靶向PLGA纳米载药体系的功能化设计及其抗肿瘤作用机理研究

发布时间：2018-01-07 22:28

本文关键词：靶向PLGA纳米载药体系的功能化设计及其抗肿瘤作用机理研究　出处：《暨南大学》2016年硕士论文　论文类型：学位论文

更多相关文章： PLGA 靶向多肽 抗肿瘤活性 金纳米星

【摘要】：PLGA(聚乳酸乙醇酸)因其高效的生物可降解性、生物相容性、可忽略的毒性而成为近几十年的研究热点。本研究以PLGA高分子纳米载体制备不同类型的靶向纳米药物,开展了其体外抗肿瘤活性评估。主要研究成果如下:1.本章利用水溶性维生素E(TPGS)作为乳化剂、增溶剂和药物传递系统的修饰剂的性质,设计合成TPGS协同抗肿瘤药物PSeD的RGD靶向PLGA纳米粒子(PSeD@PCTR)。细胞实验证明,TPGS可以协同抗肿瘤药物PSeD抑制宫颈癌Siha细胞的增殖。PSeD@PCTR纳米粒子是受RGD介导的胞吞作用选择性的进入Siha细胞。而且,体外释放实验表明,在模拟血液环境下(pH为7.4),纳米粒子是实心的球体。然而在pH为5.3和溶菌酶的环境下(模拟溶酶体),纳米粒子为发散的蓬松形状并大量释放药物PSeD。在模拟生物体内环境(Siha cell lysate),纳米粒子完全降解且药物释放达到90%。结果显示该纳米粒子是具有整合素靶向、生物响应释放的双功能抗肿瘤药物,为其临床应用提供了理论基础。2.通过多肽(ACPP和AE105)的表面修饰制备双靶向纳米粒子(Au-1a@NPs/ACPP/AE105),ACPP和AE105的表面修饰增强了肿瘤细胞对纳米粒子的选择性吸收和抗肿瘤活性。Au-1a@NPs/ACPP/AE105对肿瘤细胞具有广泛的抗肿瘤效果,尤其对三阴乳腺癌MDA-MB-231细胞,其IC50为0.03μM。从细胞吸收实验表明MDA-MB-231细胞对Au-1a@NPs/ACPP/AE105纳米粒子吸收是受肿瘤微环境及uPAR介导的。相关分子机制研究表明:Au-1a@NPs/ACPP/AE105进入细胞后抑制了TrxR的活性,激发了ROS的产生。此外,Au-1a@NPs/ACPP/AE105激发了FAK的活化,促进了Ras/MEK/ERK和PI3K/Akt信号通路的活化,从而下调了uPA以及MMP-9的表达,上调TIMP-1的表达。结果显示Au-1a@NPs/ACPP/AE105抑制了MDA-MB-231细胞的侵袭迁移及增殖分化。3.肿瘤治疗中产生的放疗耐受和化疗耐受是治疗失败的重要原因。其中黑色素瘤的治疗极易产生放疗耐受和化疗耐受,这是导致其治愈率低的重要因素。无机纳米材料金纳米星具有独特的放疗及热疗的性质,近红外激光照射后能瞬时产生热量,而且是一个良好的放疗增敏剂。因此本章利用PEI的多氨基的特性和金纳米星的理化性质,制备合成了PLGA作为载体的叶酸靶向并具有X-ray和近红外响应Au@PLGA-PEI-BSeC-FA纳米粒子。细胞实验表明,Au@PLGA-PEI-BSeC-FA与X-ray(4 Gy)、近红外照射联合作用能有效抑制黑色素瘤A375细胞增殖。通过检测细胞活性氧水平表明,在X-ray和近红外激发下,细胞活性氧水平与抗肿瘤活性呈正相关。综上,Au@PLGA-PEI-BSeC-FA可实现对肿瘤细胞高效杀伤的效果,且热疗促进放疗并协同化疗药物BSeC抑制肿瘤细胞增殖。兼具热疗、放疗、化疗的Au@PLGA-PEI-BSeC-FA纳米粒子为改善黑色素瘤的治疗提供了一个新的方向。综上所述,制备出的三种新型靶向纳米药物可能在肿瘤治疗过程中具有潜在的应用价值。
[Abstract]:PLGA (polylactic glycolic acid) is highly biodegradable and biocompatible. The negligible toxicity has become a hot research topic in recent decades. In this study, different types of targeted nanopharmaceuticals were prepared on PLGA polymer nano-carriers. The main results are as follows: 1. In this chapter, water-soluble vitamin E (TPGS) was used as emulsifier, solvent and drug delivery system as modifier. To design and synthesize the RGD targeting PLGA nanoparticles of TPGS and PSeD. TPGS could inhibit the proliferation of cervical cancer Siha cells in combination with the anti-tumor drug PSeD. PSeD DER-PCTR nanoparticles were selectively entered into Siha cells by RGD mediated endocytosis. And... In vitro release experiments showed that the nanoparticles were solid spheres at pH 7.4 under simulated blood environment, but at pH 5.3 and lysozyme (simulated lysosomes). The nanoparticles are in the fluffy shape and release the drug PSeD.Siha cell lysate. in a simulated organism. The results showed that the nanoparticles were integrin-targeted and bioresponsive anti-tumor drugs. Through the surface modification of polypeptide ACPP and AE105), the double targeted nanoparticles (Au-1a NPs / ACPP / AE105) were prepared. The surface modification of ACPP and AE105 enhances the selective absorption of nanoparticles and the antitumor activity of tumor cells. Au-1a @ NPs / ACPP / AE105 has extensive effect on tumor cells. Antitumor effect. Especially for MDA-MB-231 cells of Sanyin breast cancer. Its IC50 was 0.03 渭 M. the results of cell absorption showed that the absorption of Au-1a@NPs/ACPP/AE105 nanoparticles by MDA-MB-231 cells was affected by tumor microenvironment and u. Studies on the molecular mechanisms mediated by PAR have shown that:. Au-1a@NPs/ACPP/AE105 inhibited the activity of TrxR after entering the cells. In addition, Au-1a NPs / ACPP / AE105 stimulated the activation of FAK. It promoted the activation of Ras/MEK/ERK and PI3K/Akt signaling pathway and down-regulated the expression of uPA and MMP-9. Upregulation of TIMP-1 expression. The results showed that Au-1a@NPs/ACPP/AE105 inhibited the invasion, migration, proliferation and differentiation of MDA-MB-231 cells. Radiotherapy tolerance and chemotherapy tolerance are the main causes of failure in treatment of melanoma. This is an important factor leading to the low cure rate. Inorganic nano-material gold nanospace has unique properties of radiotherapy and hyperthermia, and can produce heat instantaneously after near-infrared laser irradiation. It is also a good radiosensitizer. Therefore, this chapter uses the properties of polyamines of PEI and the physicochemical properties of gold nanoparticles. Folic acid targeted nanoparticles with PLGA as carrier and Au@PLGA-PEI-BSeC-FA nanoparticles with X-ray and near infrared response were prepared. Au@PLGA-PEI-BSeC-FA and X-rayne (4 Gy). The combined effects of NIR irradiation could effectively inhibit the proliferation of melanoma A375 cells. The level of reactive oxygen species (Ros) was positively correlated with the anti-tumor activity. In conclusion, PLGA-PEI-BSeC-FA could effectively kill tumor cells. Hyperthermia promoted radiotherapy and combined with chemotherapeutic drug BSeC to inhibit the proliferation of tumor cells, both hyperthermia and radiotherapy. Chemotherapeutic Au@PLGA-PEI-BSeC-FA nanoparticles provide a new direction for improving the treatment of melanoma. The three novel targeted nanopharmaceuticals may have potential application value in tumor therapy.
【学位授予单位】：暨南大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：TQ460.1;TB383.1

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