發(fā)布時間：2018-01-11 16:40

  本文關鍵詞：響應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：《中國科學技術(shù)大學》2017年博士論文　論文類型：學位論文

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

【摘要】：刺激響應性聚合物能夠?qū)ν饨绱碳みM行智能響應,產(chǎn)生可逆或不可逆的物化性質(zhì)和(或)化學結(jié)構(gòu)的改變,進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、組織及細胞相比,病變器官、組織及細胞的生理參數(shù)會發(fā)生變化;利用這些特異性的生理變化來發(fā)展響應性聚合物組裝體可以實現(xiàn)治療和成像試劑的選擇性傳輸。本論文集中研究了對腫瘤及炎癥微環(huán)境具有響應性的聚合物組裝體,重點是氧化還原響應性聚合物囊泡和膠束體系的設計、納米結(jié)構(gòu)的調(diào)控及多功能構(gòu)筑與集成。具體來說,本論文的工作包括以下三個方面:1.很多生理和病理過程與活性氧物質(zhì)和氧化壓力直接相關,這就為設計治療和診斷功能的納米材料提供了非常重要的生化基礎。由兩親性聚合物自組裝制備的氧化響應性聚合物膠束或者囊泡已經(jīng)進行了大量的研究。然而,在以前的氧化響應性體系研究中,包括H2O2在內(nèi)的活性氧物質(zhì)都會導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效活體內(nèi)納米反應器的應用。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器。這里,我們設計制備了一種多功能的氧化響應性聚合物囊泡,可以在細胞內(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),同時雙層膜滲透性提高,表現(xiàn)出成像能力增強和藥物釋放性能提高的性質(zhì)。通過自組裝疏水嵌段含有芳基硼酸酯保護的具有自降解側(cè)基的兩親性嵌段聚合物制備聚合物囊泡,在其表面進一步用多肽進行修飾從而得到具有線粒體靶向的H2O2響應性聚合物囊泡。內(nèi)吞進入細胞后,胞內(nèi)H2O2觸發(fā)引發(fā)連續(xù)的脫保護反應產(chǎn)生伯胺,由于新產(chǎn)生的伯胺在疏水的雙層膜中會發(fā)生酰胺化反應,導致囊泡雙層膜發(fā)生同步的交聯(lián)和疏水到親水的轉(zhuǎn)變過程。這一過程可以用于實現(xiàn)藥物可控釋放、組合化療,同時化療效果可以通過磁共振成像和熒光成像能力的增強進行實時監(jiān)測,進一步構(gòu)筑了檢測細胞質(zhì)中的含巰基的生物活性分子的熒光產(chǎn)生型納米反應器。2.開發(fā)不同生化信號響應的具有治療和診斷功能的納米醫(yī)藥用于實現(xiàn)藥物、多肽、蛋白質(zhì)以及成像試劑的選擇性和時空分辨?zhèn)鬏斠驯粡V泛地研究。其中,利用細胞外的氧化性微環(huán)境和細胞內(nèi)的還原性微環(huán)境間的氧化還原電勢梯度開發(fā)氧化還原響應性兩親性嵌段共聚物膠束納米粒子在生物醫(yī)藥方面的應用已經(jīng)被大量地報道。此外,許多方法被采用來進一步增強膠束的穩(wěn)定性,例如利用可逆連接基團進行化學交聯(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,可逆連接基團的斷裂都會引起膠束納米粒子解交聯(lián)和不穩(wěn)定化,從而導致膠束納米粒子在目標位置快速被清除進而降低富集效果。因此,對于材料設計者來說,發(fā)展新策略以實現(xiàn)選擇性的響應腫瘤和細胞內(nèi)微環(huán)境,更重要的是如何增強診療功能的聚合物膠束在活體內(nèi)目標位置的定位和富集仍是重大的挑戰(zhàn)。特別地,對于大部分二硫鍵可逆交聯(lián)的聚合物膠束納米粒子,二硫鍵斷裂僅僅導致解交聯(lián)而沒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,我們設計合成了氧化還原響應性核自交聯(lián)的膠束納米粒子,其具有長的血液循環(huán)半衰期、細胞內(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,進而表面修飾整合素靶向肽,最后通過紫外光引發(fā)二硫鍵交換反應進行交聯(lián),從而得到了腫瘤細胞靶向的還原性微環(huán)境響應的二硫鍵交聯(lián)(DCL)膠束。通過整合素介導的內(nèi)吞作用進入細胞后,細胞質(zhì)還原性微環(huán)境觸發(fā)膠束核內(nèi)發(fā)生級聯(lián)的消除反應產(chǎn)生伯胺;新生成的伯胺在疏水的膠束核中會進一步發(fā)生酰胺化反應,導致交聯(lián)方式轉(zhuǎn)換與膠束核疏水到親水轉(zhuǎn)變同時發(fā)生。該過程還被進一步用來實現(xiàn)熒光和磁共振成像指導的化學治療。3.免疫細胞主要作用就是保護機體免受感染。但是當它們被不正常激活時,就會引發(fā)很多炎癥反應,例如風濕性關節(jié)炎、動脈粥樣硬化以及糖尿病并發(fā)癥等。在這些疾病的發(fā)展過程中,包括巨噬細胞在內(nèi)的免疫細胞會產(chǎn)生多種細胞因子,例如白細胞介素(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),這些細胞因子可以加重加速對正常組織的破壞。非甾體抗炎癥藥物(NSAIDs)被廣泛用來治療疼痛、發(fā)熱以及炎癥。但是,長期使用非甾體抗炎癥藥物會產(chǎn)生一些副作用,例如腸胃損傷和中風風險增加,因而限制了它們的使用以及其他適用癥狀的研究。這里,我們設計合成了炎癥組織相關的氧化性和還原性微環(huán)境響應的聚前藥兩親性分子,其中疏水嵌段含有吲哚美辛前藥,進一步通過自組裝制備了抗炎癥的聚合物囊泡。以此為基礎,評價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于巨噬細胞的抗炎癥效果。
[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.

【學位授予單位】：中國科學技術(shù)大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：O631.1;TB383.1
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本文編號：1410373