CN117126670B - 一种硼酸功能化CdTe量子点及肿瘤靶向诊疗一体化复合纳米药物 - Google Patents
一种硼酸功能化CdTe量子点及肿瘤靶向诊疗一体化复合纳米药物 Download PDFInfo
- Publication number
- CN117126670B CN117126670B CN202311122035.8A CN202311122035A CN117126670B CN 117126670 B CN117126670 B CN 117126670B CN 202311122035 A CN202311122035 A CN 202311122035A CN 117126670 B CN117126670 B CN 117126670B
- Authority
- CN
- China
- Prior art keywords
- drug
- composite nano
- tumor
- solution
- qds
- 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
- 239000003814 drug Substances 0.000 title claims abstract description 87
- 229940079593 drug Drugs 0.000 title claims abstract description 70
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 41
- 238000011282 treatment Methods 0.000 title claims abstract description 33
- 238000003745 diagnosis Methods 0.000 title claims abstract description 26
- 239000002096 quantum dot Substances 0.000 title claims abstract description 25
- 239000002131 composite material Substances 0.000 title claims abstract description 24
- 230000008685 targeting Effects 0.000 title claims abstract description 24
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 239000004327 boric acid Substances 0.000 title claims abstract description 19
- 229910004613 CdTe Inorganic materials 0.000 title claims abstract description 15
- 201000007270 liver cancer Diseases 0.000 claims abstract description 12
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims description 44
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 claims description 28
- FXNFHKRTJBSTCS-UHFFFAOYSA-N Baicalein Natural products C=1C(=O)C=2C(O)=C(O)C(O)=CC=2OC=1C1=CC=CC=C1 FXNFHKRTJBSTCS-UHFFFAOYSA-N 0.000 claims description 20
- 229940015301 baicalein Drugs 0.000 claims description 16
- UDFLTIRFTXWNJO-UHFFFAOYSA-N baicalein Chemical compound O1C2=CC(=O)C(O)=C(O)C2=C(O)C=C1C1=CC=CC=C1 UDFLTIRFTXWNJO-UHFFFAOYSA-N 0.000 claims description 16
- 239000002245 particle Substances 0.000 claims description 16
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 claims description 14
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 claims description 14
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 claims description 14
- 229960001285 quercetin Drugs 0.000 claims description 14
- 235000005875 quercetin Nutrition 0.000 claims description 14
- AUVSUPMVIZXUOG-UHFFFAOYSA-N (4-sulfanylphenyl)boronic acid Chemical compound OB(O)C1=CC=C(S)C=C1 AUVSUPMVIZXUOG-UHFFFAOYSA-N 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 239000012670 alkaline solution Substances 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000010863 targeted diagnosis Methods 0.000 claims 3
- OBYVIBDTOCAXSN-UHFFFAOYSA-N n-butan-2-ylbutan-2-amine Chemical compound CCC(C)NC(C)CC OBYVIBDTOCAXSN-UHFFFAOYSA-N 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 15
- 210000004881 tumor cell Anatomy 0.000 abstract description 14
- 238000000799 fluorescence microscopy Methods 0.000 abstract description 7
- 230000004044 response Effects 0.000 abstract description 6
- 239000002253 acid Substances 0.000 abstract description 4
- 238000012377 drug delivery Methods 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 230000003287 optical effect Effects 0.000 abstract 1
- 230000004614 tumor growth Effects 0.000 abstract 1
- 230000000694 effects Effects 0.000 description 15
- 238000011068 loading method Methods 0.000 description 13
- 201000011510 cancer Diseases 0.000 description 10
- 239000007853 buffer solution Substances 0.000 description 9
- 239000002114 nanocomposite Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 229940041181 antineoplastic drug Drugs 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 238000005538 encapsulation Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000000502 dialysis Methods 0.000 description 5
- 239000002086 nanomaterial Substances 0.000 description 5
- 238000009777 vacuum freeze-drying Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 4
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 description 4
- 229940093265 berberine Drugs 0.000 description 4
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 description 4
- 229910052796 boron Inorganic materials 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 239000002105 nanoparticle Substances 0.000 description 4
- 229960004432 raltitrexed Drugs 0.000 description 4
- 238000001179 sorption measurement Methods 0.000 description 4
- 230000008859 change Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VOADVZVYWFSHSM-UHFFFAOYSA-L sodium tellurite Chemical compound [Na+].[Na+].[O-][Te]([O-])=O VOADVZVYWFSHSM-UHFFFAOYSA-L 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 230000005281 excited state Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000002572 peristaltic effect Effects 0.000 description 2
- -1 pezopanib Chemical compound 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 208000021959 Abnormal metabolism Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 230000003592 biomimetic effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- 238000012632 fluorescent imaging Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000006371 metabolic abnormality Effects 0.000 description 1
- 230000004066 metabolic change Effects 0.000 description 1
- 108091008104 nucleic acid aptamers Proteins 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- 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
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6923—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- A61K47/54—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 compound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0065—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle
- A61K49/0067—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle quantum dots, fluorescent nanocrystals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/08—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials
- C09K11/88—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing selenium, tellurium or unspecified chalcogen elements
- C09K11/888—Borates
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Inorganic Chemistry (AREA)
- Materials Engineering (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Ceramic Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Nanotechnology (AREA)
- Biomedical Technology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种硼酸功能化CdTe量子点及肿瘤靶向诊疗一体化复合纳米药物。本发明请求保护的复合纳米药物以硼酸功能化CdTe量子点为载体,以含顺式二羟基结构的抗肿瘤化合物为主药。该复合纳米药物具备优异的光学性质、良好的生物相容性和低毒性,且在肿瘤弱酸微环境中能快速响应释放药物,实现了肝癌HepG2细胞靶向给药及荧光成像,该纳米药物能够高效抑制肿瘤生长,具备pH响应释药和荧光发射性能。本发明所得复合纳米药物能够实现对肝癌等肿瘤细胞的精准靶向诊疗。
Description
技术领域
本发明属于医药领域,具体涉及一种硼酸功能化CdTe量子点及肿瘤靶向诊疗一体化复合纳米药物。
背景技术
恶性肿瘤是全球范围公认的严重威胁人类身体健康的一大类疾病,肿瘤细胞拥有与正常细胞不同的代谢变化,这种异常的代谢能使机体的正常功能失调,从而威胁生命。据世卫组织统计,2020年全球新发癌症病例约2000万例,癌症死亡病例达到了近1000万,其中肝癌为主要肿瘤之一。因此,对于肝癌病灶的诊断与治疗研究有待进一步深化。传统的治疗措施如化疗、手术切除等存在有限作用效果、副作用、耐药性等诸多缺点。
在科技和医疗体系的不断发展下,肿瘤治疗迎来了纳米体系的引入。纳米药物载体体系能够通过血液循环***,附着于病灶组织,同时还能被许多的官能团所修饰,能够靶向并积累于肿瘤细胞,达到持续性作用的效果。尺寸较小的纳米材料渗透能力强,能透过体内组织和屏障,有效地到达肿瘤微环境,而尺寸较大的纳米材料具有滞留肿瘤细胞效应(EPR)。因此,纳米材料在增强抗肿瘤药物作用效果和减少副作用方面发挥着重要作用,其本身所具有的多项属性,影响了在体内的利用率,具有较多的可控因素和研究方向,在肿瘤的诊断与治疗领域表现出了可观的应用前景。利用纳米体系的吸附性能和纳米尺寸等特点,构建量子点纳米颗粒载药体系,将其应用于药物递送、疾病诊断与治疗、荧光成像等方面,与传统的治疗方法相比,其具有靶向选择性、药物微小剂量、生物相容性、荧光亮度稳定等特点。据此,基于硼酸功能化量子点的载药体系具有较好的抗癌潜力,其独特的纳米尺寸和荧光特性,促进了纳米材料应用于诊断与治疗领域的研究。
癌症靶向诊疗的关键在于靶向性,而肿瘤细胞本身作为“靶标”,使得靶向诊疗能够将药物以较高的含量递送到肿瘤靶部位,降低对正常细胞的伤害,高效准确地命中肿瘤细胞,达到低毒高效的治疗作用,故癌细胞的靶向识别直接决定了癌症靶向诊疗效果。目前,科学家们在这方面进行了许多研究工作,总体来说,现有癌症靶向诊疗策略主要包括抗体、受体、核酸适配体、肿瘤靶向肽、仿生分子识别技术以及肿瘤微环境介导的靶向诊疗等几种类型。弱酸性肿瘤微环境是肿瘤的普遍特征,通过制备pH敏感的硼亲和效应和荧光发射特性的复合药物,对发展通用的肿瘤诊疗一体化新技术具有重要意义,为癌症靶向诊疗提供新思路。
发明内容
本发明目的在于提供一种硼酸功能化CdTe量子点及肿瘤靶向诊疗一体化复合纳米药物,以实现递药纳米颗粒高生物相容性、高载药量、肿瘤微环境靶向释药及药物摄入实时追踪。
本发明上述目的通过如下技术方案实现:
一种硼酸功能化CdTe量子点,通过如下步骤制备:
步骤S1,取适量CdCl2·2.5H2O与适量硫代乙醇酸TGA混合,充分搅拌,调至pH至10~11,再加入适量4-巯基苯硼酸MPBA,混合均匀;
步骤S2,向上述混合溶液中加入适量NaTeO3溶液,混合均匀,再加入适量硼氢化钠,充分搅拌,120℃恒温加热搅拌,冷凝回流反应20min-48h后得到具有荧光发射性能的BA-QDs溶液,加入适量有机溶剂提纯沉淀,将溶液底部的颗粒溶液转移至离心管中,离心收集产物,冷冻干燥得到具有荧光发射性能的硼酸功能化CdTe量子点。
优选地,步骤S1中用适量NaOH溶液调至pH至10~11。
一种肿瘤靶向诊疗一体化复合纳米药物,通过如下步骤制备:利用上述硼酸功能化CdTe量子点在碱性溶液中吸附活性药物,得到复合纳米药物;其中,所述活性药物为具有顺式二羟基结构的抗肿瘤化合物。
优选地,所述碱性溶液的pH为7.4~11。
优选地,所述肿瘤靶向诊疗一体化复合纳米药物为肝癌靶向诊疗一体化复合纳米药物。
更优选地,所述抗肿瘤化合物为黄芩素或槲皮素。
与现有技术相比,本发明具有以下有益效果:
(1)构建了一种肝癌肿瘤细胞靶向杀伤及药物体内外实时最终的纳米诊疗方法,利用硼酸功能化量子点能够实现对具备顺式二羟基结构的黄酮类药物特异性吸附,同时根据肿瘤微环境变化实现纳米复合药物靶向递药至肿瘤细胞,且释药前后纳米复合药物的荧光性能发生显著变化,有益于药物体内外实时追踪。(2)本发明所得纳米复合药物对正常细胞毒性小,生物相容性好,利用荧光发射光谱的高灵敏度、线性范围大等特点,利用活细胞工作站可以直观观测细胞等生物样品药物摄入情况,本发明利用荧光进行治疗效果实时评估,可实时检测肿瘤细胞摄入药物及细胞凋亡情况,从而实现诊疗一体化。(3)本发明所得纳米复合药物采用具有顺式二羟基结构的抗肿瘤化合物和硼酸功能化量子点靶向协同杀伤肿瘤细胞,相比单一化疗给药,其所需药物浓度显著降低,实现低毒、高效、靶向治疗肝癌等癌症。
附图说明
图1为实施例1、2、3制备得到的BA-QDs紫外激发荧光图;
图2为黄芩素/BA-QDs pH响应释放曲线;
图3为槲皮素/BA-QDs pH响应释放曲线;
图4为黄芩素纳米复合药物对HEPG2肿瘤细胞抑制率;
图5为释放黄芩素前后BA-QDs荧光强度变化;
图6为负载黄芩素、槲皮素的BA-QDs作用于HepG2细胞的荧光成像图。
具体实施方式
下面结合实施例具体介绍本发明实质性内容,但并不以此限定本发明的保护范围。
实施例1:具有绿色荧光发射性能的硼酸功能化CdTe量子点的制备
将准确称取的92mg CdCl2·2.5H2O转移至250ml烧杯中,向其中加入100mL蒸馏水,之后用100μL移液枪移取36μL硫代乙醇酸(TGA)至烧杯中。将上述溶液至于室温下充分搅拌后,用5%NaOH调至pH 11,加入10mL 4-巯基苯硼酸(MPBA)充分搅拌。将称取的20mg亚碲酸钠至100mL蒸馏水中并充分搅拌,之后将上述两种溶液混合,向其中加入160mg硼氢化钠,在超声波清洗器的作用下,使溶液中的溶质分散均匀,将混合的200mL溶液转移至圆底烧瓶中,并置于120℃的集热式恒温加热磁力搅拌器(油浴锅)中,安装冷凝管,反应20min后得到绿色荧光的BA-QDs溶液。将BA-QDs溶液转移至1L烧杯中,按照BA-QDs溶液∶无水乙醇=1∶4,即向200mL BA-QDs溶液中滴加800ml的无水乙醇,流速控制在4mL/min,提纯沉降。室温下提纯约6h后,BA-QDs颗粒沉降于烧杯底部,去掉上清液,将底部颗粒溶液转移至离心管中,通过离心(10k rpm,10min)收集产物。最后,通过真空冷冻干燥收集产物,即得到BA-QDs,马尔文ZS90纳米粒度仪测定BA-QDs粒度范围20-50nm,该BA-QDs在紫外激发状态下为呈现绿色荧光(如图1所示),用于肿瘤细胞荧光成像研究中追踪药物。
实施例2:具有黄色荧光发射性能的硼酸功能化CdTe量子点的制备
将准确称取的92mg CdCl2·2.5H2O转移至250ml烧杯中,向其中加入100mL蒸馏水,之后用100μL移液枪移取36μL硫代乙醇酸(TGA)至烧杯中。将上述溶液至于室温下充分搅拌后,用5%NaOH调至pH 10,加入10mL 4-巯基苯硼酸(MPBA)充分搅拌。将称取的20mg亚碲酸钠至100mL蒸馏水中并充分搅拌,之后将上述两种溶液混合,向其中加入160mg硼氢化钠,在超声波清洗器的作用下,使溶液中的溶质分散均匀,将混合的200mL溶液转移至圆底烧瓶中,并置于120℃的集热式恒温加热磁力搅拌器(油浴锅)中,安装冷凝管,反应4h后得到黄色荧光的BA-QDs溶液。将BA-QDs溶液转移至1L烧杯中,按照BA-QDs溶液∶甲醇=1∶4,即向200mL BA-QDs溶液中滴加800ml的甲醇,流速控制在8mL/min,提纯沉降。室温下提纯约6h后,BA-QDs颗粒沉降于烧杯底部,去掉上清液,将底部颗粒溶液转移至离心管中,通过离心(10k rpm,10min)收集产物。最后,通过真空冷冻干燥收集产物,即得到BA-QDs,马尔文ZS90纳米粒度仪测定QDs粒径为55-80nm,该BA-QDs在紫外激发状态下为呈现黄色荧光(如图1所示),用于肿瘤细胞荧光成像研究中追踪药物。
实施例3:具有红色荧光发射性能的硼酸功能化CdTe量子点的制备
将准确称取的92mg CdCl2·2.5H2O转移至250ml烧杯中,向其中加入100mL蒸馏水,之后用100μL移液枪移取36μL硫代乙醇酸(TGA)至烧杯中。将上述溶液至于室温下充分搅拌后,用5%NaOH调至pH 11,加入10mL 4-巯基苯硼酸(MPBA)充分搅拌。将称取的20mg亚碲酸钠至100mL蒸馏水中并充分搅拌,之后将上述两种溶液混合,向其中加入160mg硼氢化钠,在超声波清洗器的作用下,使溶液中的溶质分散均匀,将混合的200mL溶液转移至圆底烧瓶中,并置于120℃的集热式恒温加热磁力搅拌器(油浴锅)中,安装冷凝管,反应48h后得到红色荧光的BA-QDs溶液。将BA-QDs溶液转移至1L烧杯中,按照BA-QDs溶液∶无水乙醇=1∶4,即向200mL BA-QDs溶液中滴加800ml的无水乙醇,流速控制在10mL/min,提纯沉降。室温下提纯约6h后,BA-QDs颗粒沉降于烧杯底部,去掉上清液,将底部颗粒溶液转移至离心管中,通过离心(10k rpm,10min)收集产物。最后,通过真空冷冻干燥收集产物,即得到紫外激发的红色荧光QDs,马尔文ZS90纳米粒度仪测定QDs粒径为80-95nm,该BA-QDs在紫外激发状态下为呈现红色荧光(如图1所示),用于肿瘤细胞荧光成像研究中追踪药物。
实施例4:肿瘤靶向诊疗一体化复合纳米药物的制备
我们通过制备负载黄芩素的硼亲和量子点(Bai/BA-QDs)、负载槲皮素的硼亲和量子点(Que/BA-QDs)验证了BA-QDs作为纳米材料的载药性能。黄芩素、槲皮素均为含顺式二羟基的抗癌药物。Bai/BA-QDs、Que/BA-QDs制备具体步骤如下:分别称取4mg黄芩素、槲皮素,分别加入10mL的pH值为10的PBS缓冲溶液中(pH范围在7.4-11均可),于超声波清洁器中,利用蠕动泵逐滴加入10mL无水乙醇(1滴/s),得到20mL黄芩素和槲皮素微纳米颗粒溶液。之后,再向上述两种溶液中分别加入20mg BA-QDs(按实施例1制备),室温下进行磁力搅拌60min,离心(10000rpm,10min),将BA-QDs与黄芩素、槲皮素结合的沉淀进行真空冷冻干燥得到固体颗粒,并加入到20mLPBS缓冲溶液中,利用酶标仪,取200μL溶液在313nm激发波长下检测不同时间点下BA-QDs的荧光强度,所得黄芩素/BA-QDs、槲皮素/BA-QDs粒度范围在50-100nm,载药量分别为13.29%、17.32%,包封率分别为69.55%、86.6%。
实施例5:肿瘤靶向诊疗一体化复合纳米药物的释药性能测定
为了研究BA-QDs载药体系在肿瘤微环境中的释药性能,采用弱酸PBS缓冲液模拟肿瘤环境,利用透析袋来检测BA-QDs载药体系中抗癌药物的释放量。具体步骤如下:将实施例4制备得到的负载黄芩素、槲皮素的BA-QDs的纳米复合药物分别溶于6mL不同pH的PBS缓冲溶液,将溶液装入透析袋,用封口夹封住透析袋开口处,将其沉浸在100mL的PBS缓冲溶液中,于37℃气浴恒温振荡器中摇晃。之后在不同的时间点(1/6、1/3、1/2、1、3、6、12和24小时)进行取样补样,即取出5mL的PBS缓冲溶液作为检测样本,补充5mL相同的PBS缓冲溶液。检测样本即黄芩素、槲皮素溶液,分别于360nm、278nm、375nm检测吸光度,经过计算得到不同时间点各抗癌药物的溶出度,如图2、图3所示溶出曲线,硼酸功能化量子点载药复合物在6h释放60%以上,表明负载黄芩素、槲皮素的纳米复合药物均具有良好的pH响应释放性能。
实施例6:对肿瘤细胞的影响
为了检测量子点与BA-QDs载药体系对癌细胞的影响,以肝癌细胞(HepG2)为研究目标,通过MTT实验来检测给药后癌细胞的活性状况和荧光成像效果。
在96孔板中加入肝癌细胞并在适宜条件下培养24h,再分别加入100μg/mL、50μg/mL、25μg/mL BA-QDs(按实施例1制备),以及所载抗癌药物浓度为200μg/mL、100μg/mL、50μg/mL的两种BA-QDs载药体系(按实施例4制备)。之后,继续在适宜条件下孵育24h,在此期间对荧光成像进行观测。24h后,再加入MTT后一段时间后加入二甲基亚砜,缓慢摇匀一段时间后利用酶标仪在490nm下测定吸光度。经过计算得到各浓度载药体系样品对HepG2肝癌细胞的抑制率如图4所示,表明载药的BA-QDs具备良好的HepG2细胞抑制效果。
如图5所示为纳米复合药物在pH4、pH6缓冲溶液中释药前后的荧光强度变化,表明BA-QDs载药之后荧光强度降低,待药物释放之后荧光强度一定程度恢复;细胞摄入药物之后荧光图如图6所示,图5、图6结果表明纳米复合药物具有良好的pH响应释药和荧光发射性能,可应用于肝癌靶向。
对比实施例1:比较BA-QDs、QDs载药性能
BA-QDs载药性能数据见实施例4。
QDs载药性能测试如下,其中QDs制备方法与实施例1的区别仅仅在于制备量子点时未加入4-巯基苯硼酸MPBA,Bai/QDs制备方法及载药性测定方法与实施例4一致。结果显示,所得Bai/QDs载药量3.85%,QDs载药性能显著不如BA-QDs载药性能。
对比实施例2:对活性化合物的选择性
为了验证BA-QDs对含有顺式二羟基结构药物的特异性吸附性能,本发明还开展了黄连素、培唑帕尼、雷替曲塞等不具备该结构药物的吸附性能研究,具体步骤如下:分别称取4mg黄连素、培唑帕尼、雷替曲塞,分别加入10mL的PBS缓冲溶液中,于超声波清洁器中,利用蠕动泵逐滴加入10mL无水乙醇(1滴/s),得到20mL药物溶液,向上述三种溶液中加入20mgBA-QDs,室温下进行磁力搅拌24h吸附药物,最后离心、真空冷冻干燥得到固体颗粒,测定载药量及包封率。黄连素载药量5.31%、包封率26.55,培唑帕尼载药量3.28%、包封率16.4%,雷替曲塞载药量4.81%、包封率24.05%。以上不具备该结构的药物载药量及包封率明显较低,说明BA-QDs不能与黄连素、培唑帕尼、雷替曲塞等药物产生硼亲和作用。以上实验结果证明本发明制备得到的量子点可同时作为载体和药物实时追踪的标记物,用于制备具有含顺式二羟基结构的药物复合纳米颗粒,且所得复合纳米药物具有pH响应释药和荧光发射性能,该复合纳米药物可在肿瘤弱酸微环境响应释药、同时产生荧光信号变化,最终用于肿瘤诊断与治疗。本发明例举了包括黄芩素、槲皮素等含有顺式二羟基结构的药物以及不含上述结构的药物开展对比,需要指出的是本发明包括但不局限于上述药物还应包括其他具备顺式二羟基结构的药物(如表1所示)。
表1含顺式二羟基结构的代表性抗肿瘤药物
上述实施例的作用在于具体介绍本发明的实质性内容,但本领域技术人员应当知道,不应将本发明的保护范围局限于该具体实施例。
Claims (4)
1.一种肿瘤靶向诊疗一体化复合纳米药物,其特征在于,通过如下步骤制备:利用硼酸功能化CdTe量子点在pH为7.4~11的碱性溶液中吸附活性药物,得到复合纳米药物;其中,所述活性药物为具有顺式二羟基结构的抗肿瘤化合物;
所述硼酸功能化CdTe量子点通过如下步骤制备:
步骤S1:取适量CdCl2·2.5H2O与适量硫代乙醇酸TGA混合,充分搅拌,调至pH至10~11,再加入适量4-巯基苯硼酸MPBA,混合均匀;
步骤S2:向步骤S1得到的混合溶液中加入适量NaTeO3溶液,混合均匀,再加入适量硼氢化钠,充分搅拌,120℃恒温加热搅拌,冷凝回流反应20min-48h后得到具有荧光发射性能的BA-QDs溶液,加入适量有机溶剂提纯沉淀,将溶液底部的颗粒溶液转移至离心管中,离心收集产物,冷冻干燥得到具有荧光发射性能的硼酸功能化CdTe量子点。
2.根据权利要求1所述的肿瘤靶向诊疗一体化复合纳米药物,其特征在于:步骤S1中用适量NaOH溶液调至pH至10~11。
3.根据权利要求1所述的肿瘤靶向诊疗一体化复合纳米药物,其特征在于:所述肿瘤靶向诊疗一体化复合纳米药物为肝癌靶向诊疗一体化复合纳米药物。
4.根据权利要求3所述的肿瘤靶向诊疗一体化复合纳米药物,其特征在于:所述抗肿瘤化合物为黄芩素或槲皮素。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311122035.8A CN117126670B (zh) | 2023-09-01 | 2023-09-01 | 一种硼酸功能化CdTe量子点及肿瘤靶向诊疗一体化复合纳米药物 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311122035.8A CN117126670B (zh) | 2023-09-01 | 2023-09-01 | 一种硼酸功能化CdTe量子点及肿瘤靶向诊疗一体化复合纳米药物 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN117126670A CN117126670A (zh) | 2023-11-28 |
CN117126670B true CN117126670B (zh) | 2024-05-28 |
Family
ID=88850631
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311122035.8A Active CN117126670B (zh) | 2023-09-01 | 2023-09-01 | 一种硼酸功能化CdTe量子点及肿瘤靶向诊疗一体化复合纳米药物 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117126670B (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101776683A (zh) * | 2010-01-06 | 2010-07-14 | 东华大学 | 基于荧光纳米发光和磁性纳米材料的癌胚抗原的检测方法 |
CN110161243A (zh) * | 2018-02-13 | 2019-08-23 | 北京化工大学 | 一种用于活细胞内肿瘤标志物实时成像的纳米人工抗体抑制剂及其制备方法 |
CN110257071A (zh) * | 2019-05-08 | 2019-09-20 | 华南师范大学 | 一种量子点荧光探针及其在检测植物细胞中葡萄糖的应用 |
-
2023
- 2023-09-01 CN CN202311122035.8A patent/CN117126670B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101776683A (zh) * | 2010-01-06 | 2010-07-14 | 东华大学 | 基于荧光纳米发光和磁性纳米材料的癌胚抗原的检测方法 |
CN110161243A (zh) * | 2018-02-13 | 2019-08-23 | 北京化工大学 | 一种用于活细胞内肿瘤标志物实时成像的纳米人工抗体抑制剂及其制备方法 |
CN110257071A (zh) * | 2019-05-08 | 2019-09-20 | 华南师范大学 | 一种量子点荧光探针及其在检测植物细胞中葡萄糖的应用 |
Non-Patent Citations (1)
Title |
---|
Quantum dots functionalized with 3-mercaptophenylboronic acids as novel nanoplatforms to evaluate sialic acid content on cell membranes;Camila A.P. Monteiro等;Colloids and Surfaces B: Biointerfaces;20200516;第193卷;第111142页 * |
Also Published As
Publication number | Publication date |
---|---|
CN117126670A (zh) | 2023-11-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107802840B (zh) | 一种基于肽类树形分子修饰荧光碳点的肿瘤微环境响应纳米粒及其制备方法 | |
CN100577209C (zh) | 一种磁性肿瘤双靶向聚合物纳米胶束及其制备方法 | |
US20190224238A1 (en) | Tumor therapeutic drug | |
CN111718465B (zh) | 一种聚二硫缩醛及其制备方法和应用 | |
CN100560137C (zh) | 一种载带伯胺基药物的细菌纳米磁小体及其制备方法 | |
CN115252560B (zh) | 一种基于天然产物的自组装纳米粒及其制备方法和应用 | |
CN101831000A (zh) | 乙酰普鲁兰多糖叶酸偶联物的纯化及其纳米粒子的制备方法 | |
CN111001006A (zh) | 葫芦素b和氧化响应抗肿瘤前药共载仿生纳米粒 | |
CN108524529B (zh) | 基于两性离子及叶酸靶向的酸敏感性阿霉素前药及其制备方法与应用 | |
CN117126670B (zh) | 一种硼酸功能化CdTe量子点及肿瘤靶向诊疗一体化复合纳米药物 | |
CN113599532A (zh) | 负载药物和胶原蛋白酶的白蛋白复合纳米颗粒、制备及应用 | |
CN112972696A (zh) | 荧光多肽掺杂金属有机框架纳米材料及制备方法和应用 | |
CN112704743A (zh) | 一种可供注射的海参皂苷介孔二氧化硅纳米复合物及其制备方法和应用 | |
CN108888773B (zh) | 自组装球形药物纳米制剂及其制备方法与用途 | |
CN115192708B (zh) | 负载抗肿瘤药物的纳米复合材料、纳米载药体系及制备与应用 | |
CN111995745B (zh) | 一种双锁型聚合物及其制备方法和应用 | |
CN111202850A (zh) | 一种喜树碱前药及其制备方法和应用 | |
CN108888607A (zh) | 一种核壳结构的多功能纳米药物载体的制备方法 | |
CN108283720B (zh) | 同时键合喜树碱和阿霉素的聚磷酸酯前药及其制备方法与应用 | |
CN108653256B (zh) | 一种复合纳米钻石药物及其制备方法和应用 | |
CN110384703A (zh) | 基于6-硫鸟嘌呤的金属-药物配位纳米药物及其制备方法和应用 | |
CN104998274B (zh) | 一种核‑壳结构纳米复合多功能载药体及其制备方法 | |
CN112999152B (zh) | 一种基于gebp11修饰的靶向聚合物胶束及其制备方法与应用 | |
CN114394998B (zh) | 一种Os-Pd双金属有机分子笼及其制备方法与应用 | |
CN109568592B (zh) | 一种纳米凝胶ng1及其应用 |
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 |