纳米材料在癌症治疗中的作用研究
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摘要
第一部分光催化纳米富勒烯引起的细胞自噬及辅助化疗药物治疗癌症的研究
PARTⅠNano-C60 Sensitizes Chemotherapeutic Killing OfCancer Cells Through Autophagy Modulation
癌症化疗疗效差的主要原因之一是化疗药物对于肿瘤细胞杀伤效率低以及肿瘤细胞易产生耐药性。
细胞自噬是一个与溶酶体相关的细胞内降解过程,这一过程在进化上是保守的,并且影响着肿瘤细胞对于化疗的反应。
已有研究证明富勒烯C60可以产生静态的自噬特征,但是到目前为止人们还没有对这一过程进行具体的研究。
在第一部分中我们发现将富勒烯C60稳定地分散于水中所得到的纳米C60晶体可以引起异常的细胞自噬。这种伴随着自噬体增加和自噬循环减少的异常型自噬,受光照刺激后有所增强,并且该反应依赖于自由基。能引起细胞自噬剂量的纳米C60不会引起细胞死亡,但能增强化疗药物杀死癌细胞(包括耐药性癌细胞)的效应,且这一过程需要Atg5这个自噬必须基因的参与。
我们的实验结果首次提出了纳米-C60具有通过调节自噬过程来提高化疗药物的疗效、降低癌细胞的耐药性这一新的生物学功能,提示纳米-C60具有成为化疗药物佐剂的潜在应用价值。
第二部分聚酰胺-胺树枝形分子在癌症靶向和药物载体中的应用
PARTⅡApplications Of Poly(amidoamine) Dendrimers As CancerTargeting Device And Drug Carriers
聚酰胺-胺(PAMAM)树枝形分子是具有树的结构的人工合成大分子。这类分子具有大量的表面官能团,相对疏水的内部空腔,独特的球形几何外观,可控的尺寸和分子量,以及卓越的单分散性。Star-burst树枝形分子正成为优越的载体靶向给药平台。这部分论文中,我们主要研究了PAMAM树枝形分子在癌症靶向和药物载体中的应用以及PAMAM树枝形分子和药物的相互作用。
这部分论文分为四章。第一章对树枝形分子及其在生物医学中的应用进行了概述,尤其是对PAMAM树枝形分子。
第二章合成了基于PAMAM树枝形分子和生物素的癌症靶向载体。并通过流式细胞仪和激光共聚焦显微镜等技术探讨了聚合物在细胞水平的靶向能力及靶向机理。结果发现这类基于树枝形分子与生物素的高分子载体具有很好的靶向能力,这种靶向作用具有剂量依赖性,孵育时间依赖性,能量依赖性,高度的选择性,而且能够被生物素特异性抑制。这类高分子载体具有卓越的生物兼容性,能够作为一个有潜力的纳米载体平台应用于临床诊断与治疗中。
第三章我们报到了PAMAM树枝形分子负载抗白血病药物6-巯基嘌呤的包裹效率。常规化学疗法中通常面临一个问题是这种细胞毒性药剂的水溶性很低。大分子载体系统可以被用来提高这些这些药物的溶解度。其中被称为树枝形分子的具有高度分支的球形聚合物大分子载体从中脱颖而出。我们的研究发现氨基末端的PAMAM树枝形分子能包裹难溶性抗白血病药6-巯基嘌呤并增加其水溶性。在碱性条件下(pH 10),药物的包裹效率最高,然而,在酸性环境下,药物的包裹效率有所降低;盐离子浓度对包裹效率基本没有影响。
第四章研究了PAMAM树枝形分子与非甾体抗炎药保泰松的相互作用。溶解度结果表明,PAMAM树枝形大分子大大提高了保泰松在水中的溶解度,且增溶作用受树状分子浓度、代数、表面官能团以及pH值的很大影响。二维NOE谱清楚地表明,保泰松的质子和第三代以及第六代树枝状分子内腔的质子由于NOE效应相互作用产生了许多种交叉峰。溶解度、二维NOE和等温滴定量热法的分析结果说明,包裹作用和静电相互作用共同造成保泰松的溶解度提高。二维核磁和等温滴定量热技术是研究树枝状大分子与其被包裹的客体分子之间相互作用的非常有用的工具。
Inefficient tumor cell killing and drug resistance are among the major problems hampering the efficacy of cancer chemotherapy. Autophagy, an evolutionally-conserved intracellular degradation process involving lysosomes, influences the response of tumor cells to chemotherapeutic treatment. Fullerene C60 has been shown to induce certain static features of autophagy, but no detailed studies have been undertaken. In part 1 we show that Nano-C60, the nanocrystal of fullerene C60 stably dispersed in water, induced abberant autophagy with increased autophagosome formation and reduced autophagic turnover in a photo-enhanced and free radical-dependent fashion. The autophagy-inducing dose of Nano-C60 did not directly cause cell death but sensitized chemotherapeutic killing of normal as well as drug-resistant cancer cells, in a process that requires a functional Atg5, an autophagy-essential gene. Our results revealed for the first time a novel biological function for Nano-C60 in enhancing the cytotoxicity of chemotherapeutic agents and reducing drug resistance through autophagy modulation and may point to the potential application of Nano-C60 in adjunct chemotherapy.
Poly(amidoamine) (PAMAM) dendrimers are a class of artificial macro-molecules with tree-like structure. They are hyperbranched, monodisperse, three-dimensional molecules with well-defined shapes, molecular weights, sizes, branched layers, hydrophobic pockets, and surface functionalities. Star-burst dendrimers represent a superior carrier platform for targeted drug delivery. In this part of we explore the application of PAMAM dendrimers as cancer-targeting devie and drug carriers.The interactions between PAMAM dendrimers and drugs are also investigated.
This part of the dissertation comprises four chapters. Chapter 1 begins with a summary on dendrimer and its applications in biomedicine especially PAMAM dendrimers.
In charpter 2 of this part, polymeric nano-carriers based on PAMAM dendrimers and biotin molecules are synthesized for cancer targeting therapy and diagnosis. As revealed by flow cytometry and confocal microscopy, the dendrimer-biotin conjugate exhibits exhibited much higher cellular uptake into cancer cells than the conjugate without biotin. The uptake was energy-dependent, dose-dependent, and could be effectively blocked by dendrimer-conjugated biotin. The results indicated that the biocompatible biotin-dendrimer conjugate might be a promising nano-platform for cancer therapy and cancer diagnosis.
In chapter 3 we report the encapsulation efficiency of a PAMAM dendrimer employing antileukemic drug 6-mercaptopurine. A frequent problem encountered with conventional chemotherapy is the lack of appreciable water solubility exhibited by the cytotoxic agent.MacromoIecular carriers can be used to augment the solubility of such drugs .Of such macromolecular systems emerge a class of spherical, hyper-branched polymers known as dendrimers. Our investigation have found that the encapsulation efficiency of a PAMAM dendrimer bearing amino- terminal groups can encapsulate the poor water solubility antileukemic drug 6-mercaptopurine and enhance its solubility . It was found that under alkaline conditions (pH=10), encapsulation of the drug was the highest. However, under acidic conditions, the encapsulation of the drug was slightly lowered. We also find the concentration of salt has no effect on the encapsulation efficiency.
In Chapter 4 the interactions between PAMAM dendrimers and the non-steroidal anti-inflammatory drug phenylbutazone are investigated. Solubility results showed that PAMAM dendrimers significantly enhanced the aqueous solubility of phenylbutazone and the solubilization was much influenced by dendrimer concentration, generation, surface function group and pH value. The 2D-NOESY spectra clearly showed that there were several kinds of cross-peaks from NOE interactions between the protons of phenylbutazone and the protons in interior cavities of both generation 6 and generation 3 PAMAM dendrimers. Evidence from the solubility, 2D-NOESY results and ITC analysis suggest that encapsulation and electrostatic interaction together caused the solubility enhancement of phenylbutazone. The new techniques such as two-dimensional NMR and Isothermal Titration Calorimetry techniques used in this study are useful tools in investigating the interactions between dendrimers and guest molecules.
PARTⅠNano-C60 Sensitizes Chemotherapeutic Killing OfCancer Cells Through Autophagy Modulation
癌症化疗疗效差的主要原因之一是化疗药物对于肿瘤细胞杀伤效率低以及肿瘤细胞易产生耐药性。
细胞自噬是一个与溶酶体相关的细胞内降解过程,这一过程在进化上是保守的,并且影响着肿瘤细胞对于化疗的反应。
已有研究证明富勒烯C60可以产生静态的自噬特征,但是到目前为止人们还没有对这一过程进行具体的研究。
在第一部分中我们发现将富勒烯C60稳定地分散于水中所得到的纳米C60晶体可以引起异常的细胞自噬。这种伴随着自噬体增加和自噬循环减少的异常型自噬,受光照刺激后有所增强,并且该反应依赖于自由基。能引起细胞自噬剂量的纳米C60不会引起细胞死亡,但能增强化疗药物杀死癌细胞(包括耐药性癌细胞)的效应,且这一过程需要Atg5这个自噬必须基因的参与。
我们的实验结果首次提出了纳米-C60具有通过调节自噬过程来提高化疗药物的疗效、降低癌细胞的耐药性这一新的生物学功能,提示纳米-C60具有成为化疗药物佐剂的潜在应用价值。
第二部分聚酰胺-胺树枝形分子在癌症靶向和药物载体中的应用
PARTⅡApplications Of Poly(amidoamine) Dendrimers As CancerTargeting Device And Drug Carriers
聚酰胺-胺(PAMAM)树枝形分子是具有树的结构的人工合成大分子。这类分子具有大量的表面官能团,相对疏水的内部空腔,独特的球形几何外观,可控的尺寸和分子量,以及卓越的单分散性。Star-burst树枝形分子正成为优越的载体靶向给药平台。这部分论文中,我们主要研究了PAMAM树枝形分子在癌症靶向和药物载体中的应用以及PAMAM树枝形分子和药物的相互作用。
这部分论文分为四章。第一章对树枝形分子及其在生物医学中的应用进行了概述,尤其是对PAMAM树枝形分子。
第二章合成了基于PAMAM树枝形分子和生物素的癌症靶向载体。并通过流式细胞仪和激光共聚焦显微镜等技术探讨了聚合物在细胞水平的靶向能力及靶向机理。结果发现这类基于树枝形分子与生物素的高分子载体具有很好的靶向能力,这种靶向作用具有剂量依赖性,孵育时间依赖性,能量依赖性,高度的选择性,而且能够被生物素特异性抑制。这类高分子载体具有卓越的生物兼容性,能够作为一个有潜力的纳米载体平台应用于临床诊断与治疗中。
第三章我们报到了PAMAM树枝形分子负载抗白血病药物6-巯基嘌呤的包裹效率。常规化学疗法中通常面临一个问题是这种细胞毒性药剂的水溶性很低。大分子载体系统可以被用来提高这些这些药物的溶解度。其中被称为树枝形分子的具有高度分支的球形聚合物大分子载体从中脱颖而出。我们的研究发现氨基末端的PAMAM树枝形分子能包裹难溶性抗白血病药6-巯基嘌呤并增加其水溶性。在碱性条件下(pH 10),药物的包裹效率最高,然而,在酸性环境下,药物的包裹效率有所降低;盐离子浓度对包裹效率基本没有影响。
第四章研究了PAMAM树枝形分子与非甾体抗炎药保泰松的相互作用。溶解度结果表明,PAMAM树枝形大分子大大提高了保泰松在水中的溶解度,且增溶作用受树状分子浓度、代数、表面官能团以及pH值的很大影响。二维NOE谱清楚地表明,保泰松的质子和第三代以及第六代树枝状分子内腔的质子由于NOE效应相互作用产生了许多种交叉峰。溶解度、二维NOE和等温滴定量热法的分析结果说明,包裹作用和静电相互作用共同造成保泰松的溶解度提高。二维核磁和等温滴定量热技术是研究树枝状大分子与其被包裹的客体分子之间相互作用的非常有用的工具。
Inefficient tumor cell killing and drug resistance are among the major problems hampering the efficacy of cancer chemotherapy. Autophagy, an evolutionally-conserved intracellular degradation process involving lysosomes, influences the response of tumor cells to chemotherapeutic treatment. Fullerene C60 has been shown to induce certain static features of autophagy, but no detailed studies have been undertaken. In part 1 we show that Nano-C60, the nanocrystal of fullerene C60 stably dispersed in water, induced abberant autophagy with increased autophagosome formation and reduced autophagic turnover in a photo-enhanced and free radical-dependent fashion. The autophagy-inducing dose of Nano-C60 did not directly cause cell death but sensitized chemotherapeutic killing of normal as well as drug-resistant cancer cells, in a process that requires a functional Atg5, an autophagy-essential gene. Our results revealed for the first time a novel biological function for Nano-C60 in enhancing the cytotoxicity of chemotherapeutic agents and reducing drug resistance through autophagy modulation and may point to the potential application of Nano-C60 in adjunct chemotherapy.
Poly(amidoamine) (PAMAM) dendrimers are a class of artificial macro-molecules with tree-like structure. They are hyperbranched, monodisperse, three-dimensional molecules with well-defined shapes, molecular weights, sizes, branched layers, hydrophobic pockets, and surface functionalities. Star-burst dendrimers represent a superior carrier platform for targeted drug delivery. In this part of we explore the application of PAMAM dendrimers as cancer-targeting devie and drug carriers.The interactions between PAMAM dendrimers and drugs are also investigated.
This part of the dissertation comprises four chapters. Chapter 1 begins with a summary on dendrimer and its applications in biomedicine especially PAMAM dendrimers.
In charpter 2 of this part, polymeric nano-carriers based on PAMAM dendrimers and biotin molecules are synthesized for cancer targeting therapy and diagnosis. As revealed by flow cytometry and confocal microscopy, the dendrimer-biotin conjugate exhibits exhibited much higher cellular uptake into cancer cells than the conjugate without biotin. The uptake was energy-dependent, dose-dependent, and could be effectively blocked by dendrimer-conjugated biotin. The results indicated that the biocompatible biotin-dendrimer conjugate might be a promising nano-platform for cancer therapy and cancer diagnosis.
In chapter 3 we report the encapsulation efficiency of a PAMAM dendrimer employing antileukemic drug 6-mercaptopurine. A frequent problem encountered with conventional chemotherapy is the lack of appreciable water solubility exhibited by the cytotoxic agent.MacromoIecular carriers can be used to augment the solubility of such drugs .Of such macromolecular systems emerge a class of spherical, hyper-branched polymers known as dendrimers. Our investigation have found that the encapsulation efficiency of a PAMAM dendrimer bearing amino- terminal groups can encapsulate the poor water solubility antileukemic drug 6-mercaptopurine and enhance its solubility . It was found that under alkaline conditions (pH=10), encapsulation of the drug was the highest. However, under acidic conditions, the encapsulation of the drug was slightly lowered. We also find the concentration of salt has no effect on the encapsulation efficiency.
In Chapter 4 the interactions between PAMAM dendrimers and the non-steroidal anti-inflammatory drug phenylbutazone are investigated. Solubility results showed that PAMAM dendrimers significantly enhanced the aqueous solubility of phenylbutazone and the solubilization was much influenced by dendrimer concentration, generation, surface function group and pH value. The 2D-NOESY spectra clearly showed that there were several kinds of cross-peaks from NOE interactions between the protons of phenylbutazone and the protons in interior cavities of both generation 6 and generation 3 PAMAM dendrimers. Evidence from the solubility, 2D-NOESY results and ITC analysis suggest that encapsulation and electrostatic interaction together caused the solubility enhancement of phenylbutazone. The new techniques such as two-dimensional NMR and Isothermal Titration Calorimetry techniques used in this study are useful tools in investigating the interactions between dendrimers and guest molecules.
引文
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