本文選題：黑色素瘤 + 小干擾核糖核酸　； 參考：《中國(guó)科學(xué)技術(shù)大學(xué)》2017年碩士論文

【摘要】：黑色素瘤是一種惡性腫瘤,主要存在于皮膚。它的特點(diǎn)為死亡率高、發(fā)病廣、轉(zhuǎn)移快和預(yù)后差。近年來(lái),利用小干擾核糖核酸(siRNA)誘導(dǎo)黑色素瘤細(xì)胞凋亡,從而治療黑色素瘤成為一種新興的手段。當(dāng)前,siRNA主要通過(guò)注射的方式進(jìn)入體內(nèi),這種方式不但無(wú)法避免肝臟的首過(guò)效應(yīng),可控性也比較差。透皮給藥是一種新穎的給藥方式,它可以克服傳統(tǒng)給藥方式的不足,但皮膚尤其角質(zhì)層的屏障作用使得大分子藥物難以透過(guò)皮膚。透皮蛋白(肽)TD、SPACE、TAT等的發(fā)現(xiàn),為大分子藥物的透皮提供了有效的載體。近來(lái),已有研究實(shí)驗(yàn)證實(shí)SPACE可調(diào)控siRNA經(jīng)皮治療黑色素瘤,但相關(guān)理論模型還未見(jiàn)報(bào)道。本文建立了一個(gè)數(shù)學(xué)模型以描述SPACE-EGF調(diào)控siRNA透過(guò)皮膚抵達(dá)黑色素瘤、誘導(dǎo)腫瘤細(xì)胞凋亡、抑制腫瘤生長(zhǎng)的過(guò)程。主要研究?jī)?nèi)容如下:(1)建立了 siRNA在SPACE-EGF調(diào)控下的輸運(yùn)模型,耦合了皮膚、腫瘤中宏觀的siRNA擴(kuò)散輸運(yùn)的過(guò)程以及微觀的siRNA被腫瘤細(xì)胞吸附、內(nèi)化以及消耗的過(guò)程。(2)建立了 siRNA抑制下的黑色素瘤生長(zhǎng)模型。該模型將黑色素瘤細(xì)胞視為不可壓縮流體,利用Darcy定律模擬腫瘤的生長(zhǎng)邊界,并考慮腫瘤生長(zhǎng)對(duì)皮膚形態(tài)的影響。(3)基于文獻(xiàn)中的實(shí)驗(yàn)數(shù)據(jù),驗(yàn)證了模型的可靠性。通過(guò)擬合的腫瘤細(xì)胞增殖速率以及腫瘤細(xì)胞凋亡速率與藥物濃度的關(guān)系式,模擬了腫瘤生長(zhǎng)曲線。模擬的腫瘤生長(zhǎng)曲線與實(shí)驗(yàn)測(cè)量的結(jié)果吻合較好。本文的研究結(jié)果表明:(Ⅰ)在皮膚層中,藥物濃度隨深度下降;在黑色素瘤中,每一點(diǎn)處藥物濃度均隨時(shí)間增加,但增加速率不同,導(dǎo)致了藥物分布不均勻;(Ⅱ)siRNA對(duì)腫瘤的生長(zhǎng)造成了明顯的抑制,由于藥物分布不均勻,這種抑制也不均勻;(Ⅲ)高劑量、高頻率的給藥將會(huì)造成更為明顯的腫瘤生長(zhǎng)抑制:當(dāng)劑量或頻率足夠高時(shí),一段時(shí)間后腫瘤大小將會(huì)下降;延遲給藥時(shí)間將延遲藥物對(duì)腫瘤的抑制作用;(Ⅳ)當(dāng)腫瘤先生長(zhǎng)后萎縮時(shí),皮膚會(huì)出現(xiàn)先隆起后逐漸恢復(fù)的現(xiàn)象。本文建立的理論模型有助于全面理解SPACE調(diào)控siRNA經(jīng)皮治療黑色素瘤過(guò)程、預(yù)測(cè)治療效果以及優(yōu)化給藥策略,為黑色素瘤的臨床治療提供了重要的參考。
[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.
【學(xué)位授予單位】：中國(guó)科學(xué)技術(shù)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R739.5

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本文編號(hào)：2053670