本文選題：D-甘露糖 + BODIPY光敏劑��； 參考：《江南大學(xué)》2017年碩士論文

【摘要】：傳統(tǒng)的癌癥(惡性腫瘤)治療手段包括手術(shù)、化療、放療等,其中化療是最主要的治療手段之一。但由于化療全身給藥的特點(diǎn),降低了抗癌藥物的生物利用度,同時(shí)也會對正常組織和細(xì)胞產(chǎn)生毒副作用并引起癌細(xì)胞的耐藥性等問題,這些嚴(yán)重限制了其在癌癥治療中的應(yīng)用和療效。通過不斷研究與探索,科研工作者開發(fā)出各種靶向藥物輸送體系,在改善化療性能方面成果顯著。目前,一種新型安全高效的靶向光動力療法被開發(fā)出來,并將其用于癌癥治療中,取得了很好的效果。它利用靶向輸送載體,將低暗毒性的光敏藥物富集于腫瘤部位,經(jīng)特定波長的光照后,誘導(dǎo)產(chǎn)生氧化性很強(qiáng)的單線態(tài)氧,進(jìn)而實(shí)現(xiàn)對癌細(xì)胞的殺傷。由于光敏藥物良好的生物相容性和高效的光療性能,這種用于光動力療法的納米光敏制劑在治療惡性腫瘤的研究與應(yīng)用中具有很大的潛力。本研究設(shè)計(jì)合成了一種共價(jià)鍵連金剛烷的三臂BODIPY光敏劑分子,通過β-環(huán)糊精和金剛烷超分子識別作用將D-甘露糖化環(huán)糊精固定到光敏劑納米粒子表面,從而制備了表面甘露糖分子功能修飾的光敏劑納米粒子(BTA@CD-Man7)。這種設(shè)計(jì)賦予了BTA@CD-Man7的甘露糖受體靶向性和光動力治療的功能。CD-Man7和BTA的分子結(jié)構(gòu)通過核磁共振氫譜和時(shí)間輔助飛行質(zhì)譜等進(jìn)行確認(rèn)。BTA@CD-Man7的形貌和流體力學(xué)直徑及溶液穩(wěn)定性通過透射電鏡和動態(tài)光散射進(jìn)行考察,結(jié)果表明,甘露糖對于維持生物溶劑中BTA@CD-Man7納米結(jié)構(gòu)的均一穩(wěn)定方面具有重要作用。通過熒光分光光度計(jì)測定單線態(tài)氧捕獲劑ABDA熒光強(qiáng)度的變化來表征不同狀態(tài)下BTA@CD-Man7產(chǎn)單線態(tài)氧的性能,結(jié)果表明BTA@CD-Man7需解組裝釋放光敏劑BTA,并在665 nm LED光源輻射下,才能產(chǎn)生單線態(tài)氧。以表面甘露糖受體過度表達(dá)的人乳腺癌MDA-MB-231細(xì)胞作為模型,通過激光共聚焦顯微鏡評價(jià)BTA@CD-Man7經(jīng)受體識別介導(dǎo)的細(xì)胞內(nèi)吞作用和光動力治療性能。實(shí)驗(yàn)結(jié)果表明表面甘露糖受體高表達(dá)的癌細(xì)胞MDA-MB-231能夠大量攝取BTA@CD-Man7,并在溶酶體中解組裝釋放光敏劑BTA,在665 nm LED燈光照下生成大量的單線態(tài)氧,單態(tài)氧能與附近的生物大分子發(fā)生氧化反應(yīng),產(chǎn)生細(xì)胞毒性進(jìn)而導(dǎo)致癌細(xì)胞凋亡。而對于表面甘露糖受體低表達(dá)的正常細(xì)胞MCF-10A,BTA@CD-Man7則很少被攝取,且光動力治療效率低。最后,采用MTT細(xì)胞毒性評價(jià)法評價(jià)BTA@CD-Man7和BTA@CD的細(xì)胞光暗毒性。結(jié)果表明BTA@CD-Man7和BTA@CD具有良好的生物相容性,在黑暗條件下,兩者對癌細(xì)胞與正常細(xì)胞幾乎沒有細(xì)胞毒性,而在給予665 nm LED光照的條件下,BTA@CD-Man7表現(xiàn)出更加高效的靶向光療性能。荷瘤(MDA-MB231)小鼠光療實(shí)驗(yàn)進(jìn)一步證明BTA@CD-Man7在靶向光動力治療乳腺癌的應(yīng)用中很有潛力。
[Abstract]:The traditional treatment of cancer (malignant tumor) includes surgery, chemotherapy, radiotherapy and so on, among which chemotherapy is one of the most important treatment methods. However, because of the characteristics of systemic chemotherapy, the bioavailability of anticancer drugs is reduced, and at the same time, toxic side effects on normal tissues and cells and drug resistance of cancer cells are also caused. These severely limit its application and efficacy in cancer treatment. Through continuous research and exploration, researchers have developed various targeted drug delivery systems, which have achieved remarkable results in improving the performance of chemotherapy. At present, a new type of safe and efficient targeted photodynamic therapy has been developed and used in cancer treatment, and good results have been obtained. It uses the targeted transport carrier to enrich the low dark toxic Guang Min drugs in the tumor site, and after a specific wavelength of light, induces the production of highly oxidizing singlet oxygen, and then realizes the killing of cancer cells. Because of the good biocompatibility and high phototherapy performance of Guang Min drugs, this kind of nanometer Guang Min preparation used in photodynamic therapy has great potential in the research and application of malignant tumor treatment. In this study, a three-arm BODIPY Guang Min molecule with covalent bond and adamantane was designed and synthesized. D-mannose cyclodextrin was immobilized on the surface of Guang Min nanoparticles by 尾 -cyclodextrin and adamantane supramolecular recognition. Therefore, Guang Min nanoparticles modified by mannose molecular function were prepared. This design gives BTA@CD-Man7 the function of mannose receptor targeting and photodynamic therapy. CD-Man7 and BTA molecular structures are confirmed by NMR and time-assisted flight mass spectrometry. The morphology and hydrodynamic diameter and solution of BTA CD-Man7 are confirmed by nuclear magnetic resonance spectroscopy (NMR) and time-assisted flight mass spectrometry (TFAMS). The stability was investigated by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The results show that mannose plays an important role in maintaining the homogeneity and stability of BTA@CD-Man7 nanostructures in biological solvents. The change of fluorescence intensity of single line oxygen trapping agent (ABDA) was measured by fluorescence spectrophotometer to characterize the properties of single line oxygen produced by BTA@CD-Man7 in different states. The results showed that BTA@CD-Man7 needed to be unassembled and released Guang Min, which was irradiated by LED light source at 665nm. In order to produce singlet oxygen. Human breast cancer MDA-MB-231 cells with overexpression of mannose receptor on the surface were used as a model to evaluate the intracellular endocytosis and photodynamic therapy of BTA@CD-Man7 mediated by receptor recognition by confocal laser microscopy. The experimental results showed that MDA-MB-231, which was highly expressed on the surface of mannose receptor, was able to ingest BTA-CD-Man7 in large quantities, and unassemble and release Guang Min in lysosome, resulting in a large amount of singlet oxygen under the irradiation of 665nm LED light. Single state oxygen can oxidize the nearby biomolecules, resulting in cytotoxicity and apoptosis of cancer cells. However, MCF-10AnBTACD-Man7 cells with low surface mannose receptor expression were rarely ingested, and the photodynamic therapy efficiency was low. Finally, the cytotoxicity of BTA@CD-Man7 and BTA@CD was evaluated by MTT cytotoxicity evaluation method. The results showed that BTA@CD-Man7 and BTA@CD had good biocompatibility. Under dark conditions, BTA@CD-Man7 and BTA@CD had little cytotoxicity to cancer cells and normal cells, while CD-Man7 showed a more efficient phototherapeutic performance under the irradiation of 665nm LED. The phototherapy of mice with MDA-MB231 further demonstrated the potential of BTA@CD-Man7 in the application of targeted photodynamic therapy for breast cancer.
【學(xué)位授予單位】：江南大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R730.5;TB383.1

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相關(guān)碩士學(xué)位論文 前3條

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3 王丹;兩親性多糖衍生物納米膠束負(fù)載光敏劑的研究[D];中山大學(xué);2010年

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本文編號：1931641