CN110575545B - 具有电荷翻转能力的氧化应激性药物系统及其制备方法 - Google Patents
具有电荷翻转能力的氧化应激性药物系统及其制备方法 Download PDFInfo
- Publication number
- CN110575545B CN110575545B CN201910740182.9A CN201910740182A CN110575545B CN 110575545 B CN110575545 B CN 110575545B CN 201910740182 A CN201910740182 A CN 201910740182A CN 110575545 B CN110575545 B CN 110575545B
- Authority
- CN
- China
- Prior art keywords
- solution
- manganese dioxide
- imidazole
- concentration
- water
- 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.)
- Expired - Fee Related
Links
- 230000036542 oxidative stress Effects 0.000 title claims abstract description 21
- 239000003814 drug Substances 0.000 title claims description 28
- 229940079593 drug Drugs 0.000 title claims description 25
- 238000002360 preparation method Methods 0.000 title claims description 14
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims abstract description 68
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 55
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims abstract description 45
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 229920002873 Polyethylenimine Polymers 0.000 claims abstract description 20
- 229940074391 gallic acid Drugs 0.000 claims abstract description 19
- 235000004515 gallic acid Nutrition 0.000 claims abstract description 19
- 229920000805 Polyaspartic acid Polymers 0.000 claims abstract description 17
- 229910052742 iron Inorganic materials 0.000 claims abstract description 17
- 108010064470 polyaspartate Proteins 0.000 claims abstract description 17
- 239000013256 coordination polymer Substances 0.000 claims abstract description 16
- 229920001795 coordination polymer Polymers 0.000 claims abstract description 16
- 239000011159 matrix material Substances 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- 239000000243 solution Substances 0.000 claims description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000008367 deionised water Substances 0.000 claims description 22
- 229910021641 deionized water Inorganic materials 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 22
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 20
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 20
- 238000004108 freeze drying Methods 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 239000000725 suspension Substances 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 14
- 239000007983 Tris buffer Substances 0.000 claims description 13
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 10
- KDHWOCLBMVSZPG-UHFFFAOYSA-N 3-imidazol-1-ylpropan-1-amine Chemical compound NCCCN1C=CN=C1 KDHWOCLBMVSZPG-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims description 6
- 239000007853 buffer solution Substances 0.000 claims description 6
- 238000000502 dialysis Methods 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000000377 silicon dioxide Substances 0.000 claims description 6
- 235000012239 silicon dioxide Nutrition 0.000 claims description 6
- 239000012265 solid product Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 9
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 abstract description 32
- 239000003937 drug carrier Substances 0.000 abstract description 23
- 230000000694 effects Effects 0.000 abstract description 17
- 229960003180 glutathione Drugs 0.000 abstract description 16
- 206010028980 Neoplasm Diseases 0.000 abstract description 12
- 210000004027 cell Anatomy 0.000 abstract description 11
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 abstract description 10
- 210000004881 tumor cell Anatomy 0.000 abstract description 10
- 108010024636 Glutathione Proteins 0.000 abstract description 5
- 230000002378 acidificating effect Effects 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 3
- 238000011068 loading method Methods 0.000 abstract description 3
- 238000011282 treatment Methods 0.000 abstract description 3
- 230000002708 enhancing effect Effects 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- 125000002883 imidazolyl group Chemical group 0.000 abstract description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 6
- 230000002194 synthesizing effect Effects 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 229960000907 methylthioninium chloride Drugs 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229910004298 SiO 2 Inorganic materials 0.000 description 3
- 238000004140 cleaning Methods 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 239000002086 nanomaterial Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000003795 desorption Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- -1 hydroxyl free radical Chemical class 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000036457 multidrug resistance Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 244000282866 Euchlaena mexicana Species 0.000 description 1
- 229910021577 Iron(II) chloride Inorganic materials 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- 238000003917 TEM image Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000008810 intracellular oxidative stress Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- WSSMOXHYUFMBLS-UHFFFAOYSA-L iron dichloride tetrahydrate Chemical compound O.O.O.O.[Cl-].[Cl-].[Fe+2] WSSMOXHYUFMBLS-UHFFFAOYSA-L 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/52—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种药物载体体系,是以中空二氧化锰(HMDN)为基体,装载没食子酸和铁的配位聚合物(GA‑Fe),通过支链化的聚乙烯亚胺(PEI)封装后,再用接枝咪唑的聚天冬氨酸(PASP‑API)包封而得到的。本发明提供的药物载体系统,可以通过咪唑基的电离,药物载体实现电荷翻转克服EPR效应到达肿瘤部位。同时,该药物载体系统在肿瘤细胞微酸性环境下分解,释放GA‑Fe作为芬顿反应的催化剂,使肿瘤细胞内的过氧化氢能够持续生成羟基自由基(·OH),杀死肿瘤细胞;且HMDN能够和肿瘤细胞内的谷胱甘肽(GSH)反应,有效抑制了GSH消耗·OH,增强了细胞内的氧化应激,极大提高了治疗效果。
Description
技术领域
本发明属于药物载体领域,具体涉及一种具有电荷翻转能力的氧化应激性药物系统及其制备方法。
背景技术
近年来,随着自然环境的恶化,癌症的发病率越来越高。传统的癌症治疗手段包括:手术治疗,化疗和放疗。化疗是抗肿瘤的主要治疗方案,但化疗受到多药耐药(MDR)的挑战,这在很大程度上限制了化疗的疗效。且往往采用高剂量并增加给药频率。但是,高剂量和增加给药频率不会显著提高治疗效果,反而往往会给正常组织细胞带来严重的不良副作用,有可能进一步恶化耐药性。
近年来基于ROS的纳米治疗技术的研究进展研究纳米材料的潜在材料化学,通过纳米材料产生或清除活性氧以提高治疗效果结果。ROS,包括超氧化物阴离子,过氧化氢(H2O2),单线态氧和羟基自由基(·OH),具有杀死癌细胞的能力破坏生物分子,如脂类、蛋白质和DNA等,近年来,研究者在这方面进行了大量的努力,基于ROS的癌症治疗策略的发展,尤其是化学动力疗法(CDT)铁介导的芬顿反应诱导细胞内氧化压力通过将反应性较差的H2O2转化为·OH而产生的有害活性氧。但这种铁介导的物质很难运输到肿瘤部位,需要一个很好的药物载体才能实现体内运输;并且即使通过血液循环运输到肿瘤组织,部分药物载体也很难被肿瘤细胞吸收,进入肿瘤内部释放药物;谷胱甘肽(GSH)在细胞保护中起重要作用抗多种有害物质,GSH升高癌细胞的水平也被证明会增加抵抗力应用化学、无线电和光动力疗法,作为一个著名的细胞内的抗氧化剂,谷胱甘肽表现出强大的对所产生的高反应性·OH具有清除作用化学动力剂,从而大大增加了电阻癌细胞对氧化应激的抑制作用;还有很多药物载体,产生相应的作用后,会在体内不断积累,很难被人体清除,影响正常的生命活动。
发明内容
本发明所要解决的技术问题是针对上述现有技术存在的不足而提供一种药物载体系统,可以通过咪唑基的电离,药物载体实现电荷翻转;同时,该药物载体系统在微酸性环境下分解,释放GA-Fe作为芬顿反应的催化剂,使过氧化氢能够持续生成羟基自由基(·OH);且HMDN能够和谷胱甘肽(GSH)反应,有效抑制了GSH消耗·OH。
本发明为解决上述提出的问题所采用的技术方案为:
一种具有电荷翻转能力的氧化应激性药物系统,它以中空二氧化锰(HMDN)为基体,装载没食子酸和铁的配位聚合物(GA-Fe),通过聚乙烯亚胺(PEI)封装后,再用接枝咪唑的聚天冬氨酸(PASP-API)包封而得到的。
上述的氧化应激性药物系统的制备方法,主要包括如下步骤:将中空二氧化锰溶解在缓冲溶液中,加入没食子酸和铁的配位聚合物后在25~35℃条件下避光搅拌20~30h;然后加入滴加聚乙烯亚胺溶液,反应1~3h;接着加入接枝咪唑的聚天冬氨酸,反应20~25h,经洗涤、冻干,得到所述具有电荷翻转能力的氧化应激性药物系统。
按上述方案,中空二氧化锰为球形,外径尺寸为70~150nm,内径尺寸为50~130nm,壁厚为15~25nm;没食子酸和铁的配位聚合物的粒径在2nm~10nm。
按上述方案,中空二氧化锰、没食子酸和铁的配位聚合物在缓冲溶液中的浓度范围分别均为1~3mg/mL、0.5~1.5mg/mL;缓冲溶液的pH范围为7.5-8.5。
按上述方案,聚乙烯亚胺溶液为聚乙烯亚胺的tris溶液,浓度为10~30mg/mL,pH在 7.0~7.8范围内。
按上述方案,中空二氧化锰与接枝咪唑的聚天冬氨酸的质量比为1:(1~2),中空二氧化锰与聚乙烯亚胺的质量比为1:(4~20)。
按上述方案,中空二氧化锰的制备方法,包括如下步骤:
(1)将正硅酸四乙酯加到乙醇、水、氨水的混合溶液中,在室温下搅拌0.2~1h,形成白色胶状悬浮液,清洗、冻干,得到固体二氧化硅;其中,正硅酸四乙酯、乙醇、水、氨水的体积比为(2.0~4.0):(30~60):(30~60):(1~6),氨水浓度为25%-28%;
(2)取固体二氧化硅分散在水中,浓度控制在0.5~2mg/mL,标记为溶液A;将十六烷基三甲基溴化铵分散在乙醇和氨水、水的混合液中,十六烷基三甲基溴化铵浓度控制在4~6mg/mL,混合液中去离子水乙醇和氨水的体积比为(38~62):(38~62):(1~6),标记为溶液B;将溶液A与溶液B混合后,在室温下搅拌0.2~1h,加入KMnO4继续反应3~9h,离心收集带核和模板的二氧化锰,再分散在30~60mL去离子水中,得到悬浮液;其中,固体二氧化硅、十六烷基三甲基溴化铵、KMnO4的质量比为(0.5~1.5):(2.5~4):(2~3.5);
(3)将Na2CO3加到步骤(2)所得悬浮液中,在40~60℃下搅拌8~14h,所得固体产物洗涤、冻干后,得到去核带模板的二氧化锰;其中,Na2CO3与悬浮液中带核和模板的二氧化锰的质量比为(2~8):1;
(4)将步骤(3)所得去核带模板的二氧化锰分散在甲醇和氨水的混合溶液中,分散后浓度在0.8~2g/mL范围内,然后在50~90℃下回流40~50h,洗涤干燥后,得到中空二氧化锰;其中,甲醇和氨水的体积比为(80~130):(8~10)。
按上述方案,没食子酸和铁的配位聚合物的制备方法如下:将FeCl2·4H2O、PVP和水按质量比1:(2~4.5):(60~250)混合搅拌均匀,然后逐滴加入浓度为5~15mg/mL没食子酸水溶液,没食子酸的有效质量与FeCl2·4H2O的质量比为(0.3~1.5):1;加入完成后,在氮气条件下搅拌20~28h,经透析、冷冻干燥,得到没食子酸和铁的配位聚合物。
按上述方案,接枝咪唑的聚天冬氨酸的制备方法如下:
1)配制浓度为0.05~0.1g/mL的聚琥珀酰亚胺的DMF溶液;配制浓度为0.03~0.07mg/mL的1-(3-氨丙基)咪唑的DMF溶液;接着,将聚琥珀酰亚胺的DMF溶液与1-(3-氨丙基)咪唑的DMF溶液按体积比0.4~2混合,然后在50~70℃、N2保护下反应20~30h;
2)所将步骤1)得反应液在冰浴条件下加入NaOH水溶液,反应12~16h;反应结束后用酸调节pH至中性后,经透析、冻干,得固体产物咪唑接枝的聚天冬氨酸。其中,1-(3-氨丙基)咪唑和NaOH的质量比(1~5):1,NaOH水溶液的浓度为0.005-0.015g/mL。
与现有技术相比,本发明的有益效果是:
首先,本发明提供的药物载体系统,用中空的二氧化锰作为基体,大大提高了载药量。二氧化锰纳米结构能够在酸性条件下或还原性条件下分解,在肿瘤微环境作用下分解生成 Mn2+离子,达到智能释放药物效果。
第二,该药物载体系统中,用到GA-Fe作为芬顿反应的催化剂,使肿瘤细胞内的过氧化氢能够持续生成羟基自由基(·OH),杀死肿瘤细胞;且HMDN能够和肿瘤细胞内的谷胱甘肽(GSH)反应,有效抑制了GSH消耗·OH,增强了细胞内的氧化应激,极大提高了治疗效果。
第三、本发明用两种高分子聚合物聚乙烯亚胺和聚天冬氨酸封装药物载体,封装效果大大增强,避免药物提前释放,减少损害正常组织细胞。
第四、本发明用咪唑修饰聚天冬氨酸,使整个药物载体系统带负电,中性环境下带负电的载药系统可有效避免被正常细胞吞噬以促进其经充分循环后到达肿瘤组织;在肿瘤组织的微酸性环境下,实现电荷翻转以促进载体更好地进入肿瘤细胞,可防止药物对正常组织细胞的伤害,并有效提高药物的利用率及治疗效果。
通过以上一系列的设计,本发明可以构建一种具备电荷翻转能力的氧化应激性药物系统,可以降低对正常组织细胞的损害,相比传统的载药载体,该系统可以有效提高药物利用率并降低其毒副作用。
附图说明
图1为实施例所采用的HMDN的TEM图;
图2为实施例所采用的GA-Fe的粒径图;
图3为实施例所采用的GA-Fe的傅里叶红外图;
图4为实施例1各步骤产物的傅里叶红外图;
图5为实施例1各步骤产物的傅里叶热重分析图;
图6为实施例1各步骤产物的吸脱附曲线分析图;
图7为实施例1各步骤产物的孔径分布分析图;其中,图4-7中,HMDN-PEI、HMDN-PEI-PASP-API分别代表GA-Fe@HMDN-PEI、GA-Fe@HMDN-PEI-PASP-API。
图8为实施例1所述的氧化应激性药物系统药物载体系统的电荷与pH值的关系图。
图9为实施例1所述的氧化应激性药物系统药物载体系统的产生·OH效果图。
具体实施方式
为了更好地理解本发明,下面结合实施例进一步阐明本发明的内容,但本发明不仅仅局限于下面的实施例。
本发明所述具有电荷翻转能力的氧化应激性药物系统药物载体系统,其制备方法主要包括如下步骤:
步骤一,合成中空二氧化锰HMDN
(1)用2.0~4.0mL TEOS(正硅酸四乙酯)快速加到含30~60mL乙醇,30~60mL去离子水1~6mL氨水(25%-28%)的混合溶液中,在室温下搅拌0.2~1h,形成白色胶状悬浮的固体SiO2,用去离子水和乙醇离心清洗SiO2(醇两次/水两次,冻干不能有有机溶剂)冻干得到sSiO2;
(2)180~300mg sSiO2充分分散在去离子水中,这悬浮液加到含500~800mg CTAB的混合液中(去38~62mL离子水,38~62mL乙醇和1~6mL氨水);所得混合液在室温下搅拌0.2~1h,400~700mg KMnO4迅速加入,继续反应3~9h,离心收集后再分散在30~60 mL去离子水中,得到sSiO2@CTAB/HMDN;
(3)在强力搅拌下,将0.8~3g Na2CO3加到sSiO2@CTAB/HMDN悬浮液中,在 40~60℃下搅拌8~14h,产物通过离心用去离子和乙醇清洗数次,冻干得到CTAB/SiO2;
(4)将步骤(3)所得CTAB/HMDN分散在80~130mL甲醇和8~10mL氨水中 50~90℃下回流40~50h后,甲醇清洗数次真空干燥,得到HMDN。
步骤二,合成没食子酸和铁的配位聚合物GA-Fe
FeCl2·4H2O(20~30mg)和PVP(70~90mg)被添加到2~5mL去离子水,在室温下搅拌几分钟之后,将GA(1~3mL,10mg/mL水溶液)逐滴加入上述液体中,并在氮气条件下搅拌24h;然后用透析袋(25000Da)透析3~8天,冷冻干燥得到GA-Fe。
步骤三,合成接枝咪唑的聚天冬氨酸PASP-API
1)称取1.0~2.0g聚琥珀酰亚胺PSI(10.3mmol重复单元)于100mL两口烧瓶中,加15~25mL DMF将其溶解;然后,向其中加入10~20mL含1-(3-氨丙基)咪唑(API) (647uL,0.6786g,5.15mmol)的DMF溶液,50~70℃、N2保护下反应24h后,将反应液冷却至室温;
2)冰浴条件下,将20mL NaOH水溶液(含NaOH 0.206g,5.15mmol)极缓慢地逐滴加至上述步骤1)所得反应液中,反应过夜;反应结束后用稀盐酸调节反应液pH至7后,移入透析袋(MWCO 8~12kDa)中用去离子水透析3~6天,冻干得固体产物咪唑接枝的聚天冬氨酸(PASP-API)。
步骤四,合成具有电荷翻转能力的氧化应激性药物系统药物载体系统GA-Fe@HMDN- PEI-PASP-API
称取HMDN 100~300mg溶解在100ml PBS(pH 8.0)中,加入50~130mg GA-Fe,在25~35℃条件下氮气保护避光搅拌20~30h,然后加入滴加PEI的tris溶液60~100ml(20mg/mL、pH 7.4)反应2h,再加入100~300mg PASP-API反应20~25h,最后用tris和去离子水洗,冻干后得到载体系统GA-Fe@HMDN-PEI-PASP-API。
实施例1
一种具有电荷翻转能力的氧化应激性药物系统的制备方法,具体包括如下步骤:
1.制备中空二氧化锰HMDN
(1)用3.0mL TEOS快速加到含37mL乙醇、5mL去离子水、1.6mL氨水(氨水浓度25%-28%)的混合溶液中,在室温下搅拌0.5h,形成白色胶状悬浮的固体SiO2,用去离子水和乙醇离心清洗SiO2(醇两次/水两次,冻干不能有有机溶剂),冻干得到sSiO2;
(2)200mg sSiO2充分分散在40mL去离子水中,然后将该悬浮液加到含600mg CTAB的混合液中(混合液由60mL去离子水,60mL乙醇和4.5mL氨水组成,接着在室温下搅拌0.5h,迅速加入600mg KMnO4后继续反应6h,离心收集后分散在40mL去离子水中,得到sSiO2@CTAB/HMDN悬浮液;
(3)在强力搅拌下,将1g Na2CO3加到sSiO2@CTAB/HMDN悬浮液中,在50℃下搅拌12h,通过离心用去离子和乙醇清洗数次,经冻干得到CTAB/HMDN;
(4)将CTAB/HMDN分散在100mL甲醇和10mL氨水中,于60℃下回流48h后,经甲醇清洗数次,真空干燥得到HMDN。
由图1可知,所合成的中空二氧化锰在110nm左右,分散均匀的中空球。
2.合成没食子酸和铁的配位聚合物GA-Fe
FeCl2·4H2O(23mg)和PVP(80mg)添加到4ml去离子水,在室温下搅拌5分钟;之后逐滴加入GA(1mL,10mg/mL水溶液),并在氮气条件下搅拌24h;然后所得GA-Fe(II)紫色纳米配合物用透析袋(25000Da)透析4天,冷冻干燥得到GA-Fe。
由图2可知,没食子酸和铁的配位聚合物GA-Fe的粒径在2nm~10nm,由图3可知,相应的红外峰发生变化,最终合成产物峰值和文献中GA-Fe对应。
3.合成接枝咪唑的聚天冬氨酸PASP-API
1)称取1.0g PSI(10.3mmol重复单元)于100mL两口烧瓶中,加15mL DMF将其溶解,接着向其中加入10mL含1-(3-氨丙基)咪唑(API)(647uL,0.6786g,5.15mmol, PSI重复单元的50%)的DMF溶液,于70℃、N2保护下反应24h后,将反应液冷却至室温;
2)冰浴条件下,将20mL NaOH水溶液(含NaOH 0.206g,5.15mmol)极缓慢地逐滴加至步骤1)所得反应液中,反应过夜;反应结束后用稀盐酸调节反应液pH至7后将反应液移入透析袋(MWCO 8~12kDa)中用去离子水透析6天,冻干得固体产物咪唑接枝的聚天冬氨酸(PASP-API)。
4.合成具有电荷翻转能力的氧化应激性药物系统药物载体系统GA-Fe@HMDN-PEI-PASP-API
称取HMDN 200mg溶解在100mL PBS(pH 8.0)中,加入100mg GA-Fe,在25~35℃条件下氮气保护避光搅拌24h,然后加入滴加PEI的tris溶液100ml(20mg/mL、pH 7.4)反应2h(得到GA-Fe@HMDN-PEI溶液),接着加入200mg PASP-API反应24h,最后用tris 和去离子水洗涤、冻干,得到具有电荷翻转能力的氧化应激性药物系统药物载体系统GA- Fe@HMDN-PEI-PASP-API。
由图3、4可知,红外峰图中,各步骤产物接枝成功;同时,结合图5,失重率不断降低,进一步证明确实有新物质接枝成功。由图6、7可知,其吸脱附曲线不断降低,且孔径分布也逐渐减小,证明药物封装效果较好,能够达到相应效果。
应用测试
1、pH值对GA-Fe@HMDN-PEI-PASP-API的影响:GA-Fe@HMDN-PEI-PASP-API分别分散在pH=7.4和6.5的tris缓冲溶液中,放置在37摄氏度的摇床中24小时,取不同时间点的溶液离心清洗,溶解在水中检测电位。
由图8可知,在pH=7.4时GA-Fe@HMDN-PEI-PASP-API的电荷为负值,在pH=6.5时GA-Fe@HMDN-PEI-PASP-API变为正值,表明纳米粒子具有电荷翻转能力,有利于载体系统被肿瘤细胞吸收。
2、GA-Fe@HMDN-PEI-PASP-API产羟基自由基(·OH)的效果测试:本次测试用亚甲基蓝(MB)做为测试剂,通过用紫外光度计测MB吸光度来反应产生·OH的效果,首先将实验分为五组,每组加等量的MB(2mM)和过氧化氢,其次是GA-Fe(30mM)和载体(30 mM)分别加到两组中、然后其中两组加入GSH(30mM),最后加入PBS补充到相同体积,反应2h后测吸光度。
由图9可知,曲线不断降低,合成的GA-Fe能产生·OH,但GSH对其有抑制效果,然而载体能够克服这种困难,从曲线上看,加了GSH后载体任然有强的产生·OH能力,且在酸性条件下,载体分解后,释放更多GA-Fe,效果更强。整体数据来看,本发明所述载药系统符合之前的预期,将有利于提高治疗效果。
实施例2
具有电荷翻转能力的氧化应激性药物系统的制备方法,具体包括如下步骤:称取HMDN 200mg溶解在100mL tris(pH 8.0)中,加入200mg GA-Fe,在25~35℃条件下氮气保护避光搅拌24h,然后加入滴加PEI的tris溶液100ml(30mg/ml、pH 7.4)反应2h,最后加入200mg PASP-API反应24h,再经用tris和去离子水洗涤并冻干即可。
实施例3
具有电荷翻转能力的氧化应激性药物系统的制备方法,具体包括如下步骤:称取HMDN 100mg溶解在100ml tris(pH 8.0)中,加入200mg GA-Fe,在25~35℃条件下氮气保护避光搅拌24h,然后加入滴加PEI的tris溶液10ml(20mg/mL、pH 7.4)反应2h,最后加入100mgPASP-API反应24h,再经用tris和去离子水洗涤并冻干即可。
以上所述仅是本发明的优选实施方式,应当指出,对于本领域的普通技术人员来说,在不脱离本发明创造构思的前提下,还可以做出若干改进和变换,这些都属于本发明的保护范围。
Claims (10)
1.一种具有电荷翻转能力的氧化应激性药物系统,其特征在于,它以中空二氧化锰为基体,装载没食子酸和铁的配位聚合物,通过聚乙烯亚胺封装后,再用接枝咪唑的聚天冬氨酸包封而得到的。
2.权利要求1所述的氧化应激性药物系统的制备方法,其特征在于主要包括如下步骤:将中空二氧化锰溶解在缓冲溶液中,加入没食子酸和铁的配位聚合物后在25~35 ℃条件下通氮气避光搅拌20~30 h;然后滴加聚乙烯亚胺溶液,反应1~3 h;接着加入接枝咪唑的聚天冬氨酸,反应20~25 h,经洗涤、冻干,得到所述具有电荷翻转能力的氧化应激性药物系统。
3.根据权利要求2所述的制备方法,其特征在于,中空二氧化锰为球形,外径尺寸为70~150 nm,内径尺寸为50~130 nm,壁厚为15~25 nm。
4.根据权利要求2所述的制备方法,其特征在于,中空二氧化锰、没食子酸和铁的配位聚合物在缓冲溶液中的浓度范围分别为1~3 mg/mL、0.5~1.5 mg/mL;缓冲溶液的pH范围为7.5~8.5。
5.根据权利要求2所述的制备方法,其特征在于,聚乙烯亚胺溶液为聚乙烯亚胺的tris溶液,浓度为10~30 mg/mL,pH在7.0~7.8范围内。
6.根据权利要求2所述的制备方法,其特征在于,中空二氧化锰与接枝咪唑的聚天冬氨酸的质量比为1:(1~2),中空二氧化锰与聚乙烯亚胺的质量比为1:(4~20)。
7.根据权利要求2所述的制备方法,其特征在于,中空二氧化锰的制备方法,包括如下步骤:
(1)将正硅酸四乙酯加到乙醇、水、氨水的混合溶液中,在室温下搅拌0.2~1 h,形成白色胶状悬浮液,清洗、冻干,得到固体二氧化硅;其中,正硅酸四乙酯、乙醇、水、氨水的体积比为(2.0~4.0):(30~60):(30~60):(1~6),氨水浓度为25%-28%;
(2)取固体二氧化硅分散在水中,浓度控制在0.5~2 mg/mL,标记为溶液A;将十六烷基三甲基溴化铵分散在乙醇和氨水、水的混合液中,十六烷基三甲基溴化铵浓度控制在4~6mg/mL,混合液中水、乙醇和氨水的体积比为(38~62):(38~62):(1~6),标记为溶液B;将溶液A与溶液B混合后,在室温下搅拌 0.2~1 h,加入KMnO4继续反应3~9 h,离心收集带核和模板的二氧化锰,再分散在30~60 mL去离子水中,得到悬浮液;其中,固体二氧化硅、十六烷基三甲基溴化铵、KMnO4的质量比为(0.5~1.5):(2.5~4):(2~3.5);
(3)将Na2CO3加到步骤(2)所得悬浮液中,在40~60 ℃下搅拌8~14 h,所得固体产物洗涤、冻干后,得到去核带模板的二氧化锰;其中,Na2CO3与悬浮液中带核和模板的二氧化锰的质量比为(2~8):1;
(4)将步骤(3)所得去核带模板的二氧化锰分散在甲醇和氨水的混合溶液中,分散后浓度在0.8~2 g/mL范围内,然后在50~90 ℃下回流40~50 h,洗涤干燥后,得到中空二氧化锰;其中,甲醇和氨水的体积比为(80~130):(8~10)。
8.根据权利要求2所述的制备方法,其特征在于,没食子酸和铁的配位聚合物的制备方法如下:
将FeCl2·4H2O、PVP和水按质量比1:(2~4.5):(60~250)混合搅拌均匀,然后逐滴加入浓度为5~15 mg/mL没食子酸水溶液,没食子酸的有效质量与FeCl2·4H2O的质量比为(0.3~1.5):1;加入完成后,在氮气条件下搅拌20~28 h,经透析、冷冻干燥,得到没食子酸和铁的配位聚合物。
9.根据权利要求2所述的制备方法,其特征在于,接枝咪唑的聚天冬氨酸的制备方法如下:
(1)配制浓度为0.05~0.1 g/mL的聚琥珀酰亚胺的DMF溶液;配制浓度为0.03~0.07 mg/mL的1-(3-氨丙基)咪唑的DMF溶液;接着,将聚琥珀酰亚胺的DMF溶液与1-(3-氨丙基)咪唑的DMF溶液按体积比1:(0.4~2)混合,然后在50~70 ℃、N2保护下反应 20~30 h;
(2)将步骤(1)所得反应液在冰浴条件下加入NaOH水溶液,反应12~16 h;反应结束后用酸调节pH至中性后,经透析、冻干,得固体产物咪唑接枝的聚天冬氨酸。
10.根据权利要求9所述的制备方法,其特征在于,1-(3-氨丙基)咪唑和氢氧化钠的质量比(1~5):1,NaOH水溶液的浓度为0.005-0.015 g/mL。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910740182.9A CN110575545B (zh) | 2019-08-12 | 2019-08-12 | 具有电荷翻转能力的氧化应激性药物系统及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910740182.9A CN110575545B (zh) | 2019-08-12 | 2019-08-12 | 具有电荷翻转能力的氧化应激性药物系统及其制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110575545A CN110575545A (zh) | 2019-12-17 |
CN110575545B true CN110575545B (zh) | 2022-10-14 |
Family
ID=68810612
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910740182.9A Expired - Fee Related CN110575545B (zh) | 2019-08-12 | 2019-08-12 | 具有电荷翻转能力的氧化应激性药物系统及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110575545B (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111407746B (zh) * | 2020-04-02 | 2022-04-22 | 山东大学齐鲁医院 | GA/Fe2+纳米颗粒、其复合纳米颗粒、制备和应用 |
CN111759824B (zh) * | 2020-08-21 | 2021-12-24 | 西南大学 | 一种他达那非超分子纳米颗粒及其制备方法和应用 |
CN113041393B (zh) * | 2021-03-18 | 2022-04-26 | 苏州大学 | 可调控活性氧自由基的复合材料及其制备方法与应用 |
CN114106321B (zh) * | 2021-11-25 | 2023-03-14 | 吉林大学 | 一种活性氧响应性材料pei-sh的制备方法与应用 |
CN115594841B (zh) * | 2022-10-09 | 2024-06-04 | 四川大学 | 没食子酸-聚赖氨酸螯合剂及其制备方法与应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109675064A (zh) * | 2018-12-10 | 2019-04-26 | 中国药科大学 | 用于诊疗一体化的铁-没食子酸配位聚合物及其制备方法和应用 |
CN109796047A (zh) * | 2019-03-06 | 2019-05-24 | 东华大学 | 一种中空二氧化锰纳米颗粒及其制备方法 |
-
2019
- 2019-08-12 CN CN201910740182.9A patent/CN110575545B/zh not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109675064A (zh) * | 2018-12-10 | 2019-04-26 | 中国药科大学 | 用于诊疗一体化的铁-没食子酸配位聚合物及其制备方法和应用 |
CN109796047A (zh) * | 2019-03-06 | 2019-05-24 | 东华大学 | 一种中空二氧化锰纳米颗粒及其制备方法 |
Non-Patent Citations (3)
Title |
---|
Polyaspartic acid coated manganese oxide nanoparticles for efficient liver MRI;Ruijun Xing,et al.;《Nanoscale》;20110331(第3期);4943-4945 * |
Polyethyleneimine-Coated Manganese Oxide Nanoparticles for Targeted Tumor PET/MR Imaging;Jingyi Zhu,et al.;《ACS Appl Mater Interfaces.》;20181017;第10卷(第41期);34954-34964 * |
侧链含咪唑取代基聚(L-天冬酰胺)高效基因载体研究;薛亚楠等;《高分子学报》;20110820(第08期);874-882 * |
Also Published As
Publication number | Publication date |
---|---|
CN110575545A (zh) | 2019-12-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110575545B (zh) | 具有电荷翻转能力的氧化应激性药物系统及其制备方法 | |
Wang et al. | Nanoscale metal–organic frameworks for drug delivery: a conventional platform with new promise | |
Che et al. | Paclitaxel/gelatin coated magnetic mesoporous silica nanoparticles: Preparation and antitumor efficacy in vivo | |
Estevão et al. | Rose Bengal incorporated in mesostructured silica nanoparticles: structural characterization, theoretical modeling and singlet oxygen delivery | |
CN111467491A (zh) | 铂修饰MOF 2-Pt-FA作为双向增强光动力治疗药物的合成及在肿瘤治疗中的应用 | |
CN110639019B (zh) | 基于碳点和中空二氧化锰的荧光共振能量转移的药物载体系统 | |
Chu et al. | NIR Responsive Doxorubicin‐Loaded Hollow Copper Ferrite@ Polydopamine for Synergistic Chemodynamic/Photothermal/Chemo‐Therapy | |
CN110200943B (zh) | 一种聚氨基酸配位纳米粒子及其制备方法和作为在声动力肿瘤治疗的药物的应用 | |
Cheng et al. | Cu-doped cerium oxide-based nanomedicine for tumor microenvironment-stimulative chemo-chemodynamic therapy with minimal side effects | |
CN108553644B (zh) | 基于介孔硅/环糊精/氧化锌量子点构建的双阀门多刺激响应型药物载体及其制备方法 | |
CN113941009B (zh) | 一种金属有机骨架纳米载体及其制备方法与应用 | |
CN112315941A (zh) | 一种具有pH和还原双敏感的纳米疫苗的制备方法及所得产品 | |
CN112618514B (zh) | 氨硼烷/中空介孔聚多巴胺/聚乙二醇纳米复合粒子及其制备与应用 | |
CN113209106A (zh) | 一种聚乙二醇-苯硼酸修饰的树状大分子包裹铜离子/替拉扎明复合物及其制备方法和应用 | |
CN110755617B (zh) | 一种层状双氢氧化物纳米载药复合物及其制备和应用 | |
CN107281220B (zh) | 一种介孔氧化硅基活性氧(ros)放疗增敏剂及其制备方法 | |
Ma et al. | A DNA-engineered metal–organic-framework nanocarrier as a general platform for activatable photodynamic cancer cell ablation | |
Liu et al. | Polymer-coated calcium peroxide nanoparticles as an oxygen self-supplying platform for enhanced photodynamic therapy | |
CN113577273B (zh) | 一种掺杂铜、锰的类普鲁士蓝-二硫化钼纳米复合材料及其制备和应用 | |
CN108785276B (zh) | 一种放疗增敏纳米材料的用途 | |
Bai et al. | Pillar [6] arene-based supramolecular self-assemblies for two-pronged GSH-consumption-augmented chemo/photothermal therapy | |
Liao et al. | Biodegradable MnFe-hydroxide nanocapsules to enable multi-therapeutics delivery and hypoxia-modulated tumor treatment | |
CN111228513A (zh) | 一种具有诱导肿瘤细胞铁死亡效应的无定型碳酸钙复合纳米药物及其制备方法 | |
Deng et al. | A unique corrole-based metal–organic polymer for synergistic phototherapy | |
Kim et al. | Microporous organic network nanoparticles for dual chemo-photodynamic cancer therapy |
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 | ||
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: 20221014 |