基于透皮肽的siRNA经皮治疗黑色素瘤的理论研究

发布时间：2018-06-22 17:50

本文选题：黑色素瘤 + 小干扰核糖核酸　；参考：《中国科学技术大学》2017年硕士论文

【摘要】：黑色素瘤是一种恶性肿瘤,主要存在于皮肤。它的特点为死亡率高、发病广、转移快和预后差。近年来,利用小干扰核糖核酸(siRNA)诱导黑色素瘤细胞凋亡,从而治疗黑色素瘤成为一种新兴的手段。当前,siRNA主要通过注射的方式进入体内,这种方式不但无法避免肝脏的首过效应,可控性也比较差。透皮给药是一种新颖的给药方式,它可以克服传统给药方式的不足,但皮肤尤其角质层的屏障作用使得大分子药物难以透过皮肤。透皮蛋白(肽)TD、SPACE、TAT等的发现,为大分子药物的透皮提供了有效的载体。近来,已有研究实验证实SPACE可调控siRNA经皮治疗黑色素瘤,但相关理论模型还未见报道。本文建立了一个数学模型以描述SPACE-EGF调控siRNA透过皮肤抵达黑色素瘤、诱导肿瘤细胞凋亡、抑制肿瘤生长的过程。主要研究内容如下:(1)建立了 siRNA在SPACE-EGF调控下的输运模型,耦合了皮肤、肿瘤中宏观的siRNA扩散输运的过程以及微观的siRNA被肿瘤细胞吸附、内化以及消耗的过程。(2)建立了 siRNA抑制下的黑色素瘤生长模型。该模型将黑色素瘤细胞视为不可压缩流体,利用Darcy定律模拟肿瘤的生长边界,并考虑肿瘤生长对皮肤形态的影响。(3)基于文献中的实验数据,验证了模型的可靠性。通过拟合的肿瘤细胞增殖速率以及肿瘤细胞凋亡速率与药物浓度的关系式,模拟了肿瘤生长曲线。模拟的肿瘤生长曲线与实验测量的结果吻合较好。本文的研究结果表明:(Ⅰ)在皮肤层中,药物浓度随深度下降;在黑色素瘤中,每一点处药物浓度均随时间增加,但增加速率不同,导致了药物分布不均匀;(Ⅱ)siRNA对肿瘤的生长造成了明显的抑制,由于药物分布不均匀,这种抑制也不均匀;(Ⅲ)高剂量、高频率的给药将会造成更为明显的肿瘤生长抑制:当剂量或频率足够高时,一段时间后肿瘤大小将会下降;延迟给药时间将延迟药物对肿瘤的抑制作用;(Ⅳ)当肿瘤先生长后萎缩时,皮肤会出现先隆起后逐渐恢复的现象。本文建立的理论模型有助于全面理解SPACE调控siRNA经皮治疗黑色素瘤过程、预测治疗效果以及优化给药策略,为黑色素瘤的临床治疗提供了重要的参考。
[Abstract]:Melanoma is a malignant tumor, mainly in the skin. It is characterized by high mortality, wide incidence, rapid metastasis and poor prognosis. In recent years, small interfering ribonucleic acid (siRNA) has been used to induce apoptosis of melanoma cells and to treat melanoma. Currently, siRNA is mainly injected into the body, which can not only avoid the first pass effect of liver, but also has poor controllability. Transdermal administration is a novel drug delivery method, which can overcome the shortcomings of traditional drug delivery methods, but the barrier of skin, especially the cuticle, makes it difficult for macromolecular drugs to penetrate the skin. The discovery of transdermal protein (peptide) TD- SPACETAT provides an effective carrier for the transdermal delivery of macromolecular drugs. Recently, it has been confirmed that space can regulate siRNA for percutaneous treatment of melanoma, but relevant theoretical models have not been reported. In this paper, a mathematical model was established to describe the process of SPACE-EGF regulating siRNA reaching melanoma through the skin, inducing tumor cell apoptosis and inhibiting tumor growth. The main contents are as follows: (1) the transport model of siRNA under the regulation of SPACE-EGF was established, which coupled the skin, the diffusion and transport process of siRNA in tumor and the absorption of siRNA by tumor cells. The process of internalization and consumption. (2) the growth model of melanoma inhibited by siRNA was established. In this model, melanoma cells are regarded as incompressible fluid. Darcy's law is used to simulate the growth boundary of the tumor, and the influence of tumor growth on the skin morphology is considered. (3) based on the experimental data in the literature, the reliability of the model is verified. The tumor growth curve was simulated by fitting the relationship between tumor cell proliferation rate, tumor cell apoptosis rate and drug concentration. The simulated tumor growth curve is in good agreement with the experimental results. The results show that: (I) in the skin layer, the drug concentration decreases with the depth; in melanoma, the drug concentration increases with time at every point, but the increase rate is different. This resulted in uneven distribution of drugs; (II) siRNA significantly inhibited the growth of tumors, and the inhibition was also uneven due to the uneven distribution of drugs; (III) high doses, High frequency of administration will result in more obvious tumor growth inhibition: when the dose or frequency is high enough, the tumor size will decrease after a period of time; The delayed administration time will delay the inhibition effect of the drug on the tumor. (IV) when the tumor Mr. long atrophy, the skin will protrude first and then recover gradually. The theoretical model established in this paper is helpful to fully understand the process of SPACE-regulated siRNA percutaneous treatment of melanoma, predict the therapeutic effect and optimize the drug delivery strategy, and provide an important reference for the clinical treatment of melanoma.
【学位授予单位】：中国科学技术大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R739.5

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