聚磷酸酯纳米凝胶作为抗癌药物输送载体的研究
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摘要
纳米凝胶具有一个亲水性交联网络结构的内核,已经被广泛应用于亲水性抗癌药物、蛋白分子、核酸类药物的输送。本论文的研究中,利用多种方法构建了基于聚磷酸酯的纳米凝胶,证明了这些纳米凝胶具有良好的生物相容性。这些纳米凝胶能高效负载抗癌药物阿霉素,并成功将药物分子输送到细胞内,其中具有肝靶向修饰的纳米凝胶在化学药物诱导的原发性大鼠肝癌的治疗中显示良好的效果。本文的研究分为以下4个部分：
第一部分：我们制备了一系列基于聚磷酸酯和聚乙二醇的大分子单体,利用反相微乳液体系,通过氧化／还原自由基引发体系引发大分子单体聚合,获得了尺寸在250 nm左右的纳米凝胶。使用CPC、NMR、FT-IR对大分子单体的结构及组成进行了详细的分析,并通过动态光散射、TEM对纳米凝胶的分散及形态进行了研究。我们进一步将这种纳米凝胶作为载体,输送抗癌药物阿霉素,通过实验证明这种载体能高效负载阿霉素,并显著抑制人乳腺癌细胞MCF-7的增殖。
第二部分：我们充分利用高分子链段的特殊磷酸酯具有温度敏感性的特点,通过“无模板法”制备了具有交联内核的纳米凝胶。温度响应性的三嵌段聚合物PEEP151-PEG2000-PEEP151的二丙烯酸酯在温度高于它的最低临界溶解温度(LCST)时在水溶液中自组装成纳米颗粒,进一步将纳米颗粒进行交联固定后,在室温下形成一种内核亲水的纳米凝胶。我们通过流式细胞计数技术和共聚焦激光扫描显微镜等研究方法证实了负载阿霉素的纳米凝胶能够高效被人肺癌肿瘤细胞A549摄取,并在细胞内释放药物。与游离阿霉素分子相比,这种载药纳米凝胶能显著抑制A549肿瘤细胞的增殖。
第三部分：我们通过“一步合成法”制备了一种具有聚乙二醇壳层及交联磷酸酯内核的纳米凝胶。这种纳米凝胶的表面键和了半乳糖配体,特异性被去唾液酸糖蛋白受体(ASGP-R)所识别。我们将其作为肝靶向性的纳米载药体系输送阿霉素,用于肝癌全身性治疗。研究结果表明,这种带有半乳糖配体的纳米凝胶载体能特异性被HepG2肝癌细胞识别,并显著增强阿霉素在肝脏部位的累积。虽然与非靶向性的纳米凝胶载体相比,在体内分布上该纳米凝胶并未能体现其靶向能力的优势,但研究观察其负载的阿霉素在肝脏部位的累积方式时,发现靶向配体修饰的纳米凝胶载体显著提高肝实质细胞对其的摄取。不仅如此,这种靶向性载药纳米凝胶在二乙基亚硝胺诱导的Wistar大鼠原发性肝癌的治疗中显示了优越的抗肿瘤生成与发展的能力。
此外,为了研究聚磷酸酯和细胞的相互作用,以及聚磷酸酯对细胞功能的影响,我们使用聚2-氨乙基丙烯基磷酸酯作为聚阳离子与其它聚电解质构建了表面为聚磷酸酯的层层自组装薄膜。我们将这种聚磷酸酯为表面的薄膜材料作为成骨细胞(osteoblast)的培养基质,研究了成骨细胞在薄膜表面的粘附、生长及增殖情况,检测了成骨细胞表型的表达,并对生长在这种聚磷酸酯薄膜材料上的成骨细胞功能进行了评价。实验结果发现这种薄膜不仅能促进成骨细胞的粘附,而且能显著增强成骨细胞的分化能力；同时通过检测生长在聚磷酸酯薄膜上的成骨细胞功能,发现其表型蛋白碱性磷酸酶、Ⅰ型胶原的表达量都明显高于培养在细胞培养板表面的成骨细胞,并且钙离子的沉积量也显著增加,证明了这种基于聚磷酸酯材料的薄膜能促进成骨细胞的分化。
With the hydrophilic and crosslinked interior core, nano-sized hydrogel particles, also termed nanogels are attractive as carriers of anti-cancer drugs, protein, nucleic acid and so on. In this dissertation, biocompatible nanogels consisting of degradable polyphosphoester and poly(ethylene glycol) have been fabricated by multiple methods, including polymerization of macromer in an inverse microemulsion system or by a template-free method. The nanogel has also been made by a one-step ring-opening polymerization. Anti-cancer drug, doxorubicin has been conveniently encapsulated in the nanogel systems by simply mixing the drug with nanogel particles at high drug loading contents and efficiencies. The nanogels can successfully deliver the payload into cells, and the targeted nanogel with surface galactose modification exhibits enhanced therapeutic effect to hepatocellular carcinoma (HCC) induced by diethylnitrosamine in rats.
In the first part of this dissertation, inverse microemulsion polymerization was employed to synthesize biocompatible nanogel with controlled size, morphology, and compositions. We synthesized a series of macromers based on polyphosphoester and poly(ethylene glycol), and initiated the polymerization of macromers by an oxidation-reduction system. The obtained nanogel particles possessed an average diameter around 250 nm, while the properties of nanogels were investigated by NMR, light scattering and transmission electron microscopy observations. The nanogels exhibited extended stability in aqueous media and low cytotoxicity. It was also demonstrated that with loading of doxorubicin, the nanogel showed enhanced inhibition to MCF-7 tumor cell proliferation.
In the second part, biodegradable nanogels with tunable sizes were synthesized by a template-free method. The nanogels are obtained by crosslinking thermo-induced nanoparticles, with subsequent swelling at low temperatures, which were based on a thermosensitive and biocompatible triblock copolymer composed of poly(ethylene glycol) and poly(ethyl ethylene phosphate). The nanogels loaded with doxorubicin are efficiently taken up by A549 tumor cells and the drug could be released intracellularly, demonstrated by flow cytometric analyses and confocal laser scanning microscope observations. It results in enhanced growth inhibition activity to tumor cells in comparison with free doxorubicin treatment.
In the third part, we developed galactosylated core-shell nanogel (Gal-PPE) consisting of cross-linked polyphosphate core and galactosylated poly(ethylene glycol) arms by one-step ring-opening polymerization. This nanogel was used as a nanocarrier for targeted doxorubicin delivery to diethylnitrosamine-induced hepatocellular carcinoma in rats. Gal-PPE nanogel exhibited high affinity to HepG2 cells in vitro, mediated by asialoglycoprotein receptor. In vivo studies revealed that doxorubicin was more accumulated in liver with the delivery of either Gal-PPE or non-galactosylated m-PPE nanogel following intravenous injection, in comparison with free doxorubicin administration, while negligible difference was observed between Gal-PPE and m-PPE. However, Gal-PPE nanogel particles were taken up more efficiently by hepatocytes, in contrast to m-PPE nanogel particles, which were dominantly excluded by Kupffer cells. Consequently, targeted doxorubicin delivery with Gal-PPE significantly inhibited the progress of HCC, reducing neoplastic liver nodules and prolonging survival time of HCC rats more significantly. The efficacious anti-HCC effect of targeted Gal-PPE delivery system was further confirmed by down-regulated expressions of tumor-associated proteins in HCC.
In addition, to understand the interaction between polyphosphoester and cells, and the effect of polyphosphoester to the cell function, we fabricated multilayer film of degradable cationic poly(2-aminoethyl propylene phosphate) with other polyanion by a layer-by-layer assembly approach. We cultured mouse osteoblast cells on the multilayer film with the outmost layer of poly(2-aminoethyl propylene phosphate), and studied the cell adhesion and proliferation on the surface. It was observed that the multilayer film facilitated initial mouse osteoblast cell adhesion onto the surface enhanced the expressions of alkaline phosphatase and type I collagen, and also increased cellular calcium accumulation, which implied that differentiation of osteoblast cells was induced by multilayer film at poly(2-aminoethyl propylene phosphate) surface.
第一部分：我们制备了一系列基于聚磷酸酯和聚乙二醇的大分子单体,利用反相微乳液体系,通过氧化／还原自由基引发体系引发大分子单体聚合,获得了尺寸在250 nm左右的纳米凝胶。使用CPC、NMR、FT-IR对大分子单体的结构及组成进行了详细的分析,并通过动态光散射、TEM对纳米凝胶的分散及形态进行了研究。我们进一步将这种纳米凝胶作为载体,输送抗癌药物阿霉素,通过实验证明这种载体能高效负载阿霉素,并显著抑制人乳腺癌细胞MCF-7的增殖。
第二部分：我们充分利用高分子链段的特殊磷酸酯具有温度敏感性的特点,通过“无模板法”制备了具有交联内核的纳米凝胶。温度响应性的三嵌段聚合物PEEP151-PEG2000-PEEP151的二丙烯酸酯在温度高于它的最低临界溶解温度(LCST)时在水溶液中自组装成纳米颗粒,进一步将纳米颗粒进行交联固定后,在室温下形成一种内核亲水的纳米凝胶。我们通过流式细胞计数技术和共聚焦激光扫描显微镜等研究方法证实了负载阿霉素的纳米凝胶能够高效被人肺癌肿瘤细胞A549摄取,并在细胞内释放药物。与游离阿霉素分子相比,这种载药纳米凝胶能显著抑制A549肿瘤细胞的增殖。
第三部分：我们通过“一步合成法”制备了一种具有聚乙二醇壳层及交联磷酸酯内核的纳米凝胶。这种纳米凝胶的表面键和了半乳糖配体,特异性被去唾液酸糖蛋白受体(ASGP-R)所识别。我们将其作为肝靶向性的纳米载药体系输送阿霉素,用于肝癌全身性治疗。研究结果表明,这种带有半乳糖配体的纳米凝胶载体能特异性被HepG2肝癌细胞识别,并显著增强阿霉素在肝脏部位的累积。虽然与非靶向性的纳米凝胶载体相比,在体内分布上该纳米凝胶并未能体现其靶向能力的优势,但研究观察其负载的阿霉素在肝脏部位的累积方式时,发现靶向配体修饰的纳米凝胶载体显著提高肝实质细胞对其的摄取。不仅如此,这种靶向性载药纳米凝胶在二乙基亚硝胺诱导的Wistar大鼠原发性肝癌的治疗中显示了优越的抗肿瘤生成与发展的能力。
此外,为了研究聚磷酸酯和细胞的相互作用,以及聚磷酸酯对细胞功能的影响,我们使用聚2-氨乙基丙烯基磷酸酯作为聚阳离子与其它聚电解质构建了表面为聚磷酸酯的层层自组装薄膜。我们将这种聚磷酸酯为表面的薄膜材料作为成骨细胞(osteoblast)的培养基质,研究了成骨细胞在薄膜表面的粘附、生长及增殖情况,检测了成骨细胞表型的表达,并对生长在这种聚磷酸酯薄膜材料上的成骨细胞功能进行了评价。实验结果发现这种薄膜不仅能促进成骨细胞的粘附,而且能显著增强成骨细胞的分化能力；同时通过检测生长在聚磷酸酯薄膜上的成骨细胞功能,发现其表型蛋白碱性磷酸酶、Ⅰ型胶原的表达量都明显高于培养在细胞培养板表面的成骨细胞,并且钙离子的沉积量也显著增加,证明了这种基于聚磷酸酯材料的薄膜能促进成骨细胞的分化。
With the hydrophilic and crosslinked interior core, nano-sized hydrogel particles, also termed nanogels are attractive as carriers of anti-cancer drugs, protein, nucleic acid and so on. In this dissertation, biocompatible nanogels consisting of degradable polyphosphoester and poly(ethylene glycol) have been fabricated by multiple methods, including polymerization of macromer in an inverse microemulsion system or by a template-free method. The nanogel has also been made by a one-step ring-opening polymerization. Anti-cancer drug, doxorubicin has been conveniently encapsulated in the nanogel systems by simply mixing the drug with nanogel particles at high drug loading contents and efficiencies. The nanogels can successfully deliver the payload into cells, and the targeted nanogel with surface galactose modification exhibits enhanced therapeutic effect to hepatocellular carcinoma (HCC) induced by diethylnitrosamine in rats.
In the first part of this dissertation, inverse microemulsion polymerization was employed to synthesize biocompatible nanogel with controlled size, morphology, and compositions. We synthesized a series of macromers based on polyphosphoester and poly(ethylene glycol), and initiated the polymerization of macromers by an oxidation-reduction system. The obtained nanogel particles possessed an average diameter around 250 nm, while the properties of nanogels were investigated by NMR, light scattering and transmission electron microscopy observations. The nanogels exhibited extended stability in aqueous media and low cytotoxicity. It was also demonstrated that with loading of doxorubicin, the nanogel showed enhanced inhibition to MCF-7 tumor cell proliferation.
In the second part, biodegradable nanogels with tunable sizes were synthesized by a template-free method. The nanogels are obtained by crosslinking thermo-induced nanoparticles, with subsequent swelling at low temperatures, which were based on a thermosensitive and biocompatible triblock copolymer composed of poly(ethylene glycol) and poly(ethyl ethylene phosphate). The nanogels loaded with doxorubicin are efficiently taken up by A549 tumor cells and the drug could be released intracellularly, demonstrated by flow cytometric analyses and confocal laser scanning microscope observations. It results in enhanced growth inhibition activity to tumor cells in comparison with free doxorubicin treatment.
In the third part, we developed galactosylated core-shell nanogel (Gal-PPE) consisting of cross-linked polyphosphate core and galactosylated poly(ethylene glycol) arms by one-step ring-opening polymerization. This nanogel was used as a nanocarrier for targeted doxorubicin delivery to diethylnitrosamine-induced hepatocellular carcinoma in rats. Gal-PPE nanogel exhibited high affinity to HepG2 cells in vitro, mediated by asialoglycoprotein receptor. In vivo studies revealed that doxorubicin was more accumulated in liver with the delivery of either Gal-PPE or non-galactosylated m-PPE nanogel following intravenous injection, in comparison with free doxorubicin administration, while negligible difference was observed between Gal-PPE and m-PPE. However, Gal-PPE nanogel particles were taken up more efficiently by hepatocytes, in contrast to m-PPE nanogel particles, which were dominantly excluded by Kupffer cells. Consequently, targeted doxorubicin delivery with Gal-PPE significantly inhibited the progress of HCC, reducing neoplastic liver nodules and prolonging survival time of HCC rats more significantly. The efficacious anti-HCC effect of targeted Gal-PPE delivery system was further confirmed by down-regulated expressions of tumor-associated proteins in HCC.
In addition, to understand the interaction between polyphosphoester and cells, and the effect of polyphosphoester to the cell function, we fabricated multilayer film of degradable cationic poly(2-aminoethyl propylene phosphate) with other polyanion by a layer-by-layer assembly approach. We cultured mouse osteoblast cells on the multilayer film with the outmost layer of poly(2-aminoethyl propylene phosphate), and studied the cell adhesion and proliferation on the surface. It was observed that the multilayer film facilitated initial mouse osteoblast cell adhesion onto the surface enhanced the expressions of alkaline phosphatase and type I collagen, and also increased cellular calcium accumulation, which implied that differentiation of osteoblast cells was induced by multilayer film at poly(2-aminoethyl propylene phosphate) surface.
引文
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