多功能复合纳米粒子的制备及其在生物医学领域中的应用
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摘要
本论文成功合成了不同代数的树枝状分子PAMAM，并对其结构进行了表征。由于其结构特殊及表面含有大量的官能团，可以进行多种功能化修饰及作为无机纳米粒子表面配体。首先将阿霉素通过pH敏感化学键-腙连接在G3.5PAMAM上，并在其表面修饰上FA分子，同时这种靶向释放配体可以与磁性纳米粒子进行配体交换，得到可用于靶向治疗，MRI成像检测的多功能体系。对靶向纳米释药体系及小鼠MRI成像方面进行了研究。另外通过化学键将FA以及抗癌药紫杉醇，顺磁性纳米氧化铁联系起来，并对树状分子表面修饰荧光分子Cy5.5，得到了可用于肿瘤检测和靶向治疗的多功能纳米复合物。它可以作为一种双探针分子，进行荧光和MRI双重检测试剂，并表现出了优良的性质。制备以mPEG-G3.5PAMAM为载体，通过两次配体交换的修饰方法，成功将QDs与IONPs复合在一起，然后对其表面修饰上anti-VEGF，构筑靶向双模态的分子影像探针，并通过多种检测手段，对其结进行了详尽的表征，从体外共聚焦显微镜照片及小鼠MRI肿瘤成像，对双探针分子进行了研究。同时应用相同的靶向机制，我们成功制备荧光靶向载药释放体系。它是由载体分子G3.5PAMAM及抗肿瘤药物DOX，通过配体交换的方法对QDs进行修饰，得到靶向复合载药纳米粒子，并对各项性质进行了详尽的表征。在靶向树枝状载体FA-PEG-G3.5的表面，修饰上DTPA合成了FA-PEG-G3.5-DTPA配体。这种配体不但可以通过表面的羧基与量子点进行配体交换，得到一种大分子荧光制剂，而且它的表面可以螯合顺磁性Gd离子，制备MRI成像与荧光成像一体的双探针分子，并在细胞实验与小鼠MRI成像实验中，对双探针分子进行了评估。
本论文设计合成的多功能纳米复合物，具有良好的生物相容性，应用于肿瘤的靶向治疗及生物探针分子，特点鲜明，优势突出，对于肿瘤的早期诊断及靶向治疗方面有重要的意义。
Nanobiotechnology is the hot spot of today's scientific research, which is anintersection of nanotechnology and biotechnology.The functional nanoparticleshas agreat prospect in the biomedical field, such as biological probes, magnetictransfection and protein separation, targeted drug delivery, drug delivery, etc. To studythe interaction between the nanoparticles and the biologically active substance bymodifyingthe surface of the nanoparticles, in which lay the theoretical foundation forits subsequent applications in the field of biomedical. The ligand-exchange reactionmethodis based on the binding affinity of multidentateamine groups to the QDs orIONPs surface. After the ligand exchange, the NPs were converted from oil-soluble towater-soluble. At last, the stable multifunctional water-soluble nanoparticles wereobtained.
The dendrimer PAMAM is a carrier, which is widely used in this paper. PAMAMdendrimers were prepared by a divergent synthesis scheme using the reagent excessmethod starting from EDA by consecutive Michael addition and ester amidationreaction. For the surface of PAMAM with numerous functional groups (amine,carboxyl, and hydroxyl), and it can be modified with different functionalities(conjugation of anti cancer drug and targeting moiety). After the modification of PEG,the pharmacokinetic properties of drugs and the drug distribution in vivo can beimprove, the stability in the body is increased, the toxicity and immunogenicity arereduced. And then the liand wascombined with nanoparticles, which is used asbiological probes and targeted drug delivery.
A tumor targeted and pH-responsive drug release system that is based on folicacid (FA) conjugated to poly(ethylene glycol)(PEG)-modified dendrimers (PAMAM)with doxorubicin (DOX) andsuperparamagnetic iron oxide (Fe3O4) has beenconstructed andcharacterized.IONPs were stabilized by FA-PEG-G3.5PAMAMdendrimers. The anticancer drugDOX was conjugated to the dendrimer segments ofamino-stabilized IONPs using hydrazine as thelinker via hydrazone bonds, which areacid cleavable and can be used as an ideal pH-responsive drugrelease system. Notably,these novel nanoparticlescontaining DOX conjugates showed great potential forapplicationin both MRI detection and cancer therapy by virtue oftheir targetingfunction, in addition to EPR accumulation, whichallowed the anticancer drug to beorientated directly to thetarget sites, although the nanoparticles without tagetingmoiety.
A tumor targeted and drug-loaded system that is based on folic acid (FA)conjugated to poly(ethylene glycol)(PEG)-modified dendrimers (PAMAM) withpaclitaxel (PTX), Cy5.5fluorophore and superparamagnetic ironoxide (IONPs) hasbeen constructed and characterized. And through a variety of detection methods tocharacterize the size of its structure, morphology, both the physical and chemicalproperties were studied. The attached FA could facilitate the use of the conjugates as afolate receptor-targeted drug deliverysystem. TheCLSMpictures of cell in vitro canprove that the role the targeting molecule FA plays in the uptake of NPconjugates bythe cell.These novel PTX-loaded conjugates have the potential to enhance the effectof fluorescenceimaging, MRI contrast and cancer therapy in the course of deliveringdrugs to target sites.This provides the research foundation for tumor detection andtargeted therapy.
We have developed an imaging system by co-conjugating QDs and IONPs withmPEG-G3.5PAMAM for both of MRI and fluorescent imaging concurrently, whichcombination of QDs and IO as a single probe strives to improve imaging withpractical clinical feasibility andthe anti-VEGF was selected as the targetingmoiety.These preliminarydata demonstrated that the conjugation of anti-VEGF moleculesto the surface of the NPs, which favors the anti-VEGF receptorrecognition,was responsible for the targeting ability of anti-VEGF-PEG-G3.5-QDs@IONPs, andin turn beneficial to theirentry into the cells through endocytosis or macropinocytosis.It isparently seen that anti-VEGF conjugated NPs exhibitedefficientreceptor-mediated endocytosis in VEGF receptoroverexpressingcancer cells, ascompared to non-targeted NPs.Conjugation of hybridnanoparticles show better cancerimaging ability as an MRcontrast agent in vivo and fluorescent imaging effects exvivo asthe result of the combined anti-VEGF, thereby greatly improvingthe efficacyof imaging.
The same applications of targeting mechanism of targeting molecules anti-VEGFspecific binding of VEGF overexpressing of the tumor surface, after preparing thefluorescent the targeted drug loading release system. The ligand-exchange reaction isbased on the binding affinity of the anticancer drugs DOX modified-G3.5PAMAM tothe QDs surface. Doxorubicin and quantum dots are connected through this effectivemethod, by this way the QDs were converted to high quantum yield ofwater-soluble complexes so that the composite nanoparticles can play an importantrole in cancer targeted treatment. Meanwhile, the PEGylation of PAMAM dendrimermodified onto the surface of the nanoparticle, which greatly improve the stability ofquantum dots. And the good biocompatibility and low toxicity of PEG and PAMAMmake its application in biology.
Optical and magnetic resonance (MR) imaging probes were integrated byconjugating DTPAgadolinium(Gd) derivative to quantum dot based FA-PEG-G3.5PAMAM. It is known that carboxyl canbe used to stabilize QDs with oleic acidcoating, and obtained water-soluble macromolecular fluorescent QDs. The remainingcarboxyl groups can chelate Gd to preparea dual probe, which contains MR imagingand fluorescence imaging molecules, then through a series of characterizationmethods to characterize its structure.The dual probe shows better cancer imaging ability as an MRcontrast agent in vivo and fluorescent imaging effects ex vivo astheresult of the combined FA, thereby greatly improvingthe efficacy of imaging.
本论文设计合成的多功能纳米复合物，具有良好的生物相容性，应用于肿瘤的靶向治疗及生物探针分子，特点鲜明，优势突出，对于肿瘤的早期诊断及靶向治疗方面有重要的意义。
Nanobiotechnology is the hot spot of today's scientific research, which is anintersection of nanotechnology and biotechnology.The functional nanoparticleshas agreat prospect in the biomedical field, such as biological probes, magnetictransfection and protein separation, targeted drug delivery, drug delivery, etc. To studythe interaction between the nanoparticles and the biologically active substance bymodifyingthe surface of the nanoparticles, in which lay the theoretical foundation forits subsequent applications in the field of biomedical. The ligand-exchange reactionmethodis based on the binding affinity of multidentateamine groups to the QDs orIONPs surface. After the ligand exchange, the NPs were converted from oil-soluble towater-soluble. At last, the stable multifunctional water-soluble nanoparticles wereobtained.
The dendrimer PAMAM is a carrier, which is widely used in this paper. PAMAMdendrimers were prepared by a divergent synthesis scheme using the reagent excessmethod starting from EDA by consecutive Michael addition and ester amidationreaction. For the surface of PAMAM with numerous functional groups (amine,carboxyl, and hydroxyl), and it can be modified with different functionalities(conjugation of anti cancer drug and targeting moiety). After the modification of PEG,the pharmacokinetic properties of drugs and the drug distribution in vivo can beimprove, the stability in the body is increased, the toxicity and immunogenicity arereduced. And then the liand wascombined with nanoparticles, which is used asbiological probes and targeted drug delivery.
A tumor targeted and pH-responsive drug release system that is based on folicacid (FA) conjugated to poly(ethylene glycol)(PEG)-modified dendrimers (PAMAM)with doxorubicin (DOX) andsuperparamagnetic iron oxide (Fe3O4) has beenconstructed andcharacterized.IONPs were stabilized by FA-PEG-G3.5PAMAMdendrimers. The anticancer drugDOX was conjugated to the dendrimer segments ofamino-stabilized IONPs using hydrazine as thelinker via hydrazone bonds, which areacid cleavable and can be used as an ideal pH-responsive drugrelease system. Notably,these novel nanoparticlescontaining DOX conjugates showed great potential forapplicationin both MRI detection and cancer therapy by virtue oftheir targetingfunction, in addition to EPR accumulation, whichallowed the anticancer drug to beorientated directly to thetarget sites, although the nanoparticles without tagetingmoiety.
A tumor targeted and drug-loaded system that is based on folic acid (FA)conjugated to poly(ethylene glycol)(PEG)-modified dendrimers (PAMAM) withpaclitaxel (PTX), Cy5.5fluorophore and superparamagnetic ironoxide (IONPs) hasbeen constructed and characterized. And through a variety of detection methods tocharacterize the size of its structure, morphology, both the physical and chemicalproperties were studied. The attached FA could facilitate the use of the conjugates as afolate receptor-targeted drug deliverysystem. TheCLSMpictures of cell in vitro canprove that the role the targeting molecule FA plays in the uptake of NPconjugates bythe cell.These novel PTX-loaded conjugates have the potential to enhance the effectof fluorescenceimaging, MRI contrast and cancer therapy in the course of deliveringdrugs to target sites.This provides the research foundation for tumor detection andtargeted therapy.
We have developed an imaging system by co-conjugating QDs and IONPs withmPEG-G3.5PAMAM for both of MRI and fluorescent imaging concurrently, whichcombination of QDs and IO as a single probe strives to improve imaging withpractical clinical feasibility andthe anti-VEGF was selected as the targetingmoiety.These preliminarydata demonstrated that the conjugation of anti-VEGF moleculesto the surface of the NPs, which favors the anti-VEGF receptorrecognition,was responsible for the targeting ability of anti-VEGF-PEG-G3.5-QDs@IONPs, andin turn beneficial to theirentry into the cells through endocytosis or macropinocytosis.It isparently seen that anti-VEGF conjugated NPs exhibitedefficientreceptor-mediated endocytosis in VEGF receptoroverexpressingcancer cells, ascompared to non-targeted NPs.Conjugation of hybridnanoparticles show better cancerimaging ability as an MRcontrast agent in vivo and fluorescent imaging effects exvivo asthe result of the combined anti-VEGF, thereby greatly improvingthe efficacyof imaging.
The same applications of targeting mechanism of targeting molecules anti-VEGFspecific binding of VEGF overexpressing of the tumor surface, after preparing thefluorescent the targeted drug loading release system. The ligand-exchange reaction isbased on the binding affinity of the anticancer drugs DOX modified-G3.5PAMAM tothe QDs surface. Doxorubicin and quantum dots are connected through this effectivemethod, by this way the QDs were converted to high quantum yield ofwater-soluble complexes so that the composite nanoparticles can play an importantrole in cancer targeted treatment. Meanwhile, the PEGylation of PAMAM dendrimermodified onto the surface of the nanoparticle, which greatly improve the stability ofquantum dots. And the good biocompatibility and low toxicity of PEG and PAMAMmake its application in biology.
Optical and magnetic resonance (MR) imaging probes were integrated byconjugating DTPAgadolinium(Gd) derivative to quantum dot based FA-PEG-G3.5PAMAM. It is known that carboxyl canbe used to stabilize QDs with oleic acidcoating, and obtained water-soluble macromolecular fluorescent QDs. The remainingcarboxyl groups can chelate Gd to preparea dual probe, which contains MR imagingand fluorescence imaging molecules, then through a series of characterizationmethods to characterize its structure.The dual probe shows better cancer imaging ability as an MRcontrast agent in vivo and fluorescent imaging effects ex vivo astheresult of the combined FA, thereby greatly improvingthe efficacy of imaging.
引文
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