本文選題：腫瘤　切入點(diǎn)：診斷治療　出處：《河北大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：診斷治療學(xué)已成為藥學(xué)、醫(yī)學(xué)、化學(xué)等多學(xué)科交叉領(lǐng)域的前沿和熱點(diǎn)。診療試劑能夠?yàn)榘┌Y的高效診治提供一個(gè)集早期實(shí)時(shí)監(jiān)測、定位診斷與個(gè)性化干預(yù)治療于一體的多功能平臺(tái)。抗腫瘤診療試劑主要通過內(nèi)部刺激(如pH、乏氧等)或外部刺激(如光照、磁場等)來實(shí)現(xiàn)藥物的可控釋放。乏氧已被應(yīng)用于腫瘤的診斷與治療,但由于某些其他疾病也會(huì)引起組織乏氧,導(dǎo)致藥物在非腫瘤部位釋放從而引起毒副作用。光響應(yīng)診療劑具有在特定的時(shí)間和空間實(shí)現(xiàn)藥物可控釋放的優(yōu)點(diǎn)。上轉(zhuǎn)換納米發(fā)光材料(Upconversion Nanoparticles,UCNPs)能夠?qū)⒔t外光轉(zhuǎn)換成可見光和紫外光。近紅外光能夠有效避免生物體自體熒光的干擾,對生物組織有較高的穿透能力,對生物樣品的光損傷也比較小。然而,光響應(yīng)診療劑所釋放的藥物不可避免會(huì)對所輻照區(qū)域的正常組織產(chǎn)生毒副作用。若將腫瘤的乏氧(內(nèi)在特征)和光照(外部刺激)巧妙結(jié)合設(shè)計(jì)新型診療試劑,則可通過乏氧和光照雙重控制藥物的釋放,達(dá)到降低抗腫瘤藥物的毒副作用和精準(zhǔn)治療的目的。本文以氟脲苷(FDU)作抗腫瘤藥物模型,Yb~(3+)、Tm~(3+)摻雜的NaYF_4上轉(zhuǎn)換發(fā)光納米顆粒(UCNP)作為光轉(zhuǎn)換載體,取代E-鄰羥基肉桂酸(CAE)作為光敏基團(tuán)(熒光染料的前體),4-硝基芐醚作為乏氧響應(yīng)基團(tuán),經(jīng)親核取代反應(yīng)、Wittig反應(yīng)、水解反應(yīng)、酯化反應(yīng)、縮合反應(yīng)、Click反應(yīng)等反應(yīng)合成了乏氧和近紅外光照雙重控制的診療試劑UCNP-CAE-FDU/NO_2。采用TEM、NMR、MS及IR方法對診療劑及中間體的進(jìn)行表征;采用HPLC及HRMS法研究了其釋藥機(jī)制;采用熒光光譜法探討乏氧孵育及近紅外光照時(shí)間對釋藥量的影響;采用MTT法探討在不同乏氧加近紅外光照條件下UCNP-CAE-FDU/NO_2對MCF-7細(xì)胞活力的影響;采用雙光子激光共聚焦熒光成像法對乏氧細(xì)胞內(nèi)藥物釋放情況進(jìn)行檢測。結(jié)果表明:納米診療試劑UCNP-CAE-FDU/NO_2,分散性良好,尺寸單一,平均粒徑為30 nm。經(jīng)乏氧孵育和近紅外光照射,能夠釋放出FDU,并同時(shí)生成香豆素衍生物;香豆素衍生物的熒光強(qiáng)度可以反映FD U的釋放量,并且FDU釋放量隨乏氧孵育及光照時(shí)間的延長而增加;診療劑在乏氧和近紅外光照條件下對MCF-7細(xì)胞產(chǎn)生毒性;釋放出的香豆素衍生物可用于報(bào)告腫瘤細(xì)胞乏氧程度及細(xì)胞內(nèi)藥物釋放情況。該診療試劑利用乏氧結(jié)合光照的策略可實(shí)現(xiàn)藥物的精確釋放,為實(shí)現(xiàn)乏氧腫瘤的診斷治療一體化提供了一種新方法。
[Abstract]:Diagnostic therapeutics has become the frontier and hotspot in the interdisciplinary fields of pharmacy, medicine, chemistry and so on. The diagnostic and therapeutic reagents can provide an early and real-time monitoring for the effective diagnosis and treatment of cancer. A multifunctional platform for localizing diagnosis and individualized intervention therapy. Antitumor agents are mainly obtained through internal stimuli (e.g. pH, hypoxia, etc.) or external stimuli (e.g. light, light, etc.). Hypoxia has been used in the diagnosis and treatment of tumors, but some other diseases can also cause tissue hypoxia. Light response diagnostic agents have the advantage of controlled drug release at a specific time and space. Upconversion nanoluminescent material can be used to convert UCNPsto infrared light. The drug can be released in non-tumor sites and cause toxic side effects. Photo-responsive diagnostic agents have the advantage of controlled drug release at a specific time and space. The up-conversion nano-luminescence material can be used to convert UCNPsto near infrared light. Visible light and ultraviolet light. Near infrared light can effectively avoid the interference of organism autofluorescence. Higher penetration to biological tissue and less light damage to biological samples. However, Drugs released by photo-responsive diagnostic agents will inevitably produce toxic side effects on normal tissues in irradiated areas. If the tumor's hypoxia (intrinsic characteristics) and light (external stimuli) are skillfully combined to design new diagnostic and therapeutic reagents, The release of the drug can be controlled by both hypoxia and light. In order to reduce the toxicity and side effects of antitumor drugs and to treat them accurately, the NaYF_4 up-conversion luminescent nanoparticles (UCNP) doped with fluorouracil (FDU) as the antitumor drug model were used as optical conversion carrier. Substituted E- o-hydroxycinnamic acid (CAE) was used as Guang Min group (the precursor of fluorescent dyestuff, Con 4- nitrobenzyl ether) as anoxic responsive group, which was treated by nucleophilic substitution reaction, Wittig reaction, hydrolysis reaction and esterification reaction. UCNP-CAE-FDU / NOS2 was synthesized by condensation reaction and Click reaction. The drug release mechanism of UCNP-CAE-FDU / NOS2 was studied by HPLC and HRMS, and the diagnosis and treatment agents and intermediates were characterized by TEMP-NMRMS and IR methods, and the drug release mechanism of UCNP-CAE-FDU / NOS2 was studied by HPLC and HRMS. The effects of hypoxic incubation and near-infrared illumination time on drug release were investigated by fluorescence spectrometry, and the effects of UCNP-CAE-FDU/NO_2 on the activity of MCF-7 cells under different hypoxic and near-infrared illumination conditions were investigated by MTT method. Two-photon laser confocal fluorescence imaging was used to detect the drug release in hypoxic cells. The results showed that the nano-diagnostic reagent UCNP-CAE-FDU / no _ 2 had good dispersion, single size and an average particle size of 30 nm. The fluorescence intensity of coumarin derivative can reflect the amount of FDU release, and the amount of FDU release increases with the increase of hypoxia incubation and illumination time, and the fluorescence intensity of coumarin derivative can reflect the amount of FDU release, and the fluorescence intensity of coumarin derivative can reflect the amount of FDU release. The diagnostic and therapeutic agents were toxic to MCF-7 cells under hypoxia and near infrared illumination. The released coumarin derivatives can be used to report the degree of hypoxia and intracellular drug release in tumor cells. It provides a new method for the diagnosis and treatment of hypoxic tumor.
【學(xué)位授予單位】：河北大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R730.4;TB383.1

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