新型兩親性聚合物納米材料的制備及其在藥物輸送中的應用
發(fā)布時間：2018-11-06 16:32
【摘要】：高分子納米材料具有獨特的物理和化學性質(zhì),使其在不同領域中得到廣泛的應用。與此同時具有各種功能的高分子納米材料在生物醫(yī)藥領域的發(fā)展也十分迅速。作為藥物載體的兩親性嵌段聚合物中,能用作疏水性鏈段的聚合物種類單一,因此尋找新的疏水性鏈段迫在眉睫。本文主要通過開環(huán)聚合(ROP)、可逆加成-斷裂鏈轉(zhuǎn)移聚合(RAFT)和自由基聚合等聚合手段,設計并合成一系列新型嵌段共聚物和聚合物熒光納米顆粒并應用于藥物緩釋和細胞成像中。具體內(nèi)容如下:1、為了提高疏水性抗癌藥物阿霉素(DOX)在腫瘤治療中藥物的利用率,我們以聚十三碳二元酸環(huán)乙撐酯(Poly(ethylene brassylate),PEB)作為疏水性鏈段制備了聚乙二醇單甲醚-b-聚十三碳二元酸環(huán)乙撐酯(PEG-b-PEB)兩親性嵌段聚合物,并用作抗癌藥物DOX的載體。我們通過調(diào)節(jié)反應時間以及單體和引發(fā)劑的比例制備出含不同PEB分子量的嵌段聚合物。采用核磁共振波譜儀(1H NMR)和凝膠滲透色譜儀(GPC)對嵌段聚合物的化學結(jié)構(gòu)進行了確認,同時對分子量大小及分布進行了測試。并采用透射電子顯微鏡(TEM)和動態(tài)光散射儀(DLS)對PEG-b-PEB的自組裝納米膠束的形貌和粒徑進行表征。最后我們以DOX為藥物模型考察了不同分子量PEG-b-PEB膠束的藥物緩釋性能。2、為了克服傳統(tǒng)的線型兩親性嵌段聚合物載藥膠束在體內(nèi)循環(huán)過程中穩(wěn)定性不佳的問題,我們通過開環(huán)聚合和可逆加成-斷裂鏈轉(zhuǎn)移聚合的方法制備出結(jié)構(gòu)新穎的四臂星型嵌段聚合物。合成過程中,我們首先以季戊四醇為引發(fā)劑開環(huán)聚合十三碳二元酸環(huán)乙撐酯得到四臂星型均聚物(S-PEB),然后通過簡單的酯化反應在S-PEB鏈末端修飾鏈轉(zhuǎn)移劑(CTA),最后通過RAFT聚合的方法合成四臂嵌段聚合物聚十三碳二元酸環(huán)乙撐酯-b-聚乙二醇甲基丙烯酸甲酯(S-PEB-b-P(PEGM A))。在水溶液中,S-PEB-b-P(PEGMA)能自組裝形成以PEB為核以P(PEGMA)為殼的核-殼納米膠束。我們利用TEM和DLS對S-PEB-b-P(PEGMA)自組裝膠束的形貌和粒徑分布進行觀察研究。體外藥物緩釋實驗結(jié)果表明,S-PEB-b-P(PEGMA)自組裝膠束具有較高的載藥量和良好的緩釋效果。3、為了改善疏水性碳量子點(Carbon Dots,CDs)在水溶液中的分散性和熒光性能,我們通過在疏水性碳點表面修飾上甲基丙烯酰氯,制備出可聚合的碳量子點。隨后將可聚合的碳量子點和N-異丙基丙烯酰胺單體(NIPAM)共聚得到聚N-異丙基丙烯酰胺(PNIPAM)接枝CDs熒光聚合物(CDs-g-PNIPAM)。相比于單純的CDs,CDs-g-PNIPAM在水溶液中具有良好的溶解性以及優(yōu)異的溫度響應性。MTT實驗結(jié)果表明,CDs-g-PNIPAM與人體永生化表皮細胞(HaCaT細胞)共培養(yǎng)時,即使CDs-g-PNIPAM濃度達到2000μg mL-1時,細胞相對存活率仍然能維持在85%以上。體外細胞成像實驗表明,CDs-g-PNIPAM在細胞內(nèi)具有很好的熒光穩(wěn)定性,非常適用于細胞長效成像。
[Abstract]:Polymer nanomaterials are widely used in different fields because of their unique physical and chemical properties. At the same time, polymer nanomaterials with various functions are developing rapidly in the field of biomedicine. Among the amphiphilic block polymers used as drug carriers, the kinds of polymers that can be used as hydrophobic segments are single, so it is urgent to find new hydrophobic segments. In this paper, the reversible addition-break chain transfer polymerization (RAFT) and free radical polymerization of (ROP), were carried out. A series of novel block copolymers and polymer fluorescent nanoparticles were designed and synthesized for drug delivery and cell imaging. The specific contents are as follows: 1. In order to improve the utilization rate of adriamycin (DOX), a hydrophobic anticancer drug, we used poly (tridecyl dicarboxylic acid) cycloethylenes (Poly (ethylene brassylate),) in tumor therapy. Polyethylene glycol monomethyl ether (PEG-b-PEB) amphiphilic block polymer (PEG-b-PEB) was prepared by using PEB as hydrophobic segment and used as a carrier of anticancer drug DOX. Block polymers with different molecular weights of PEB were prepared by adjusting the reaction time and the ratio of monomer to initiator. The chemical structure of the block polymer was confirmed by 1H NMR and (GPC). The molecular weight and distribution of the block polymer were also tested. The morphology and particle size of self-assembled nano-micelles of PEG-b-PEB were characterized by transmission electron microscope (TEM) (TEM) and dynamic light scattering (DLS). Finally, we used DOX as a drug model to investigate the drug release properties of PEG-b-PEB micelles with different molecular weights. 2. In order to overcome the problem of poor stability of traditional linear amphiphilic block polymer micelles in vivo circulation. Novel four-arm star block polymers were prepared by ring-opening polymerization and reversible addition-break chain transfer polymerization. In the synthesis process, pentaerythritol was used as initiator to polymerize cycloethylene-tridecarbamate to obtain four-arm star homopolymer (S-PEB), and then (CTA), was modified at the end of S-PEB chain by simple esterification reaction. Finally, the four-arm block polymer poly (cycloethylene-tridecanoic acid) -b- poly (ethylene glycol methacrylate) (S-PEB-b-P (PEGM A).) was synthesized by RAFT polymerization. In aqueous solution, S-PEB-b-P (PEGMA) can self-assemble into core-shell nano-micelles with PEB as core and P (PEGMA) as shell. The morphology and particle size distribution of S-PEB-b-P (PEGMA) self-assembled micelles were observed by TEM and DLS. In vitro drug release experiments showed that S-PEB-b-P (PEGMA) self-assembled micelles had high drug loading and good sustained release effect. 3. In order to improve hydrophobic carbon quantum dot (Carbon Dots, The dispersibility and fluorescence properties of CDs) in aqueous solution. We prepared polymerizable carbon quantum dots by modifying methacryloyl chloride on the surface of hydrophobic carbon spots. The polymerizable carbon quantum dots (QDs) were then copolymerized with N-isopropylacrylamide monomer (NIPAM) to obtain poly (N-isopropylacrylamide) (PNIPAM) grafted CDs fluorescent polymer (CDs-g-PNIPAM). Compared with pure CDs,CDs-g-PNIPAM, it has good solubility and excellent temperature response in aqueous solution. MTT results show that CDs-g-PNIPAM is co-cultured with human immortalized epidermal cells (HaCaT cells). Even when the concentration of CDs-g-PNIPAM reached 2000 渭 g mL-1, the relative survival rate of the cells remained above 85%. In vitro cell imaging experiments show that CDs-g-PNIPAM has good fluorescence stability in cells and is very suitable for long-term imaging of cells.
【學位授予單位】：西南大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：O631;TQ460.1
本文編號：2314839
[Abstract]:Polymer nanomaterials are widely used in different fields because of their unique physical and chemical properties. At the same time, polymer nanomaterials with various functions are developing rapidly in the field of biomedicine. Among the amphiphilic block polymers used as drug carriers, the kinds of polymers that can be used as hydrophobic segments are single, so it is urgent to find new hydrophobic segments. In this paper, the reversible addition-break chain transfer polymerization (RAFT) and free radical polymerization of (ROP), were carried out. A series of novel block copolymers and polymer fluorescent nanoparticles were designed and synthesized for drug delivery and cell imaging. The specific contents are as follows: 1. In order to improve the utilization rate of adriamycin (DOX), a hydrophobic anticancer drug, we used poly (tridecyl dicarboxylic acid) cycloethylenes (Poly (ethylene brassylate),) in tumor therapy. Polyethylene glycol monomethyl ether (PEG-b-PEB) amphiphilic block polymer (PEG-b-PEB) was prepared by using PEB as hydrophobic segment and used as a carrier of anticancer drug DOX. Block polymers with different molecular weights of PEB were prepared by adjusting the reaction time and the ratio of monomer to initiator. The chemical structure of the block polymer was confirmed by 1H NMR and (GPC). The molecular weight and distribution of the block polymer were also tested. The morphology and particle size of self-assembled nano-micelles of PEG-b-PEB were characterized by transmission electron microscope (TEM) (TEM) and dynamic light scattering (DLS). Finally, we used DOX as a drug model to investigate the drug release properties of PEG-b-PEB micelles with different molecular weights. 2. In order to overcome the problem of poor stability of traditional linear amphiphilic block polymer micelles in vivo circulation. Novel four-arm star block polymers were prepared by ring-opening polymerization and reversible addition-break chain transfer polymerization. In the synthesis process, pentaerythritol was used as initiator to polymerize cycloethylene-tridecarbamate to obtain four-arm star homopolymer (S-PEB), and then (CTA), was modified at the end of S-PEB chain by simple esterification reaction. Finally, the four-arm block polymer poly (cycloethylene-tridecanoic acid) -b- poly (ethylene glycol methacrylate) (S-PEB-b-P (PEGM A).) was synthesized by RAFT polymerization. In aqueous solution, S-PEB-b-P (PEGMA) can self-assemble into core-shell nano-micelles with PEB as core and P (PEGMA) as shell. The morphology and particle size distribution of S-PEB-b-P (PEGMA) self-assembled micelles were observed by TEM and DLS. In vitro drug release experiments showed that S-PEB-b-P (PEGMA) self-assembled micelles had high drug loading and good sustained release effect. 3. In order to improve hydrophobic carbon quantum dot (Carbon Dots, The dispersibility and fluorescence properties of CDs) in aqueous solution. We prepared polymerizable carbon quantum dots by modifying methacryloyl chloride on the surface of hydrophobic carbon spots. The polymerizable carbon quantum dots (QDs) were then copolymerized with N-isopropylacrylamide monomer (NIPAM) to obtain poly (N-isopropylacrylamide) (PNIPAM) grafted CDs fluorescent polymer (CDs-g-PNIPAM). Compared with pure CDs,CDs-g-PNIPAM, it has good solubility and excellent temperature response in aqueous solution. MTT results show that CDs-g-PNIPAM is co-cultured with human immortalized epidermal cells (HaCaT cells). Even when the concentration of CDs-g-PNIPAM reached 2000 渭 g mL-1, the relative survival rate of the cells remained above 85%. In vitro cell imaging experiments show that CDs-g-PNIPAM has good fluorescence stability in cells and is very suitable for long-term imaging of cells.
【學位授予單位】：西南大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：O631;TQ460.1
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