanshinone IIA combined anti-tumor nano-delivery system according to claim 1, which is characterized in that: the ratio of AZO to pyridine in the step (1) is 3-3.2 mg: 1.8-2 mL; the molar ratio of AZO to CMCS was 1:1, the molar mass of CMCS was 1 x 104, and the degree of carboxymethyl substitution was 85%; the reaction solution is transferred into a 3.5kDa dialysis bag for packaging, deionized water is used as dialysis medium, and the reaction solution is dialyzed for 36-48h, and medium is changed once in the period of 4 h.
3. The method for preparing the doxorubicin and tanshinone IIA combined anti-tumor nano-delivery system according to claim 1, which is characterized in that: in the step (2), the mass ratio of CMCS-AZO to DOX is 3-4.5 mg/1 mg; the dialysis is to pack the reaction solution into a 3.5kDa dialysis bag, dialyze for 12 hours by taking a mixed solution of dimethyl sulfoxide and deionized water as a dialysis medium in a ratio of 3:7, and dialyze for 48 hours by deionized water, wherein the dialysis solution is changed every 4-6 hours.
4. The method for preparing the doxorubicin and tanshinone IIA combined anti-tumor nano-delivery system according to claim 1, which is characterized in that: the drug loading rate of the CMCS-AZO-DOX polymer prodrug obtained in the step (2) is 10.10% -14.45%. Wherein the drug loading is measured by ultraviolet spectrophotometry.
5. The method for preparing the doxorubicin and tanshinone IIA combined anti-tumor nano-delivery system according to claim 1, which is characterized in that: in the step (3), the mass ratio of the CMCS-AZO-DOX polymer prodrug to the traditional Chinese medicine active ingredient TSIIA is 2:1-10:1.
6. The method for preparing the doxorubicin and tanshinone IIA combined anti-tumor nano-delivery system according to claim 1, which is characterized in that: the low-temperature ultrasonic crushing in the step (3) is performed by using an ultrasonic cell crusher, probe ice bath protection, ultrasonic waves at low temperature for 3.0s and intermittent 2.0s, and the ultrasonic cell crusher works in a pulse mode with power of 90w for 10min.
7. The method for preparing the doxorubicin and tanshinone IIA combined anti-tumor nano-delivery system according to claim 1, which is characterized in that: the grain diameter range of the doxorubicin and tanshinone IIA combined anti-tumor nanoparticle obtained in the step (3) is 180-220nm, the drug loading rate of the tanshinone IIA is 6.21% -17.87%, and the encapsulation rate is 51.76% -73.59%. Wherein, the particle size of the nano particles is measured by a dynamic light scattering instrument (DLS); the drug-loading rate and encapsulation efficiency of tanshinone IIA are both determined by high performance liquid chromatography.
8. An adriamycin and tanshinone IIA combined anti-tumor nano-delivery system is characterized in that: the delivery system is characterized in that carboxymethyl chitosan and doxorubicin are connected through amide reaction to form amphiphilic polymer prodrug with hypoxia responsiveness, tanshinone IIA is continuously added into an aqueous solution containing CMCS-AZO-DOX polymer prodrug through a dripping method, and after being stirred and mixed uniformly, the combined anti-tumor nanoparticle loaded with doxorubicin and tanshinone IIA simultaneously is obtained through ultrasonic crushing and dialysis self-assembly, namely the nano delivery system.
9. The method of combining anti-tumor nano-delivery system of doxorubicin and tanshinone IIA according to claim 8, wherein the method comprises the steps of: the delivery system is produced by any of the methods of claims 1-7.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211487041.9A CN115990144A (en) | 2022-11-23 | 2022-11-23 | Adriamycin and tanshinone IIA combined anti-tumor nano-delivery system and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211487041.9A CN115990144A (en) | 2022-11-23 | 2022-11-23 | Adriamycin and tanshinone IIA combined anti-tumor nano-delivery system and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115990144A true CN115990144A (en) | 2023-04-21 |
Family
ID=85989622
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211487041.9A Pending CN115990144A (en) | 2022-11-23 | 2022-11-23 | Adriamycin and tanshinone IIA combined anti-tumor nano-delivery system and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115990144A (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006075881A1 (en) * | 2005-01-14 | 2006-07-20 | Korea Institute Of Science And Technology | Cholanic acid-chitosan complex forming self-aggregates and preparation method thereof |
| CN105708848A (en) * | 2016-02-04 | 2016-06-29 | 武汉艾美博特医疗用品有限公司 | Environmentally responsive tumor targeted combined administration transfer system |
| CN111467500A (en) * | 2020-03-23 | 2020-07-31 | 北京工业大学 | Low-oxygen dual-targeting AGT inhibitor conjugate and preparation method and application thereof |
| CN112480289A (en) * | 2020-11-30 | 2021-03-12 | 西安交通大学 | Core-shell structure type chitosan-based nano prodrug carrying doxorubicin and platinum drugs together, and preparation method and application thereof |
| CN112608398A (en) * | 2020-11-30 | 2021-04-06 | 西安交通大学 | reduction/pH sensitive polysaccharide-based nano prodrug carrying adriamycin and platinum drugs together, and preparation method and application thereof |
| CN114369175A (en) * | 2022-01-13 | 2022-04-19 | 福州大学 | Low-oxygen-response chitosan polymer and preparation method and application thereof |
| CN114652699A (en) * | 2022-03-09 | 2022-06-24 | 华中科技大学 | Size-transition type nano drug delivery carrier and preparation method and application thereof |
-
2022
- 2022-11-23 CN CN202211487041.9A patent/CN115990144A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006075881A1 (en) * | 2005-01-14 | 2006-07-20 | Korea Institute Of Science And Technology | Cholanic acid-chitosan complex forming self-aggregates and preparation method thereof |
| CN105708848A (en) * | 2016-02-04 | 2016-06-29 | 武汉艾美博特医疗用品有限公司 | Environmentally responsive tumor targeted combined administration transfer system |
| CN111467500A (en) * | 2020-03-23 | 2020-07-31 | 北京工业大学 | Low-oxygen dual-targeting AGT inhibitor conjugate and preparation method and application thereof |
| CN112480289A (en) * | 2020-11-30 | 2021-03-12 | 西安交通大学 | Core-shell structure type chitosan-based nano prodrug carrying doxorubicin and platinum drugs together, and preparation method and application thereof |
| CN112608398A (en) * | 2020-11-30 | 2021-04-06 | 西安交通大学 | reduction/pH sensitive polysaccharide-based nano prodrug carrying adriamycin and platinum drugs together, and preparation method and application thereof |
| CN114369175A (en) * | 2022-01-13 | 2022-04-19 | 福州大学 | Low-oxygen-response chitosan polymer and preparation method and application thereof |
| CN114652699A (en) * | 2022-03-09 | 2022-06-24 | 华中科技大学 | Size-transition type nano drug delivery carrier and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| XUDONG LI等: "A BODIPY-based activatable nanotheranostics for tumor hypoxia imaging and hypoxia-induced drug resistance reversal", 《APPLIED MATERIALS TODAY》, vol. 29, 4 November 2022 (2022-11-04), pages 1 - 15 * |
| 袁源等: "丹参酮IIA对乳腺癌细胞阿霉素化疗敏感度的影响及其相关机制", 《肿瘤防治研究》, vol. 46, no. 7, 31 December 2019 (2019-12-31), pages 594 - 599 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Su et al. | Polymeric complex micelles based on the double-hydrazone linkage and dual drug-loading strategy for pH-sensitive docetaxel delivery | |
| Afkham et al. | Chitosan (CMD)-mediated co-delivery of SN38 and Snail-specific siRNA as a useful anticancer approach against prostate cancer | |
| Wang et al. | A synergistic combination therapy with paclitaxel and doxorubicin loaded micellar nanoparticles | |
| Danhier et al. | Vitamin E-based micelles enhance the anticancer activity of doxorubicin | |
| CN109999197B (en) | Tumor-targeted nano-composite, preparation method and application thereof in precise sonodynamic-mediated tumor treatment | |
| Xu et al. | NLG919/cyclodextrin complexation and anti-cancer therapeutic benefit as a potential immunotherapy in combination with paclitaxel | |
| Pang et al. | Reactive oxygen species-responsive nanococktail with self-amplificated drug release for efficient co-delivery of paclitaxel/cucurbitacin B and synergistic treatment of gastric cancer | |
| Lu et al. | Construction of carboxymethyl chitosan-based nanoparticles of hypoxia response for co-loading doxorubicin and tanshinone IIA | |
| CN112656951B (en) | Cross-linked acid-responsive natural polysaccharide polymer prodrug, preparation method and application | |
| CN115990144A (en) | Adriamycin and tanshinone IIA combined anti-tumor nano-delivery system and preparation method thereof | |
| US10039713B1 (en) | Drug-loaded ganglioside micelle and the preparation method and use thereof | |
| CN109953974B (en) | Preparation method of enzyme-reduction dual-responsiveness hyaluronic acid-polypropylene sulfide copolymer nanocapsule | |
| CN108721643B (en) | pH sensitive liposome for immune chemotherapy | |
| Wang et al. | An activatable, carrier-free, triple-combination nanomedicine for ALK/EGFR-mutant non-small cell lung cancer highly permeable targeted chemotherapy | |
| CN115581707A (en) | Preparation method of chitosan oligosaccharide-curcumin nano complex | |
| Lu et al. | Ginsenoside Rb1 stabilized and paclitaxel/protopanaxadiol co-loaded nanoparticles for synergistic treatment of breast tumor | |
| CN113143867B (en) | CMCS-DSP-IPI549 anti-tumor nano-delivery system and preparation method thereof | |
| CN109666087B (en) | Cyclodextrin derivative and preparation method and application thereof | |
| CN107982543B (en) | Protein-isothiocyanate bond and application thereof | |
| CN112843090A (en) | Preparation method and application of hydroxyapatite nanoparticles for reversing tumor drug resistance | |
| CN116173009B (en) | Preparation method and application of gossypol-dihydroartemisinin self-assembled nanoparticles | |
| CN104069501B (en) | Targeted drug delivery carrier based on PAMAM (polyamide amine) and preparation method of targeted drug delivery carrier | |
| Wang et al. | Deguelin and Paclitaxel Loaded PEG-PCL Nano-Micelles for Suppressing the Proliferation and Inducing Apoptosis of Breast Cancer Cells | |
| CN109793721B (en) | Doxorubicin and glycyrrhetinic acid double-drug nano delivery system and preparation method thereof | |
| CN113318234B (en) | Arginine and ursolic acid modified chitosan nano drug delivery carrier and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |