CN110664760B - 一种负载vegfr靶向抑制剂的药物载体及其制备方法和应用 - Google Patents
一种负载vegfr靶向抑制剂的药物载体及其制备方法和应用 Download PDFInfo
- Publication number
- CN110664760B CN110664760B CN201911031467.1A CN201911031467A CN110664760B CN 110664760 B CN110664760 B CN 110664760B CN 201911031467 A CN201911031467 A CN 201911031467A CN 110664760 B CN110664760 B CN 110664760B
- Authority
- CN
- China
- Prior art keywords
- targeted inhibitor
- vegfr
- carrier
- vegfr targeted
- inhibitor
- 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.)
- Active
Links
- 108091008605 VEGF receptors Proteins 0.000 title claims abstract description 58
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 title claims abstract description 58
- 239000003112 inhibitor Substances 0.000 title claims abstract description 49
- 239000003937 drug carrier Substances 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims abstract description 77
- 229910021536 Zeolite Inorganic materials 0.000 claims abstract description 32
- 239000010457 zeolite Substances 0.000 claims abstract description 32
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000011065 in-situ storage Methods 0.000 claims abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 claims description 20
- 239000002138 L01XE21 - Regorafenib Substances 0.000 claims description 14
- 229960004836 regorafenib Drugs 0.000 claims description 14
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims description 12
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 10
- XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 claims description 8
- 229960002412 cediranib Drugs 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- 238000011068 loading method Methods 0.000 claims description 6
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 150000004934 Regorafenib derivatives Chemical group 0.000 claims description 2
- 238000004140 cleaning Methods 0.000 claims description 2
- 238000005538 encapsulation Methods 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 34
- 239000003814 drug Substances 0.000 abstract description 34
- 229940079593 drug Drugs 0.000 abstract description 32
- 238000011282 treatment Methods 0.000 abstract description 14
- 230000008685 targeting Effects 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 8
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 238000010521 absorption reaction Methods 0.000 description 13
- 230000002137 anti-vascular effect Effects 0.000 description 8
- 238000002211 ultraviolet spectrum Methods 0.000 description 8
- 230000007935 neutral effect Effects 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 239000012621 metal-organic framework Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000003917 TEM image Methods 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 4
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000001878 scanning electron micrograph Methods 0.000 description 4
- 231100000263 cytotoxicity test Toxicity 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000002626 targeted therapy Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 239000004066 vascular targeting agent Substances 0.000 description 3
- XIOUDVJTOYVRTB-UHFFFAOYSA-N 1-(1-adamantyl)-3-aminothiourea Chemical compound C1C(C2)CC3CC2CC1(NC(=S)NN)C3 XIOUDVJTOYVRTB-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940044683 chemotherapy drug Drugs 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000011056 performance test Methods 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 229940124674 VEGF-R inhibitor Drugs 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000013259 porous coordination polymer Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- -1 zeolite imidazole ester Chemical class 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Nanotechnology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Manufacturing & Machinery (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- Physics & Mathematics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- General Physics & Mathematics (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种负载VEGFR靶向抑制剂的药物载体，所述药物载体包括沸石咪唑类骨架，以及包埋于沸石咪唑类骨架中的VEGFR靶向抑制剂。本发明还公开了一种负载VEGFR靶向抑制剂的药物载体的制备方法：通过原位包埋法将VEGFR靶向抑制剂封装在沸石咪唑类骨架中，得到VEGFR靶向抑制剂‑沸石咪唑类骨架载体。本发明还公开了一种VEGFR靶向抑制剂的药物载体在制备抗肿瘤治疗药物中的应用。本发明提供的负载VEGFR靶向抑制剂的药物载体提高了VEGFR靶向抑制剂的理化稳定性，并赋予药物肿瘤靶向性，从而解决了VEGFR靶向抑制剂在肿瘤治疗中利用率低的问题，并减少了药物治疗的毒副作用；本发明提供的制备方法简单，可以得到具有高负载量VEGFR靶向抑制剂的药物载体。
Description
技术领域
本发明涉及靶向载体，具体涉及一种负载VEGFR靶向抑制剂的药物载体及其制备方法和应用。
背景技术
全球范围内，恶性肿瘤的死亡率在疾病中均处于较高位置。针对肿瘤的新型治疗模式有待研发和探讨。由于恶性肿瘤的复杂性和异质性，目前恶性肿瘤的靶向治疗效果仍不理想。
抗血管治疗是当前恶性肿瘤靶向治疗的核心环节，增加肿瘤内部药物量是解决抗血管药物治疗瓶颈的关键。目前经批准应用于恶性肿瘤的靶向药物中，有不少药物拥有抗血管功能，而VEGFR信号通路都是这些药物的主要靶点。VEGFR通路在血管发生和形成中发挥着中枢性的调节作用，因而在肿瘤的发生发展起到了关键性作用。由此可知，靶向抗血管治疗是当前临床恶性肿瘤靶向治疗的重要环节。瑞格菲尼(regorafenib)是新近被批准用于临床的靶向抗血管药物，目前可用于很多肿瘤的治疗。西地尼布(cediranib)也是一种高效的VEGFR抑制剂。
然而，当前肿瘤单药抗血管治疗的效果并不理想。肿瘤治疗的抗血管策略在一定程度上扮演着“双刃剑”的角色，这主要体现在血管抑制后肿瘤内化疗药物投递减少，进而导致肿瘤内的药物浓度减少。因此，增加肿瘤内部药物量是解决抗血管药物治疗瓶颈的关键。
纳米材料的医学应用是当前的研究热点之一。金属有机骨架(Metal-organicFrameworks,MOFs)又称多孔配位聚合物，具有比较好的稳定性，较高的比表面积，是近年来研究比较广泛的多孔材料。金属有机骨架材料一般由特定的金属离子或金属簇与相应的有机配体通过强的配位键连接而成并具有一定的周期性网络结构。金属有机骨架同时包含无机金属和有机分子，因而具备无机材料和有机材料的双重特点。作为一种良好的药物载体，金属有机骨架材料沸石咪唑酯骨架(ZIF-8)还具备了pH响应的特性。由于ZIF-8对酸性环境敏感，可选择性地降解于酸性环境中，而肿瘤组织往往具有酸性的环境，所以，ZIF-8就拥有了针对肿瘤组织的被动靶向作用。因此，基于ZIF-8的pH响应性纳米载药系统可使化疗药物获得肿瘤靶向性，从而促进药物在肿瘤组织中浓聚，提高药物治疗效果。
综上所述，肿瘤单药抗血管治疗的效果不理想；增加肿瘤内部药物浓度是解决肝癌抗血管靶向治疗瓶颈的关键；ZIF-8纳米载药系统可有效提高肿瘤内药物浓度；基于ZIF-8纳米载药系统可以赋予药物靶向性，针对性解决肿瘤靶向抗血管药物导致的瘤内化疗药物投递减少，增强治疗效果。
发明内容
本发明的目的在于针对现有技术的不足，提供了一种负载VEGFR靶向抑制剂的药物载体及制备方法，本发明提供的提高了VEGFR靶向抑制剂的理化稳定性，并赋予药物肿瘤靶向性，从而解决了VEGFR靶向抑制剂在肿瘤治疗中利用率低的问题，并减少了药物治疗的毒副作用；本发明提供的制备方法简单，可以得到具有高负载量VEGFR靶向抑制剂的药物载体。
本发明所提供的技术方案为：
一种负载VEGFR靶向抑制剂的药物载体(靶向载体)，包括沸石咪唑类骨架、包埋于沸石咪唑类骨架中的VEGFR靶向抑制剂。
作为优选，所述VEGFR靶向抑制剂为瑞格菲尼或西地尼布。
作为优选，所述药物载体中瑞格菲尼或西地尼布的负载量为18-20％。
本发明通过原位包埋法将VEGFR靶向抑制剂封装在沸石咪唑类骨架内。VEGFR靶向抑制剂具有抑制肿瘤血管形成的能力，沸石咪唑类骨架对于VEGFR靶向抑制剂具有保护作用，能够减缓VEGFR靶向抑制剂在体内非肿瘤部位的降解速度，从而延长了VEGFR靶向抑制剂在血液系统中高浓度的时间；其次，沸石咪唑骨架载体具有pH靶向性，将VEGFR靶向抑制剂封装在沸石咪唑类骨架内，可以使其具有针对肿瘤组织的靶向性，能使其选择性降解于肿瘤组织部位，从而靶向针对肿瘤细胞，又能保护正常细胞。
本发明还提供一种上述的负载VEGFR靶向抑制剂的药物载体的制备方法，通过原位包埋法将VEGFR靶向抑制剂封装在沸石咪唑类骨架中，得到VEGFR靶向抑制剂-沸石咪唑类骨架载体(负载VEGFR靶向抑制剂的药物载体)。
作为优选，通过原位包埋法将瑞格菲尼(标记为REG)封装在沸石咪唑类骨架(ZIF-8)中，得到瑞格菲尼-沸石咪唑类骨架载体(标记为REG@ZIF-8)；
作为优选，通过原位包埋法将西地尼布(标记为CED)封装在沸石咪唑类骨架(ZIF-8)中，得到西地尼布-沸石咪唑类骨架载体(标记为CED@ZIF-8)；
本发明提供的制备方法合成方法简单，制备的药物载体中瑞格菲尼或西地尼布的负载量为18-20％，提高了药物的利用率和药效。
作为优选，所述原位包埋法包括：
硝酸锌与VEGFR靶向抑制剂反应形成配位化合物；
配位化合物与2-甲基咪唑反应得到VEGFR靶向抑制剂-沸石咪唑类骨架载体。
作为优选，所述原位包埋法包括：
硝酸锌与VEGFR靶向抑制剂分别配制成甲醇溶液，室温下混合后得到配位化合物体系；进一步优选，所述混合是指搅拌1-5min；所述VEGFR靶向抑制剂、硝酸锌和无水甲醇的质量比为1-10：1-100：100；
配位化合物体系中加入2-甲基咪唑的甲醇溶液室温下混合，离心清洗干燥后，得到VEGFR靶向抑制剂-沸石咪唑类骨架载体。
进一步优选，所述混合是指搅拌15-20min；所述2-甲基咪唑与无水甲醇的投料比为2-5g:10ml。
作为优选，所述VEGFR靶向抑制剂、硝酸锌与2-甲基咪唑的质量比为1-10:10-50:20-200。
作为优选，所述VEGFR靶向抑制剂、硝酸锌与2-甲基咪唑的质量比为1:5-20:50-200。
本发明还提供一种上述的负载VEGFR靶向抑制剂的药物载体在抗肿瘤治疗中的应用。
同现有技术相比，本发明的有益效果体现在：
(1)本发明中沸石咪唑类骨架对于VEGFR靶向抑制剂具有保护作用，能够减缓药物在体内非肿瘤部位的降解速度，从而延长了药物在血液系统中高浓度的时间。
(2)本发明中沸石咪唑类骨架直径为10-500nm，能够通过细胞膜的内吞作用进入细胞，且其结构稳定，能够通过人体代谢排除，故无细胞毒性；ZIF-8具有巨大的比表面积和孔体积，从而具有较大载药量，特殊的孔道结构又使其具有药物缓释功能。
(3)本发明中，沸石咪唑骨架载体具有pH靶向性，将VEGFR靶向抑制剂封装在沸石咪唑类骨架内，可以使其具有针对肿瘤组织的靶向性，能使其选择性降解于肿瘤组织部位，从而靶向针对肿瘤细胞，针对性解决肿瘤靶向抗血管药物导致的瘤内化疗药物投递减少，增强肿瘤治疗效果。
附图说明
图1为实施例1制备的REG@ZIF-8的紫外光谱图；
图2为实施例2制备的CED@ZIF-8的紫外光谱图；
图3为实施例1制备的REG@ZIF-8的红外图谱图；
图4为实施例2制备的CED@ZIF-8的红外图谱图；
图5中的(a)和(b)分别为实施例1制备的REG@ZIF-8的扫描电镜图和透射电镜图；
图6中的(a)和(b)分别为实施例1制备的CED@ZIF-8的扫描电镜图和透射电镜图；
图7为实施例1制备的REG@ZIF-8的XRD图；
图8为实施例2制备的CED@ZIF-8的XRD图；
图9为不同pH下实施例1制备的REG@ZIF-8的药物释放曲线图；
图10为不同pH下实施例2制备的CED@ZIF-8的药物释放曲线图；
图11为中性环境下(pH7.4)实施例1制备的REG@ZIF-8的细胞毒性试验图；
图12为中性环境下(pH7.4)实施例2制备的CED@ZIF-8的细胞毒性试验图。
具体实施方式
下面结合具体的实施例对本发明作进一步说明。
实施例1：制备REG@ZIF-8
(1)将40mg REG溶于4ml甲醇与0.2g的六水硝酸锌溶于0.8ml的甲醇溶液混合，室温下搅拌5min，利用硝酸锌的锌离子和REG形成配位键；
(2)加入10ml无水甲醇、2g 2-甲基咪唑，室温下继续搅拌15min，2-甲基咪唑与配位化合物的锌离子形成ZIF-8；
(3)在11000rmp的转速下离心20min，再分别用无水乙醇和去离子的混合溶液洗涤三遍洗去未反应的试剂，真空干燥，即得到REG@ZIF-8载体；
实施例1制备的REG@ZIF-8载体中REG的负载量为19.85％。
实施例2：制备CED@ZIF-8
(1)将10mg CED溶于4ml甲醇与0.2g的六水硝酸锌溶于0.8ml的甲醇溶液混合，室温下搅拌5min，利用硝酸锌的锌离子和CED形成配位键；
(2)加入10ml无水甲醇、2g 2-甲基咪唑，室温下继续搅拌15min，2-甲基咪唑与配位化合物的锌离子形成ZIF-8；
(3)在11000rmp的转速下离心20min，再分别用无水乙醇和去离子的混合溶液洗涤三遍洗去未反应的试剂，真空干燥，即得到CED@ZIF-8载体；
实施例2制备的CED@ZIF-8载体中CED的负载量为18.96％。
表征试验1：紫外光谱检测
将干燥后的REG@ZIF-8(实施例1中制备)、REG溶解于PBS缓冲溶液中，测试其上清液的紫外光谱。紫外图谱(UV/vis)分别如图1所示。从图1中可以看出，瑞格菲尼在210nm的特征吸收峰并没有出现在REG@ZIF-8的紫外光谱图中。这说明，瑞格菲尼被包埋在了ZIF-8内部。
将干燥后的CED@ZIF-8(实施例2中制备)、CED溶解于PBS缓冲溶液中，测试其上清液的紫外光谱。紫外图谱(UV/vis)分别如图2所示。从图2中可以看出，CED在236nm的特征吸收峰并没有出现在CED@ZIF-8的紫外光谱图中。这说明，CED被包埋在了ZIF-8内部。
表征试验2：红外光谱检测
(1)将瑞格菲尼、ZIF-8、REG@ZIF-8(实施例1中制备)、CED、ZIF-8、CED@ZIF-8(实施例2中制备)进行干燥处理，然后放入研钵中，加入适量并略多于待测药品质量的KBr，研磨均匀使混合物研磨到粒度小于2μm，以免散射光影响，之后放入干燥机中进行干燥处理，在油压机上用40MPa左右的压力将混合物压成透明薄片，上机测定；
(2)红外图谱(FTIR)分别如图3、图4所示。图3中显示了瑞格菲尼中的特征基团C＝O在1721处的吸收峰和C-H在837处的吸收峰；图3中显示了ZIF-8中的特征基团-N＝C-在1420处的吸收峰；REG@ZIF-8具备1420处的吸收峰，且不存在1721处的吸收峰和837处的吸收峰，表明瑞格菲尼被包被在载体内部。图4中显示了CED中的特征基团-C-O-C-在1231处的吸收峰和C-H在905处的吸收峰；图4中显示了ZIF-8中的特征基团-N＝C-在1420处的吸收峰；REG@ZIF-8具备1420处的吸收峰，且不存在1231处的吸收峰和905处的吸收峰，表明CED被包被在载体内部。
表征试验3：扫描电镜检测与透射电镜检测
REG@ZIF-8(实施例1中制备)的扫描电镜图如附图5中的(a)所示，透射电镜图如图5中的(b)所示；CED@ZIF-8(实施例2中制备)的扫描电镜图如图6中的(a)所示，透射电镜图如图6中的(b)所示。
从电镜图中可以看出沸石咪唑类骨架为八面体，且大小在纳米级别；负载药物的ZIF-8，八面体晶型明显，并不黏连。各药物颗粒结构近似，粒径大小相对稳定。
表征试验4：X射线衍射检测
实施例1制备的REG@ZIF-8和实施例2制备的CED@ZIF-8的X射线衍射图如图7、图8所示，由图7和图8可知，负载瑞格菲尼和CED的ZIF-8载体仍然保持着沸石咪唑类骨架的晶型结构。
性能试验1：不同pH下药物释放试验
将REG@ZIF-8(实施例1中制备)和CED@ZIF-8(实施例2中制备)在不同pH液体环境下测试释放曲线。通过紫外分析上清中瑞格菲尼的含量，判定药物释放率。如图9、图10所示。由图9和图10可知，药物在中性环境中(pH7.4的PBS)中性能较稳定，在酸性环境下(pH6.0和pH 6.5的PBS)释放率显著升高。
性能试验2：中性环境中(pH7.4)药物细胞毒性试验
将REG@ZIF-8(实施例1中制备)和CED@ZIF-8(实施例2中制备)在中性液体环境中(pH7.4，MEM培养基)测试细胞毒性。采用人源性肝癌细胞株HCC-LM3为对象。通过CCK-8试验分析药物对细胞的杀伤作用。如图11、图12所示。由图11和图12可知，在中性环境中，经ZIF-8包被的药物性能稳定，显著减少细胞毒性。
Claims (7)
1.一种负载VEGFR靶向抑制剂的药物载体，其特征在于，所述药物载体包括沸石咪唑类骨架，以及包埋于沸石咪唑类骨架中的VEGFR靶向抑制剂；所述VEGFR靶向抑制剂为瑞格菲尼或西地尼布。
2.根据权利要求1所述的负载VEGFR靶向抑制剂的药物载体，其特征在于，所述药物载体中瑞格菲尼或西地尼布的负载量为18-20％。
3.一种如权利要求1所述的负载VEGFR靶向抑制剂的药物载体的制备方法，其特征在于，通过原位包埋法将VEGFR靶向抑制剂封装在沸石咪唑类骨架中，得到VEGFR靶向抑制剂-沸石咪唑类骨架载体。
4.根据权利要求3所述的VEGFR靶向抑制剂的药物载体的制备方法，其特征在于，所述原位包埋法包括：
硝酸锌与VEGFR分子靶向抑制剂反应形成配位化合物；
配位化合物与2-甲基咪唑反应得到VEGFR靶向抑制剂-沸石咪唑类骨架载体。
5.根据权利要求3或4所述的负载VEGFR靶向抑制剂的药物载体的制备方法，其特征在于，所述原位包埋法包括：
硝酸锌与VEGFR分子靶向抑制剂分别配制成甲醇溶液，室温下混合后得到配位化合物体系；
配位化合物体系中加入2-甲基咪唑的甲醇溶液室温下混合，离心清洗干燥后，得到VEGFR分子靶向抑制剂-沸石咪唑类骨架载体。
6.根据权利要求4所述的负载VEGFR靶向抑制剂的药物载体的制备方法，其特征在于，所述VEGFR靶向抑制剂、硝酸锌与2-甲基咪唑的质量比为1-10:10-50:20-200。
7.一种如权利要求1-2任一所述的VEGFR靶向抑制剂的药物载体在制备抗肿瘤治疗药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911031467.1A CN110664760B (zh) | 2019-10-28 | 2019-10-28 | 一种负载vegfr靶向抑制剂的药物载体及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911031467.1A CN110664760B (zh) | 2019-10-28 | 2019-10-28 | 一种负载vegfr靶向抑制剂的药物载体及其制备方法和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110664760A CN110664760A (zh) | 2020-01-10 |
| CN110664760B true CN110664760B (zh) | 2020-10-23 |
Family
ID=69084570
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911031467.1A Active CN110664760B (zh) | 2019-10-28 | 2019-10-28 | 一种负载vegfr靶向抑制剂的药物载体及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110664760B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113368253B (zh) * | 2020-03-10 | 2022-06-10 | 中国科学院宁波工业技术研究院慈溪生物医学工程研究所 | 基于沸石咪唑框架结构的药物载体及其制备方法与应用 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111372934B (zh) * | 2017-08-18 | 2024-04-26 | 科瑞华生物技术有限公司 | Tg02的多晶型形式 |
| CN108997436B (zh) * | 2018-07-20 | 2020-06-12 | 玉林师范学院 | 一种瑞格非尼抗肿瘤铂(ii)配合物及其制备方法与应用 |
-
2019
- 2019-10-28 CN CN201911031467.1A patent/CN110664760B/zh active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN110664760A (zh) | 2020-01-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Xiao et al. | Core–shell structured 5-FU@ ZIF-90@ ZnO as a biodegradable nanoplatform for synergistic cancer therapy | |
| Wu et al. | Tailored core‒shell dual metal–organic frameworks as a versatile nanomotor for effective synergistic antitumor therapy | |
| Son et al. | Anticancer activity of drug-loaded calcium phosphate nanocomposites against human osteosarcoma | |
| Bhavsar et al. | Formulation and development of smart pH responsive mesoporous silica nanoparticles for breast cancer targeted delivery of anastrozole: In vitro and in vivo characterizations | |
| Zhang et al. | Nanozyme-incorporated biodegradable bismuth mesoporous radiosensitizer for tumor microenvironment-modulated hypoxic tumor thermoradiotherapy | |
| Hashemzadeh et al. | Delivery of oxaliplatin to colorectal cancer cells by folate-targeted UiO-66-NH2 | |
| Dong et al. | Metal-polyphenol-network coated CaCO 3 as pH-responsive nanocarriers to enable effective intratumoral penetration and reversal of multidrug resistance for augmented cancer treatments | |
| Yan et al. | Layered double hydroxide nanosheets: towards ultrasensitive tumor microenvironment responsive synergistic therapy | |
| CN108273068B (zh) | 负载表没食子儿茶素没食子酸酯的叶酸靶向载体及其制备方法和应用 | |
| Cheng et al. | Cu-doped cerium oxide-based nanomedicine for tumor microenvironment-stimulative chemo-chemodynamic therapy with minimal side effects | |
| Ma et al. | Rationally integrating peptide-induced targeting and multimodal therapies in a dual-shell theranostic platform for orthotopic metastatic spinal tumors | |
| CN110664760B (zh) | 一种负载vegfr靶向抑制剂的药物载体及其制备方法和应用 | |
| Zhang et al. | Catalyzing Generation and Stabilization of Oxygen Vacancies on CeO2− x Nanorods by Pt Nanoclusters as Nanozymes for Catalytic Therapy | |
| CN110251684B (zh) | 具备氧化应激自放大功能的纳米复合物、制备方法及应用 | |
| Mokhtari et al. | Covalent triazine-based polyimine framework as a biocompatible pH-dependent sustained-release nanocarrier for sorafenib: An in vitro approach | |
| CN101879427B (zh) | 载有盐酸阿霉素的天然高分子-聚(3-丙烯酰胺基苯硼酸)复合纳米微球及其制法和用途 | |
| Moghadam et al. | High cancer selectivity and improving drug release from mesoporous silica nanoparticles in the presence of human serum albumin in cisplatin, carboplatin, oxaliplatin, and oxalipalladium treatment | |
| CN107998404A (zh) | 一种负载抗癌药物的叶酸靶向载体及其制备方法和应用 | |
| Saboktakin et al. | Synthesis and characterization of modified starch hydrogels for photodynamic treatment of cancer | |
| CN115054613B (zh) | 一种多功能纳米催化剂及其制备方法 | |
| Singh et al. | Development of a pH-sensitive functionalized metal organic framework: in vitro study for simultaneous delivery of doxorubicin and cyclophosphamide in breast cancer | |
| Arafa et al. | Nanosized biligated metal–organic framework systems for enhanced cellular and mitochondrial sequential targeting of hepatic carcinoma | |
| Wang et al. | Endogenous reactive oxygen species burst induced and spatiotemporally controlled multiple drug release by traceable nanoparticles for enhancing antitumor efficacy | |
| CN111603436A (zh) | 一种光动力二氧化硅纳米材料@水凝胶复合载药系统、其制备方法及其应用 | |
| Shen et al. | Hierarchically released liquid metal nanoparticles for mild photothermal therapy/chemotherapy of breast cancer bone metastases via remodeling tumor stromal microenvironment |
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 |