本文關(guān)鍵詞： 聚乙二醇化 納米藥物 自組裝 超分子 交聯(lián) 小分子前藥　出處：《浙江大學(xué)》2017年博士論文　論文類型：學(xué)位論文

【摘要】：傳統(tǒng)小分子化療藥物治療選擇性差,毒副作用大,在新研發(fā)的化療藥物中,聚乙二醇化修飾的納米藥物最有希望替代現(xiàn)有化療藥物。通過聚乙二醇化修飾,納米藥物表面水溶性增加,且可以有效防止免疫系統(tǒng)的追蹤,延長了納米藥物的體內(nèi)循環(huán)時間。然而,通過自組裝形成的納米藥物在血液循環(huán)中易解組裝,引發(fā)藥物到達腫瘤部位前提前釋放。本文設(shè)計制備了三種新型交聯(lián)固定納米結(jié)構(gòu)的還原響應(yīng)聚乙二醇化納米藥物,為聚乙二醇化納米藥物的潛在臨床應(yīng)用提供了新思路。嵌段聚合物的自組裝是制備聚合物納米藥物的主要方法之一,本文提出了一種簡易制備還原響應(yīng)核交聯(lián)聚乙二醇化納米藥物的新方法。采用免官能團保護的“一鍋”縮聚法合成了疏水段含有多巰基的聚乙二醇化脂肪族聚酯,在自組裝形成負(fù)載紫杉醇膠束的同時,通過對巰基的氧化交聯(lián)或原位巰—烯“點擊”交聯(lián)制備了核交聯(lián)載藥膠束。該聚乙二醇化納米藥物可以在還原環(huán)境下快速解交聯(lián),釋放紫杉醇,并表現(xiàn)出良好的抑制腫瘤細(xì)胞生長的能力。有望作為一種可降解納米藥物實現(xiàn)規(guī)�；苽浜蛻�(yīng)用。簡單明確的化學(xué)組成更利于納米藥物的理化性能分析及臨床審批。本文設(shè)計合成了一種僅含兩組分的核交聯(lián)聚乙二醇化納米藥物。含有兩官能度金剛烷修飾的喜樹堿前藥與疏水段含有多個環(huán)糊精的聚乙二醇嵌段聚合物自組裝形成膠束時發(fā)生主客體包合,實現(xiàn)藥物穩(wěn)定負(fù)載的同時實現(xiàn)了納米藥物的核交聯(lián)。與傳統(tǒng)化學(xué)交聯(lián)的納米藥物相比,該以主客體包合物為物理交聯(lián)點的納米藥物制備方式更加簡便,化學(xué)組成更加明確,更有利于實現(xiàn)納米藥物的臨床應(yīng)用。對于寡聚乙二醇與藥物化學(xué)鍵合形成的納米藥物,往往具有較高的臨界膠束濃度,納米藥物容易解組裝,而對其進行化學(xué)交聯(lián)將使納米藥物化學(xué)構(gòu)成復(fù)雜化,很難通過藥監(jiān)部門的審批。本文設(shè)計制備了一種基于主客體作用的超分子聚乙二醇化納米藥物:通過二硫鍵連接金剛烷與喜樹堿,合成了結(jié)構(gòu)明確的還原敏感小分子前藥;通過對環(huán)糊精的聚乙二醇化修飾,制備了含多個仲氨基團的聚乙二醇—環(huán)糊精鍵合物;以上兩者通過主客體包合即可形成兩親性超分子聚乙二醇化前藥,在水中自組裝得到納米藥物;對聚乙二醇—環(huán)糊精部分進行化學(xué)交聯(lián)可進一步提高納米藥物的穩(wěn)定性。該方法可同時實現(xiàn)聚乙二醇化納米藥物在低濃度下納米結(jié)構(gòu)的穩(wěn)定以及藥物分子的單一化學(xué)組成。該聚乙二醇化納米藥物在腫瘤微環(huán)境中可通過二硫鍵的響應(yīng)性斷裂迅速釋放出喜樹堿分子,小鼠抑瘤實驗表明其具有優(yōu)異的抗腫瘤性能,且毒副作用很小。該研究為聚乙二醇化納米藥物的設(shè)計提供了新思路。
[Abstract]:Traditional small molecular chemotherapeutic drugs have poor selectivity and toxic side effects. Among the newly developed chemotherapeutic drugs, polyethylene glycol modified nanopharmaceuticals are the most promising alternatives to existing chemotherapeutic drugs. The surface water solubility of nanopharmaceuticals is increased, and it can effectively prevent the tracking of immune system, prolonging the circulating time of nanopharmaceuticals in vivo. However, the nanopharmaceuticals formed by self-assembly are easy to be unassembled in the blood circulation. Three novel reduction-responsive polyethylene glycol nanopharmaceuticals with cross-linked fixed nanostructures were designed and prepared before the initiation drug reached the tumor site. The self-assembly of block polymers is one of the main methods to prepare polymer nanopharmaceuticals. In this paper, a new simple method for preparation of reductive nuclear cross-linked polyethylene glycol nanopharmaceuticals is proposed. The "one pot" protected by functional groups is used. Poly (ethylene glycol) aliphatic polyester containing many sulfhydryl groups in hydrophobic segment was synthesized by condensation. At the same time of self-assembly to form paclitaxel micelles. The nucleated drug carrier micelles were prepared by oxidative crosslinking of sulfhydryl groups or in situ "click-click" crosslinking of mercaptopenes. The polyethylene glycol nanoparticles could be rapidly uncrosslinked and released paclitaxel in a reduced environment. It is expected to be a biodegradable nano-drug for large-scale preparation and application. Simple and clear chemical composition is more conducive to the physical and chemical performance analysis and clinical review of nanopharmaceuticals. In this paper, we designed and synthesized a nuclear crosslinked polyethylene glycol nanopharmaceuticals containing only two components. The two functional amantadine modified camptothecin prodrugs and hydrophobic segments containing multiple cyclodextrins were self-assembled. The inclusion of the host and the object occurs when the micelles are assembled. Compared with the traditional chemically crosslinked nanopharmaceuticals, the method of preparing nanopharmaceuticals with host and guest inclusion compounds as physical crosslinking point is more convenient than that of traditional chemically crosslinked nanopharmaceuticals. Chemical composition is more clear, more conducive to the clinical application of nanopharmaceuticals. For nano-drugs formed by chemical bonding of polyethylene glycol with drugs, there is often a higher critical micelle concentration. Nanopharmaceuticals are easy to be unassembled and chemically crosslinked will complicate the chemical composition of nanopharmaceuticals. In this paper, a supramolecular polyethyleneglycol nanopharmaceuticals based on host and guest interaction were designed and prepared, which were connected with camptothecin and adamantane by disulfide bond. The reductive sensitive small molecule prodrug with clear structure was synthesized. The polyglycol-cyclodextrin bond containing several secondary amino groups was prepared by the modification of cyclodextrin. The above two can form amphiphilic supramolecular polyethylene glycol pre-drug by host and guest inclusion and self-assemble in water to obtain nano-drug. The stability of nanopharmaceuticals can be further improved by chemical crosslinking of PEG-cyclodextrin. This method can simultaneously stabilize the nanostructure of PEG-cyclodextrin at low concentration and the single drug molecule. Chemical composition. The polyethylene glycol nanopharmaceuticals can rapidly release camptothecin molecules in tumor microenvironment by disulfide bond responsive breakage. The anti-tumor test in mice showed that it had excellent anti-tumor properties and had little side effects. This study provided a new idea for the design of polyethylene glycol nanoparticles.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：TQ460.1

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