本文關(guān)鍵詞：響應(yīng)性聚合物組裝體的納米結(jié)構(gòu)調(diào)控與功能構(gòu)筑　出處：《中國(guó)科學(xué)技術(shù)大學(xué)》2017年博士論文　論文類(lèi)型：學(xué)位論文

  更多相關(guān)文章： 刺激響應(yīng)性聚合物 嵌段聚合物 自降解連接基 自組裝 交聯(lián)診療

【摘要】：刺激響應(yīng)性聚合物能夠?qū)ν饨绱碳みM(jìn)行智能響應(yīng),產(chǎn)生可逆或不可逆的物化性質(zhì)和(或)化學(xué)結(jié)構(gòu)的改變,進(jìn)而引起其組裝體的溶脹與塌縮、解離與聚集、交聯(lián)與解交聯(lián)以及形貌轉(zhuǎn)變等。另外,與正常器官、組織及細(xì)胞相比,病變器官、組織及細(xì)胞的生理參數(shù)會(huì)發(fā)生變化;利用這些特異性的生理變化來(lái)發(fā)展響應(yīng)性聚合物組裝體可以實(shí)現(xiàn)治療和成像試劑的選擇性傳輸。本論文集中研究了對(duì)腫瘤及炎癥微環(huán)境具有響應(yīng)性的聚合物組裝體,重點(diǎn)是氧化還原響應(yīng)性聚合物囊泡和膠束體系的設(shè)計(jì)、納米結(jié)構(gòu)的調(diào)控及多功能構(gòu)筑與集成。具體來(lái)說(shuō),本論文的工作包括以下三個(gè)方面:1.很多生理和病理過(guò)程與活性氧物質(zhì)和氧化壓力直接相關(guān),這就為設(shè)計(jì)治療和診斷功能的納米材料提供了非常重要的生化基礎(chǔ)。由兩親性聚合物自組裝制備的氧化響應(yīng)性聚合物膠束或者囊泡已經(jīng)進(jìn)行了大量的研究。然而,在以前的氧化響應(yīng)性體系研究中,包括H2O2在內(nèi)的活性氧物質(zhì)都會(huì)導(dǎo)致聚合物組裝體微結(jié)構(gòu)的破壞。以氧化性聚合物囊泡為例,微結(jié)構(gòu)的破壞會(huì)使囊泡內(nèi)包覆的親水性藥物和活性分子快速釋放,在某些特定情況下,限制了聚合物囊泡作為緩釋藥物載體和長(zhǎng)效活體內(nèi)納米反應(yīng)器的應(yīng)用。另外,傳統(tǒng)聚合物囊泡由于其雙層膜較厚、膜滲透性差,因而不能作為有效的藥物載體和納米反應(yīng)器。這里,我們?cè)O(shè)計(jì)制備了一種多功能的氧化響應(yīng)性聚合物囊泡,可以在細(xì)胞內(nèi)被氧化微環(huán)境刺激觸發(fā)后發(fā)生囊泡雙層膜的交聯(lián),同時(shí)雙層膜滲透性提高,表現(xiàn)出成像能力增強(qiáng)和藥物釋放性能提高的性質(zhì)。通過(guò)自組裝疏水嵌段含有芳基硼酸酯保護(hù)的具有自降解側(cè)基的兩親性嵌段聚合物制備聚合物囊泡,在其表面進(jìn)一步用多肽進(jìn)行修飾從而得到具有線粒體靶向的H2O2響應(yīng)性聚合物囊泡。內(nèi)吞進(jìn)入細(xì)胞后,胞內(nèi)H2O2觸發(fā)引發(fā)連續(xù)的脫保護(hù)反應(yīng)產(chǎn)生伯胺,由于新產(chǎn)生的伯胺在疏水的雙層膜中會(huì)發(fā)生酰胺化反應(yīng),導(dǎo)致囊泡雙層膜發(fā)生同步的交聯(lián)和疏水到親水的轉(zhuǎn)變過(guò)程。這一過(guò)程可以用于實(shí)現(xiàn)藥物可控釋放、組合化療,同時(shí)化療效果可以通過(guò)磁共振成像和熒光成像能力的增強(qiáng)進(jìn)行實(shí)時(shí)監(jiān)測(cè),進(jìn)一步構(gòu)筑了檢測(cè)細(xì)胞質(zhì)中的含巰基的生物活性分子的熒光產(chǎn)生型納米反應(yīng)器。2.開(kāi)發(fā)不同生化信號(hào)響應(yīng)的具有治療和診斷功能的納米醫(yī)藥用于實(shí)現(xiàn)藥物、多肽、蛋白質(zhì)以及成像試劑的選擇性和時(shí)空分辨?zhèn)鬏斠驯粡V泛地研究。其中,利用細(xì)胞外的氧化性微環(huán)境和細(xì)胞內(nèi)的還原性微環(huán)境間的氧化還原電勢(shì)梯度開(kāi)發(fā)氧化還原響應(yīng)性?xún)捎H性嵌段共聚物膠束納米粒子在生物醫(yī)藥方面的應(yīng)用已經(jīng)被大量地報(bào)道。此外,許多方法被采用來(lái)進(jìn)一步增強(qiáng)膠束的穩(wěn)定性,例如利用可逆連接基團(tuán)進(jìn)行化學(xué)交聯(lián),以避免不期望的解離和藥物提前釋放。值得注意的是,在所有這些情況下,可逆連接基團(tuán)的斷裂都會(huì)引起膠束納米粒子解交聯(lián)和不穩(wěn)定化,從而導(dǎo)致膠束納米粒子在目標(biāo)位置快速被清除進(jìn)而降低富集效果。因此,對(duì)于材料設(shè)計(jì)者來(lái)說(shuō),發(fā)展新策略以實(shí)現(xiàn)選擇性的響應(yīng)腫瘤和細(xì)胞內(nèi)微環(huán)境,更重要的是如何增強(qiáng)診療功能的聚合物膠束在活體內(nèi)目標(biāo)位置的定位和富集仍是重大的挑戰(zhàn)。特別地,對(duì)于大部分二硫鍵可逆交聯(lián)的聚合物膠束納米粒子,二硫鍵斷裂僅僅導(dǎo)致解交聯(lián)而沒(méi)有顯著的疏水到親水轉(zhuǎn)變,阻礙了包覆物質(zhì)完全有效的釋放。這里,我們?cè)O(shè)計(jì)合成了氧化還原響應(yīng)性核自交聯(lián)的膠束納米粒子,其具有長(zhǎng)的血液循環(huán)半衰期、細(xì)胞內(nèi)還原性微環(huán)境觸發(fā)的交聯(lián)方式轉(zhuǎn)換和膠束核從疏水到親水的轉(zhuǎn)變以及增強(qiáng)的診斷成像和藥物釋放特性。從疏水嵌段含有二硫鍵的具有自降解性質(zhì)的兩親性嵌段共聚物出發(fā),自組裝制備膠束,進(jìn)而表面修飾整合素靶向肽,最后通過(guò)紫外光引發(fā)二硫鍵交換反應(yīng)進(jìn)行交聯(lián),從而得到了腫瘤細(xì)胞靶向的還原性微環(huán)境響應(yīng)的二硫鍵交聯(lián)(DCL)膠束。通過(guò)整合素介導(dǎo)的內(nèi)吞作用進(jìn)入細(xì)胞后,細(xì)胞質(zhì)還原性微環(huán)境觸發(fā)膠束核內(nèi)發(fā)生級(jí)聯(lián)的消除反應(yīng)產(chǎn)生伯胺;新生成的伯胺在疏水的膠束核中會(huì)進(jìn)一步發(fā)生酰胺化反應(yīng),導(dǎo)致交聯(lián)方式轉(zhuǎn)換與膠束核疏水到親水轉(zhuǎn)變同時(shí)發(fā)生。該過(guò)程還被進(jìn)一步用來(lái)實(shí)現(xiàn)熒光和磁共振成像指導(dǎo)的化學(xué)治療。3.免疫細(xì)胞主要作用就是保護(hù)機(jī)體免受感染。但是當(dāng)它們被不正常激活時(shí),就會(huì)引發(fā)很多炎癥反應(yīng),例如風(fēng)濕性關(guān)節(jié)炎、動(dòng)脈粥樣硬化以及糖尿病并發(fā)癥等。在這些疾病的發(fā)展過(guò)程中,包括巨噬細(xì)胞在內(nèi)的免疫細(xì)胞會(huì)產(chǎn)生多種細(xì)胞因子,例如白細(xì)胞介素(IL-1和IL-6)、腫瘤壞死因子(TNF-α）、消化酶(膠原酶等)、前列腺素以及活性氧物質(zhì),這些細(xì)胞因子可以加重加速對(duì)正常組織的破壞。非甾體抗炎癥藥物(NSAIDs)被廣泛用來(lái)治療疼痛、發(fā)熱以及炎癥。但是,長(zhǎng)期使用非甾體抗炎癥藥物會(huì)產(chǎn)生一些副作用,例如腸胃損傷和中風(fēng)風(fēng)險(xiǎn)增加,因而限制了它們的使用以及其他適用癥狀的研究。這里,我們?cè)O(shè)計(jì)合成了炎癥組織相關(guān)的氧化性和還原性微環(huán)境響應(yīng)的聚前藥兩親性分子,其中疏水嵌段含有吲哚美辛前藥,進(jìn)一步通過(guò)自組裝制備了抗炎癥的聚合物囊泡。以此為基礎(chǔ),評(píng)價(jià)了聚合物囊泡體系氧化和還原微環(huán)境觸發(fā)的藥物可控釋放和對(duì)于巨噬細(xì)胞的抗炎癥效果。
[Abstract]:Stimuli responsive polymer to outside stimulation intelligent response, physicochemical and properties of reversible or irreversible (or) chemical structure changes, which caused the collapse of the body assembly of swelling and shrinkage, dissociation and aggregation, crosslinking and crosslinking and morphology transition. In addition, compared with normal tissues and organs, cells of diseased organs, tissues and cell physiological parameters will change; to develop selective transmission responsive polymer assembly can achieve treatment and imaging agents using these specific physiological changes. This paper focuses on the tumor and inflammatory microenvironment responsive polymer assembly, especially redox response design polymer vesicles and micelles, nanoparticles structure and multi functional architecture and integration. Specifically, the work of this paper includes the following three aspects: 1. a lot of physiological and pathological. The process of reactive oxygen species and oxidative stress are directly related, which provides an important biochemical basis of nanometer materials for the design of therapeutic and diagnostic function. By two amphiphilic polymer self-assembly prepared by oxidation responsive polymer micelles or vesicles have been studied extensively. However, in the previous oxidation response system study, reactive oxygen species including H2O2 will cause the polymer assembly micro structural damage. The oxidative polymer vesicles as an example, the micro structural damage will make vesicles coated with hydrophilic drugs and active molecules fast release, in certain circumstances, limiting the application of polymersomes as drug carrier and long-term in vivo nano reactor. In addition, the traditional polymer vesicles due to its double thick film, membrane permeability, and thus cannot be used as a drug carrier and nano reactor effectively. This , we designed and fabricated a multifunctional oxidation responsive polymer vesicles can be oxidized in the cell microenvironment after stimulation triggers cross-linking vesicle bilayers, and double membrane permeability increased, showed improvement in the quality of imaging capability enhancement and drug release properties. Through the self-assembly of hydrophobic blocks containing aryl boric acid ester protection with self degradation side group two amphiphilic block copolymers, preparation of polymer vesicles on the surface by a further modified polypeptide resulting in a mitochondrial targeting H2O2 responsive polymer vesicles. Endocytosis into cells, intracellular H2O2 trigger caused continuous amine the deprotection reaction, because the new primary amine produced by amidation reaction occurs in the bilayer hydrophobic, resulting in vesicle bilayer cross-linking and hydrophobic to hydrophilic synchronous transformation process. This process can be used for medicine Controlled release material, combination chemotherapy, and chemotherapy effect can be monitored by contrast-enhanced magnetic resonance imaging and fluorescence imaging capabilities, further build a fluorescent thiol containing biologically active molecules in the cytoplasm of the detection of producing nano reactor.2. developed different biochemical signal response with the diagnosis and treatment of functional nano medicine for drug peptides, proteins and reagents, imaging selectivity and spatial resolution transmission has been widely studied. The micro aerobic environment between the reduction potential of the redox gradient development response application of two amphiphilic block copolymer micelle nanoparticles in biomedicine have been extensively reported by reductive oxidation of the extracellular microenvironment and within the cell. In addition, many methods are used to further enhance the stability of the micelle, such as the use of chemical linkers are reversible Crosslinking, dissociation and drug release in advance to avoid undesirable. It is worth noting that, in all these cases, the fracture spacer will cause reversible crosslinking and unstable micelle nanoparticles, leading to micellar nanoparticles in the target location quickly cleared and reduce the concentration effect. Therefore, the materials for the designers. The new development strategy to achieve the selective response of tumor microenvironment and cell, more important is how to enhance the in vivo localization of target position is still the major challenge and enrichment of diagnosis and treatment of functional polymeric micelles. Especially, for most of the two disulfide polymer micelle nanoparticles reversibly crosslinked, two disulfide cross-linking solution only leads to fracture no significant change of hydrophobic to hydrophilic, hindered the coating material completely effective release. Here, we designed and synthesized redox responsive nuclear inbred lines The micellar nanoparticles, it has a long half-life of blood circulation, reducing intracellular crosslinking mode conversion trigger microenvironment and the micelles from hydrophobic to hydrophilic transformation and enhanced diagnostic imaging and drug release properties. The hydrophobic block contains two disulfide bonds with self degradation properties of two amphiphilic copolymers of the self-assembled micelles, and surface modification of integrin targeting peptide, finally by UV induced two disulfide exchange reaction was crosslinked to obtain two disulfide cross-linking reducing tumor cell targeting micro environment response (DCL) micelles. Enter cells via endocytosis mediated by integrin cytoplasmic. The reduction of micro environment triggered cascade within the micelle core elimination reaction to produce primary amines; amines generated further amidation reaction occurs in the micelle core hydrophobic, and cause the conversion of micelle crosslinking method The nuclear changes to happen at the same time. The hydrophilic hydrophobic chemical treatment of.3. cells of the immune system main function of the process can be further used to achieve fluorescence and magnetic resonance imaging guidance is to protect the body from infection. But when they are not properly activated, will cause a lot of inflammation, such as rheumatoid arthritis, atherosclerosis and diabetic complications in the development. These disease processes, including macrophages, immune cells to produce cytokines, such as interleukin (IL-6 and IL-1), tumor necrosis factor alpha (TNF- alpha), digestive enzyme (collagenase), prostaglandin and reactive oxygen species, these cytokines can aggravate the accelerated the destruction of normal tissue. The non steroid the body of anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain, fever and inflammation. However, long-term use of non steroidal anti-inflammatory drugs will produce some side effects, patients Such as gastrointestinal injury and increased risk of stroke, thus limiting their use of other suitable symptoms. Here, we designed and synthesized the inflammatory tissue oxidizing and reducing related micro environment response of poly prodrugs of two amphiphilic molecules, the hydrophobic block containing indomethacin prodrug, further through self-assembly process preparation of polymer capsule anti-inflammatory bubble. On this basis, the evaluation of polymer vesicle system of oxidation and reduction of controlled drug release and the microenvironment triggers macrophage anti-inflammatory effect.

【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】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：O631.1;TB383.1
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本文編號(hào)：1410373