蒯因(W.V. quine)在語言哲學的發展上 , 可說是當代一大重鎮. 他對傳 統上在一般經驗論者中 , 對分析與綜合(analytic-synthetic)語句的區 分以及證實說(verificationism)提出嚴厲的批判,這可算是語言哲學中的 一大轉變 . 他的整體論(holism), 理論之不可由經驗完全限定 (unederdetermination of experiences) , 物理主義(physicalism) ,自然主義(naturalism) , 翻譯的不確定性(indeteriminacy of translation),指設的不可測度(inscrutability of references),存有學 的相對性(ontological relativity) 等理論 , 試圖以( 自然) 科學, 或說廣義物理理論作為我們對知識探求的基礎. 本文所要處理的問題是: 在翻譯的不確定性理論中, 蒯因所用的理論是什麼 ? 它是否有效而可以 成立 ? 其論證間是否各自獨立或有相互關係? In the development of philosophy of language, Quine is a very important philosopher. He criticized the traditional empiricism for the analytic-synthetic division and verificationism, this is an important milestone in the history of philosophy of language. He exhausts the whole theory, like holism, underdetermination of experiences ,physicalism, naturalized epsitemology, indetermincy of translation, and inscrutability of reference or ontological relativity, and so on. He tried to use sciences or broader physics to be the base of our researching for knowledge. The topic in this paper is about "indeterminacy of translation", we want to know Quine's arguments, the validity of these arguments, the relations between these arguments, and potential questions of this doctrine.

生物科技為目前世界各國極力投入之新興產業，此產業無需大量天然資源及低污染的特性，同時又能解決人類的醫療問題並提昇生活水準的未來發展空間，更使得此一新興產業吸引了眾人的眼光。 　　本論文提出一個評估的模式，讓此產業之技術、產品或專利之價值能夠經系統化的分析後完整呈現，並可基於此分析結果作出策略上之判斷，並以GnRH vaccine技術為例。因為GnRH分子之序列早已發表，經本研究分析得兩種常用的專利保護策略，第一種是將GnRH與不同的載體進行結合，而新生成一個嵌合化合物，並申請此新化合物之專利；第二種是進行GnRH分子結構上之改變以取得新序列的專利保護，取得效果優於自然設計之分子，或藉以增加與免疫載體之結合率。經分析後發現，GnRH疫苗應用理論已經相當成熟，未來幾年應該會有成熟產品通過上市之審核過程；再隨著新科技的進步，可預期將會有更多的新產品會上市，而進一步地有效提昇產品功效並降低製造成本。 　　本研究最後針對GnRH未來在人用藥品及動物用藥之未來市場加以分析，並對於以重複免疫原在重組型疫苗製備法之開發提出行銷、財務、通路、價格、推廣、臨床實驗之建議，以期能經由策略規劃的角度將生物技術的價值作最大化的管理。 / Biotechnology attracts high attentions among many countries recently. New biotechnology will provide a key solution to cure diseases and potentially will be able to increase human life quality without damaging the environment and consuming massy natural resources. 　　In this thesis, we presented a possible process, which involved in academic, marketing and patent information analysis, to effectively evaluate the feasibility and potential of any novel biological technologies, so as to provide the managerial and strategic suggestions based on the analysis. GnRH repeat immunogens vaccine development was taken as an example to demonstrate if the proposed process can be executed adequately. After discretly cross examining the collected information, we concluded that many independent GnRH vaccine patents are available but will not be effective enough to stop to new competitors to get in this sector because GnRH sequence was disclosed in very early research and nobody held the patent for it and most of GnRH patents were granted to either different GnRH-Carrier chimeras or the GnRH analog sequences. Analysis results show that there is only one company closely approaching the final product approval at this moment. However, any improved technology can easily employed to provide a better product with higher effectiveness and lower cost following the first product's upcoming marketing clearance and then make the future market very complicated. 　　Based on those findings, we further analyze the Taiwanese current environment and provide a few managerial suggestions to maximize the value of a novel GnRH vaccine preparation technology.

根據國際咖啡組織的統計資料顯示，全球咖啡需求不斷增加，對台灣人而言，咖啡也與國人生活息息相關。隨著電子商務的蓬勃發展，許多產業已由傳統商店轉戰線上虛擬商店，在這樣的趨勢下，網頁刺激設計的重要性也越來越受到重視，特別是對於普遍、可替代性高，且相當重要的咖啡豆而言。 然而，目前網頁呈現之相關研究認為消費者實際感受普遍局限於視、聽兩覺，除了這兩種感官，其他感官無法在網頁被操控，因此本研究除了希望探討網頁刺激設計對消費者於線上購買咖啡豆時情緒、態度及購買意圖的影響外，還企圖利用不同的視、聽覺刺激的組合，確認那些組合最能激發消費者的聯覺想像。 本研究採用實驗室問卷調查法，利用影片聲音有無、類3D照片效果有無以及快慢音樂節奏等不同的視覺與聽覺刺激變數組合，設計出8個網頁，並收集共120位受測者，邀請每位受測者觀看各種不同網頁設計元素所組成的網站，並搭配問卷調查以獲得實驗數據。 經過實驗結果分析，本研究發現不同的感官刺激組合確實能為消費者內心狀態與購買意圖帶來不同的影響效果，其中，正向愉悅度、支配度與網頁態度，搭配負向激發度的情緒、狀態組合最能激發消費者購買意圖；而類3D照片搭配快音樂節奏的組合除了最能為消費者創造上述內心狀態組合外，同時也是最能激發消費者聯覺效果的網頁刺激設計元素組合。 以上研究結果於學術上突破了現有文獻認為網頁上只能帶給消費者視覺、聽覺刺激的限制，於實務上除了提供最佳網頁設計元素與情緒組合的建議外，也發現用成本較低的類3D圖片便可同時達到提升購買意圖以及聯覺效果的目的，幫助企業能在激烈的電子商務競爭中脫穎而出，跳脫原本的價格策略，改而使用網頁設計的差異化來提升銷售量。 / According to the statistical data of International Coffee Organization, the demand of coffee beans is increasing in the whole world. With the rapid development of electronic business, many industries tend to sell their products on the internet. And the importance of website stimulus design has been highly regarded, especially for those which are universal, highly substitutable, and highly valued coffee beans. However, most of the studies related to web design think that consumer perception is limited to visual and aural stimuli; all senses can’t be manipulated on the website except these two senses. This study has two goals. First, we attempt to measure the effects of website stimulus design on consumer emotion and the intention to purchase coffee beans. Second, we experiment with the combinations of different visual and aural stimuli to confirm which kind of combination is most effective to arouse consumer’s synesthesia. The study is conducted in the laboratory with questionnaires. Totally eight websites are designed with the presence or absence of video sound, quasi 3D or 2D photo, and music tempo speed. One hundred twenty (120) subjects are invited and asked to do the questionnaire after viewing these websites. The results of the experiment show that people’s organism and purchase intention are significantly affected by different website stimulus designs. Among them, the combination of positive pleasure, dominance and web attitude with negative arousal can bring consumers’ purchase intention most excitement. The combination of quasi 3D and fast-tempo music can not only help consumers to establish the internal state that we mentioned above, but also can arouse their synesthesia. In terms of the academic contribution, the results of this study break the limitation of existing literature stating that only visual and aural senses can be delivered on the website. As for the practical contribution, we not only offer the suggestion of best stimulus combination and emotional combination for a website, but also get the empirical support that sellers may increase consumers’ purchase intention and synesthesia at the same time with low-cost quasi 3D photos. The outcome of the study can help sellers stay ahead in the fierce competition in online shopping environment. Using website stimulus design can enhance sellers’ sales, rather than just using the price strategy.

星座命理節目是近年來在台灣新興崛起的一種綜藝型態，尤其在國人對於未來越來越沒有信心與安全感的現今，命理節目的存在，無疑地為國人提供一個簡便預測未來的方法。命理節目在台灣雖已行之有年，但是針對命理節目收視行為所進行的研究卻相當少，本研究運用人口變項及外控傾向、刺激尋求動機等人格特質，試圖描繪出命理節目收視族群的輪廓，並且進一步探討命理節目的收視經驗與算命態度、算命行為之間的關聯性。 本研究使用網路問卷調查方式，經過歷時三週的調查，共有653名網友參與本研究。根據調查結果顯示，命理節目的收視族群以年輕未婚女性居多，職業多為學生、服務業或待業中人士，收入則在10000元以下，並且具有高刺激尋求動機的人格特質，至於外控傾向高低對於命理節目收視經驗並無顯著影響。此外，本研究發現命理節目接觸經驗對於算命態度與算命行為中實際算命次數、算命結果滿意度、未來從事付費算命可能及自認算命結果影響性均有正向的關係，足見命理節目接觸經驗越多對於算命態度與算命行為越有提升的效果。 / Recently，Fortune telling programs are newly developed in Taiwan. Nowadays，people are losing their confidence and sense of security for future. Therefore，fortune telling programs absolutely offer an easy solution for Taiwanese. Though fortune telling programs have been produced in Taiwan for years，the researches on fortune telling programs are rare. The author intends to address the fact of the audience by utilizing demographics and psychological orientation such as locus of control and sensation seeking. Moreover，the relationships among the experience of exposing to fortune telling programs、fortune telling attitude and fortune telling behavior are discussed. There are 653 internet users recruited and invited to complete the internet questionnaire in the period of three weeks. The results from the analysis indicate that the main audience of fortune telling programs are young single women. Students、people who are engaged in service industry and the unemployed occupy higher proportion of the participants，and their monthly income is under NT10000. To conclude，these people have the character of high sensation seeking. The character of external control has no obvious effect to the experience of exposing to fortune telling programs. In addition，the research points out that the experience of exposing to fortune telling programs has positive relationship with fortune telling attitude and fortune telling behavior. Obviously，when the audience have more the experience of exposing to fortune telling programs，there are more positive effects.

京都大学 / 新制・論文博士 / 博士(工学) / 乙第13487号 / 論工博第4199号 / 新制||工||1783(附属図書館) / (主査)教授 浜地 格, 教授 森 泰生, 教授 杉野目 道紀 / 学位規則第4条第2項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

研究背景:成人午睡對於認知與情緒影響的正面效益，已獲得許多研究證實，不過兒童夜間各睡眠期所占比例與成人不同，而且至今少有兒童午睡效益的研究，因此，本研究旨在探討短暫午睡對於國小學童認知功能、學習表現與情緒狀態的影響。 實驗設計與方法:以研究一實驗室情境，配合研究二教室現場實地研究兩種方式進行探討。研究一採組內設計，以30名國小五年級學童，在睡眠實驗室分別接受單日20分鐘的午睡與清醒的實驗，並以五種神經心理測驗，進行前測與後測，並以相依樣本t考驗進行比較兩種實驗情境在五種神經心理測驗表現的差異，並以性別×情境×時間三因子變異數分析，比較睏睡度與情緒的分數差異，並以皮爾森積差相關統計分析午睡睡眠參數資料與神經心理測驗分數的相關性。研究二採組內設計，以67名五年級學童，在兩週分別接受三日教室現場的午睡以及三日清醒情境的安排，並實施國語、數學、社會教學，作為午睡效益的評量依據，並以重複樣本t考驗比較兩種實驗情境國語科、數學科、社會科學習成效測驗分數是否有所差異，另以午睡習慣×實驗情境×時間三因子變異數分析，比較睏睡度與情緒量表分數的差異性。 研究結果:研究一發現受試者經歷20分鐘的午睡後，在專心度表現顯著比清醒好，不過午睡後的抑制刺激干擾的錯誤率卻顯著比清醒時高；至於在工作記憶、敘述性記憶、程序性動作記憶的表現，兩種情境則無顯著差異。另外，發現午睡後13:10的主觀睏睡度明顯比清醒時要低，在其他情緒狀態上則無顯著差異。而且發現睡眠第一期時間與抑制刺激干擾能力表現達顯著負相關；睡眠第二期時間與敘述性記憶表現成正相關:睡眠第三期時間則與敘述性記憶表現成負相關;:研究二則發現午睡後學生睏睡度顯著比沒午睡時要低，而且三日內15:30的睏睡度皆比剛睡醒13:10時要低，且第三日15:30睏睡度有顯著降低，但其他情緒則無顯著影響。另外，國語、數學、社會三科的學習成效，在兩種實驗情境皆無顯著差異。 結論:兒童午睡過程睡眠期與成人不太相同，且從兒童夜間睡眠與認知相關研究，也可以發現兒童似乎能夠補償短暫午睡缺乏，造成對認知功能損害或情緒的負面影響，因此，短暫午睡似乎對於兒童的正面顯著效益，並不如成人ㄧ般，不過，本研究實驗室或教室研究情境，皆ㄧ致發現兒童午睡仍能減少受試者主觀睏睡度，而且也發現隨著午睡日數增加所帶來的正面效益。未來，進行實地研究可以更嚴謹的睡眠偵測及判讀工具，來確認受試者午睡情況，減少主觀判斷與檢核所產生的誤差。 / Background: It has been confirmed by many researches that taking the afternoon nap has positive effects on adult cognition and emotion. However, the proportion of children’s sleep stages at night is quite different from that of adults. Since there are few studies on the effects of children’s afternoon nap, this paper aims to discuss the effects of short nap on cognitive ability, academic performance and emotional state of elementary school pupils. Experimental Design and Methods: The study mainly adopted two methods--------- laboratory situation and field study in the classroom. The first method was conducted among 30 fifth-grade pupils from the elementary school, with each one dealing with 20-minute long nap and sober status respectively in a day. Besides, five neuropsychological tests were carried out to pre-test and post-test their performance with the paired sample t-test to compare their difference. Based on the variance analysis of gender, situation as well as time factors, sleepiness degree and emotional difference were compared and the relationship between nap parameters and neuropsychological test scores was analyzed with Pearson's correlation analysis method. The second method was conducted among 67 fifth-grade pupils from the elementary school, dealing with afternoon nap and sober situation respectively for three days in two weeks. Besides, Chinese, Mathematics and Sociology were taught as the basis to assess the effects of afternoon nap with the paired samples t-test. Based on the variance analysis of nap habits, environmental situation and time factors, sleepy degree and emotional difference were compared. Research Result: The first study showed that concentration degree of pupils after 20-minute afternoon nap was much higher than that before sleeping, so was the error rate to inhibit stimulation’s interference. As for the performance in working, declarative and procedural motor memory, there was no significant difference. In addition, we found that the subject sleepiness degree after 13:10 was lower than that when awake and there was no significant difference in other emotional states. The duration of stageⅠwas significantly negative-related to the performance to inhibit stimulation’s interference, and the duration of stageⅡwas positive-related to declarative memory performance; while the duration of stageⅢwas negative-related to declarative memory performance. The second study showed that subjective sleepiness degree of pupils after afternoon nap was much lower than that before nappinging, so was the sleepiness degree of 15:30 much lower than that of 13:10 in three days. In particular, the sleepiness degree of 15:30 in the third day decreased significantly, while other emotional states were not affected greatly. What’s more, there was no significance between these two experimental situations on study effects of Chinese, Mathematics and Sociology Conclusion: Children have a different afternoon nap course from adults. Related researches on children’s night sleep and cognition show that children seem to be able to .compensate for the lack of a short nap, resulting in cognitive impairment or emotional impact of negative.Therefore, the positive benefit of short nap of children is not as significant as that of adults. However, both laboratory and classroom situation showed that children’s afternoon nap could still reduce the subjective sleepiness. As the napping days increased, the positive effect was much more evident. In the near future, more rigorous sleep state detection and scoring tools for field study can be used to identify the nap situation and to reduce subjective misunderstanding and detection errors.

透過神經科學的研究，對於大腦的行為功能已有一定的認識，不同於以往的認識，目前認為神經行為機制不只由單一腦區或單一神經化學系統所調控。深部大腦電刺激經常被用來研究特定腦區的行為功能。但是，深部大腦電刺激的作用機制仍然不清楚。最近幾年臨床研究發現，利用電刺激在側韁核成功的治療憂鬱症患者。然而，目前認為側韁核與多巴胺系統互為負回饋作用，共同參與在動機行為的酬賞反應中。本實驗室先前的研究顯示，破壞韁核造成區辨性低頻操作式制約行為 (簡稱DRL行為)學習的障礙，然而，電刺激在側韁核造成DRL行為表現的結果還是未知的。所以，本實驗主要以電刺激在側韁核觀察大鼠行為上的改變，探討側韁核在行為上參與的功能。實驗一的結果顯示電刺激在側韁核並不影響自發性運動能力，在不同電流強度的刺激下也不會影響。實驗二的結果顯示電刺激在側韁核造成DRL 15秒的行為有類安非他命效果之行為表現，在高頻率電刺激有較顯著類安非他命的效果。實驗三的結果顯示電刺激在側韁核造成DRL 15秒的行為之影響，會被多巴胺受體抑制劑所抵消，而單獨注射巴胺受體抑制劑並不影響DRL 15秒的行為。實驗四的結果顯示電刺激在側韁核造成DRL 15秒的行為之影響，不會被正腎上腺素受體抑制劑所抵消。實驗五的結果顯示電刺激在側韁核造成DRL 72秒的行為之影響並不如DRL 15秒的行為顯著。實驗六的結果顯示電刺激在側韁核並不會造成大鼠無法區辨酬賞的量。綜合而言，側韁核在動機行為的角色，是透過影響多巴胺系統造成行為的改變。 / Behavioral function of the brain has been studied in neuroscience and progressively accumulated informative data to reveal the neurobehavioral mechanisms. It is now realized that those underlying mechanisms of behaviors is not as such simple as previous thought of limiting only in one locus of the brain or solely by one neurochemical system. The deep brain stimulation is usually used to study the behavioral function of specific brain regions. However, the mechanism of the deep brain stimulation is still unclear. The previous study has shown that electrical stimulation of the lateral habenula (LHb) successfully treated depression symptoms in the patients. It is proposed that an inhibitory role of LHb on the mibrain dopamine (DA) system which mediates the reward-related behavior. A previous study of this lab showed that lesion of habenula impaired the acquisition of differential reinforcement of low-rate responding (DRL) behavior. But, the effect of LHb stimulation on the DRL behavior is still unclear. To determine the functions of LHb involving in the behavior, the electrical stimulation was applied in LHb to observe the behavioral change of rats. The results of Experiment 1 showed that the LHb stimulation had no effect on locomotor activity. In Experiment 2, the LHb stimulation was shown to affect DRL 15-s behavior, which effects were similar to those affected by amphetamine. Experiment 3 showed that the DA receptor antagonists reversed the effects of LHb stimulation, while experiment 4 showed that norepinephrine (NE) receptor antagonists had no reversal effect on DRL 15-s behavior. In Experiment 5, the amphetamine-like behavior induced by LHb stimulation had subtle effects on DRL 72-s behavior. Experiment 6 showed that the LHb stimulation had no effect on a discrimination task. These data suggest that the LHb modulating DRL behavior is DA-dependent.

Résumé : Les copolymères à blocs sensibles aux stimuli (SR-BCPs) et leurs assemblages, tels que les micelles, les vésicules et les hydrogels, peuvent subir des changements physiques ou chimiques en réponse à l'évolution des conditions environnementales. Pour un excellent SR-BCP, habituellement, de légères modifications de l'environnement sont suffisantes pour induire des modifications relativement drastiques dans la conformation, la structure ou les propriétés du polymère. Ces polymères sont aussi appelés polymères stimuli-réactifs ou polymères intelligents et ils ont un grand potentiel d'application dans de nombreux domaines. Au cours des deux dernières décennies, un intérêt de recherche et développement particulier a été porté sur l'exploitation des SR-BCPs pour utilisation comme systèmes de relargage de médicaments. Dans de nombreux cas, les changements induits par des stimuli dans la structure ou la morphologie des assemblages de BCPs peuvent entraîner la libération de l'espèce encapsulée, parfois d'une manière contrôlable spatialement et temporellement par le choix d'un stimulus approprié et en ajustant les paramètres de la méthode de stimulation utilisée. De façon générale, le fait d’avoir un certain type de groupements réactifs à un stimulus donné dans la structure permet aux SR-BCPs de reconnaître et réagir à ce stimulus. Malgré les énormes progrès réalisés sur les SR-BCPs, un certain nombre de questions fondamentales restent à résoudre afin de leur permettre de se trouver dans des applications pratiques. Pour y arriver, la clé ou le défi réside dans l’amélioration du niveau et de la complexité de contrôle sur les SR-BCPs ainsi que la sensibilité avec laquelle ces polymères réagissent à des stimuli. Généralement, il est souhaitable d'obtenir une réaction rapide sous l'action d'une stimulation modérée. A cette fin, il est nécessaire d’effectuer des recherches fondamentales sur la conception rationnelle de nouveaux SR-BCPs ainsi que sur le développement de méthodes de stimulation qui peuvent amplifier l'effet d'un stimulus. Les travaux de recherche présentés dans cette thèse s'inscrivent dans ce domaine de recherche. Plus spécifiquement, nous avons étudié des micelles de BCPs qui répondent à deux types de stimuli. D'une part, nous avons étudié un mécanisme d'amplification basé sur l’effet des ultrasons combiné à la thermosensibilité de BCPs. D'autre part, nous avons développé une nouvelle conception de BCPs qui permet aux micelles d’être détruites soit de manière photochimique, soit par des réactions d'oxydo-réduction, tout en ayant le nombre minimum des groupes stimuli-réactifs dans la structure du polymère. Notre recherche a généré de nouvelles connaissances dans ce domaine et suggère de nouveaux moyens sur la façon dont les questions de sensibilité et de contrôle complexe des micelles SR-BCPs peuvent être abordées, contribuant ainsi à l'avancement des connaissances fondamentales. Le cœur de cette thèse est composé de trois publications résultant des projets réalisés. Dans le premier projet, afin de coupler la sensibilité aux ultrasons et la thermosensibilité, nous avons mené une étude ayant pour but de trouver des structures possibles de polymères qui sont susceptibles d'être affectées par les ultrasons. Nous avons effectué une étude comparative sur la destruction des micelles formées par divers BCPs et la libération concomitante d'un colorant hydrophobe encapsulé (rouge du Nil) par les ultrasons focalisés de haute intensité (HIFU). Nous avons constaté que toutes les micelles formées par les quatre copolymères diblocs synthétisés, étant constitués d'un même bloc du polyoxyde d'éthylène (PEO) hydrophile et d’un bloc de polyméthacrylate hydrophobe différent, peuvent être perturbées par les ultrasons. Toutefois, l'ampleur de la perturbation et la libération du colorant encapsulé dans la micelle est influencée par la structure chimique du block hydrophobe. En particulier, les micelles du PEO-b-PIBMA (poly(1-isobutoxyméthacrylate d'éthyle)) et du PEO-b-PTHPMA (poly(méthacrylate de 2-tétrahydropyrannyle)), qui possèdent une unité acétal labile dans le groupe latéral, subissent des perturbations plus importantes en raison, probablement, d’une réaction d’hydrolyse de l’ester induite par les ultrasons, donnant lieu à une libération plus rapide du colorant. En revanche, les micelles du PEO-b-PMMA (poly(méthacrylate de méthyle)), dont le bloc polyméthacrylate est plus stable, sont plus résistantes aux ultrasons et présentent une cinétique de libération du colorant plus lente que les autres micelles. De plus, l’analyse des spectres infrarouges des solutions micellaires, enregistrés avant et après l’exposition aux ultrasons, suggère une réaction d’hydrolyses pour le PEO-b-PIBMA et le PEO-b-PTHPMA, mais montre l'absence d’une quelconque réaction chimique pour le PEO-b-PMMA. L'effet de la structure de copolymère à blocs sur la réactivité des micelles à l'irradiation HIFU à hautes fréquences permet de mieux comprendre comment des micelles de BCPs sensibles aux ultrasons peuvent être conçues. Sur la base du premier projet, dans le deuxième projet, nous avons démontré une nouvelle approche pouvant amplifier l'effet de HIFU sur la destruction des micelles de BCPs en solution aqueuse. L’idée est d’introduire une petite quantité des unités comonomères sensibles aux ultrasons dans le bloc thermosensible et initialement hydrophobe. On peut alors former une micelle dont le noyau est composé du polymère sensible aux ultrasons. Si la réaction induite par les ultrasons sur le noyau permet d’augmenter la température de solution critique inférieure (LCST) du polymère thermosensible au-dessus de la température de la solution micellaire, la micelle doit être dissolue car tout le BCP est devenu soluble dans l’eau. Pour tester la validité de ce nouveau mécanisme, nous avons synthétisé et étudié un copolymère dibloc de PEO-b-P(MEO[indice inférieur 2]MA-co-THPMA) (MEO[indice inférieur 2]MA représente 2-(2-méthoxyéthoxy) méthacrylate d'éthyle), dans lequel le bloc thermosensible P(MEO[indice inférieur 2]MA-co-THPMA) est hydrophobe à T>LCST. Le THPMA a été choisi en raison de sa plus grande réactivité vis-à-vis des faisceaux HIFU que les autres monomères étudiés dans le premier projet. Les résultats montrent que les HIFU peuvent effectivement augmenter la LCST du bloc P(MEO[indice inférieur 2]MA-co-THPMA) et, par conséquent, induire la dissociation des micelles à une température constante de la solution. Une analyse spectrale en RMN [indice supérieur 13]C a fourni des preuves montrant que l'hydrolyse des groupes THPMA se produit sous l’irradiation HIFU et que la destruction des micelles provient d'une augmentation de la LCST en raison de la conversion des motifs hydrophobes THPMA en motifs acides méthacryliques (MAA) hydrophiles. Cette méthode de modifier la LCST par une irradiation des ultrasons est générale et peut être appliquée aux autres groupements sensibles aux ultrasons dans la conception de ce type de SR-BCPs. Cette étude a ainsi démontré un nouveau mécanisme d'amplification et de contrôle des micelles de BCPs via la modification induite par les ultrasons de la température de transition de phase (LCST) du bloc constituant le noyau micellaire. Le troisième projet présenté dans cette thèse portait sur une conception rationnelle de BCPs ayant un but précis: permettre aux micelles d’être perturbées par deux types de stimuli en utilisant le nombre minimal des unités sensibles à des stimuli dans la structure de BCPs. Pour ce faire, nous avons conçu et synthétisé un nouveau copolymère tribloc amphiphile de type ABC, soit le poly(oxyde d'éthylène) - disulfure – polystyrene - o-nitrobenzyle - poly(2-(diméthylamino) éthylméthacrylate) (PEO-S-S-PS-ONB-PDMAEMA). Il dispose d'une liaison disulfure redox-clivable entre les blocs PEO et PS ainsi que d'un groupe o-nitrobenzyle (ONB) photoclivable à la jonction des blocs PS et PDMAEMA. Nous avons montré que ce modèle est une stratégie utile pour permettre aux micelles de BCPs de répondre soit à un agent réducteur comme le dithiothréitol (DTT) dans une solution, soit à l'exposition à la lumière UV, tout en ayant le nombre minimum des groups stimuli-réactifs dans la structure du copolymère (deux unités par chaîne). Nos investigations ont révélé que les micelles de ce copolymère tribloc peuvent être perturbées de différentes façons. Lorsqu'un seul stimulus est appliqué, l'enlèvement d'un type des chaînes de polymère hydrophile à partir de la couronne de micelles, soit le PEO par clivage par oxydo-réduction ou le PDMAEMA par photoclivage, entraîne un effet limité de déstabilisation sur la dispersion des micelles. L'agglomération de quelques micelles apparaît mais la dispersion reste essentiellement stable. En revanche, en cas d'utilisation combinée des deux stimuli qui clivent à la fois le PEO et le PDMAEMA, une agrégation importante du polymère se produit à la suite de l'élimination de l'amphiphilicité du polymère. // Abstract : Stimuli-responsive block copolymers (SR-BCPs) and their assemblies, such as micelles, vesicles and hydrogels, can undergo physical or chemical changes in response to changing environmental conditions. For an excellent SR-BCP, usually, slight changes in the environment are sufficient to induce relatively drastic changes in either the conformation or structure or properties of the polymer. Stimuli-reactive polymers are often referred to as smart polymers and they have great application potential in many fields. Over the past two decades, particular research and development interest has been focused on exploiting SR-BCP assemblies as drug delivery systems (DDSs). In many cases, stimuli-induced changes in the structure or morphology of BCP assemblies (drug carriers) can result in the release of loaded species, sometimes in a spatially and temporally controllable manner by choosing an appropriate stimulus and adjusting the parameters of the used stimulating method. Generally speaking, by having a certain type of stimuli-reactive moieties in the structure, SR-BCP assemblies have an ability to recognize a specific stimulus and react to its presence accordingly. Despite the tremendous progress achieved on SR-BCPs, a number of fundamental issues remain to be addressed in order to enable real-life applications of these smart polymers. Of them, an increasing level and complexity of control on SR-BCPs as well as the sensitivity with which these polymers react to stimuli are key and challenging. It is highly desirable to obtain a fast reaction under the action of a modest stimulation. To this end, fundamental research is necessary on rational and creative BCP structural design as well as on development of stimulation methods that can amplify the effect of a stimulus. The research work presented in this thesis falls into this important topic. More specifically, we studied BCP micelles that are responsive to two types of stimuli. On the one hand, we investigated an amplification mechanism based on coupling the ultrasound reactivity with the thermosensitivity of BCPs. On the other hand, we developed a BCP structural design that allows micelles to be disrupted by either light or redox agents while having the minimum number of stimuli-reactive moieties in the polymer structure. Our research provided new insights into and suggested new means on how the issues of sensitivity and complex control of SR-BCP micelles can be tackled, thus contributing to the advancement of fundamental knowledge. The core of this thesis is comprised of three publications resulting from the projects realized in our research work. In order to couple the ultrasound sensitivity and thermosensitivity, in the first project, we carried out studies to find possible polymer structures that are susceptible to be affected by ultrasound. We conducted a comparative study on the disruption of the micelles formed by various BCPs and the concomitant release of an encapsulated hydrophobic dye (Nile Red) by high-intensity focused ultrasound (HIFU). It was found that all micelles formed by the four synthesized diblock copolymers, being composed of a hydrophilic poly(ethylene oxide) (PEO) block and a different polymethacrylate hydrophobic block, could be disrupted by ultrasound. However, the extent of the micellar disruption and dye release was found to be influenced by the chemical structure of the micelle-core-forming hydrophobic polymethacrylate. In particular, micelles of PEO-b-PIBMA (poly(1-(isobutoxy)ethyl methacrylate)) and PEO-b-PTHPMA (poly(2-tetrahydropyranyl methacrylate)), whose hydrophobic blocks have a labile acetal unit in the side group and are more likely to undergo ester hydrolysis, could be disrupted more severely by ultrasound, giving rise to a faster release of Nile Red. By contrast, micelles of PEO-b-PMMA (poly(methyl methacrylate)), whose polymethacrylate block is more stable, appear to be more resistant to ultrasound irradiation and exhibit a slower rate of dye release than other BCPs. Moreover, infrared spectra recorded with micelles before and after ultrasound irradiation of the aqueous solution of the micelles give evidence for the occurrence of chemical reactions, most likely hydrolysis, for PEO-b-PIBMA and PEO-b-PTHPMA, but absence of chemical reactions for PEO-b-PMMA. The effect of BCP chemical structure on the reaction of micelles to high-frequency HIFU irradiation shows the perspective of designing and developing ultrasound-sensitive BCP micelles for ultrasound-based delivery applications. On the basis of the first project, in the second project, we demonstrated a new approach that could amplify the effect of HIFU on the disassembly of BCP micelles in aqueous solution. By introducing a small amount of ultrasound-labile comonomer units into the micelle core-forming thermosensitive polymer, the ultrasound-induced reaction of the comonomer could increase the lower critical solution temperature (LCST) of the thermosensitive polymer due to a polarity change, which renders the BCP soluble in water without changing the solution temperature and, consequently, results in disassembly of BCP micelles. To prove the validity of this new mechanism, we synthesized and investigated a diblock copolymer of PEO-b-P(MEO[subscript 2]MA-co-THPMA) (MEO[subscript 2]MA stands for 2-(2-methoxyethoxy)ethyl methacrylate). In the thermosensitive random copolymer block P(MEO[subscript 2]MA-co-THPMA), which is hydrophobic at T>LCST, THPMA was chosen due to its greater reactivity under HIFU than other monomer structures investigated in the first project. We found that HIFU could indeed increase the LCST of the P(MEO[subscript 2]MA-co-THPMA) block and, as a result, dissociate the BCP micelles at a constant temperature. A [superscript 13]C NMR spectral analysis provided critical evidence that hydrolysis of the THPMA groups occurs under HIFU irradiation and the micellar disassembly originates from an increase in the LCST due to the ultrasound-induced conversion of hydrophobic comonomer units of THPMA onto hydrophilic methacrylic acid (MAA). This ultrasound-changeable-LCST approach is general and can be applied by exploring other ultrasound-labile moieties in the BCP design. By transducing an ultrasound-induced effect into a changing thermosensitivity of the micelle core-forming block, this study demonstrated a new amplification and control mechanism for SR-BCP micelles. The third project presented in this thesis dealt with a rational BCP design that had a specific purpose: allowing BCP micelles to be disrupted by two types of stimuli while using the minimum number of stimuli-reactive moieties in the BCP structure. The unveiling of such BCP structures provides insight into how to make BCP micelles sensitive to stimuli. To do this, we designed and synthesized a new amphiphilic ABC-type triblock copolymer, namely, poly(ethylene oxide)-disulfide-polystyrene- o-nitrobenzyl-poly(2-(dimethylamino)ethylmethacrylate) (PEO-S-S-PS-ONB-PDMAEMA), which features a redox-cleavable disulfide linkage between the PEO and PS blocks as well as a photocleavable ONB group as the junction of the PS and PDMAEMA blocks. We demonstrated that this design is a useful strategy to allow BCP micelles to respond to both a reducing agent like dithiothreitol (DTT) in solution and exposure to UV light while having the minimum number of stimuli-reactive moieties in the block copolymer structure (two units per chain). Our investigations found that the micelles of this triblock copolymer could be disrupted in different ways. When only one stimulus is applied, the removal of one type of hydrophilic polymer chains from the micelle corona, either PEO by redox-cleavage or PDMAEMA by photocleavage, results in a limited destabilization effect on the dispersion of the micelles. The agglomeration between a few micelles appears but the dispersion remains essentially stable. By contrast, under combined use of the two stimuli that cleaves both PEO and PDMAEMA, severe polymer aggregation occurs as a result of elimination of the polymer amphiphilicity. Moreover, by loading the hydrophobic Nile Red in the micelles, the fluorescence quenching of the dye by aqueous medium under the different uses of the two stimuli appears to correlate with the different extents of the micellar disruption. // 摘要 : 刺激响应嵌段共聚物（SR-BCPs）和它们的自组装体（例如胶束、囊泡和水凝胶）可以对环境的改变做出物理或者化学变化的响应。对于优良的SR-BCP，在通常情况下，环境中的微小变化都足以诱导无论是在聚合物构象或者结构或者性能上相对很大的变化。刺激-反应性聚合物通常被称为智能聚合物，它们在许多领域具有很大的应用潜力。在过去的二十年中，专业的研究和新产品的开发一直聚焦在利用SR-BCP自组装体作为载药体系（DDSs）。在许多情况下，刺激诱导BCP自组装体（药物载体）结构或者形貌的改变都可以导致加载药物的释放。通过选择适当的刺激和调节用于刺激方法的参数，可以实现加载药物在空间和时间上的可控释放。一般来说，通过具有特定类型的刺激-反应性结构部分，SR-BCP自组装体就具有了识别特定刺激并做出相应反应的能力。 尽管SR-BCPs已经取得了巨大的发展，但是使这些智能聚合物能够在现实生活中得到应用，一些根本性的问题仍然需要加以解决。其中的关键和挑战是增加对SR-BCPs控制的深度和复杂性，以及对刺激响应的敏感度。使SR-BCPs能够在适度的刺激作用下做出快速的反应是人们梦寐以求的。为此，对于合理地创造性地设计BCP结构以及发展可以放大刺激效应的刺激方法的基础研究是非常有必要的。在本论文中提出的研究工作属于这一重要课题。具体来说，我们研究了双重刺激响应BCP胶束。一方面，基于BCPs的超声温度双重敏感性，我们研究了一种放大机制。另一方面，我们开发设计了一种在聚合物结构中只含有最少数目刺激-反应单元的BCP结构，可以让胶束被光或者还原剂破坏。我们的研究对于如何解决SR-BCP胶束的敏感性和复杂可控性提出了新的见解和方法，从而有利于基础知识的进步。 本论文的核心是由三篇已经发表的研究工作组成。为了实现超声和温度双重敏感性，在第一个研究课题中，我们对于容易受超声影响的聚合物结构进行了研究。我们比较了由不同BCPs组成的胶束结构在高强度聚焦超声（HIFU）作用下的破坏情况以及伴随着的包覆疏水染料（尼罗红）的释放情况。实验结果显示，四种以聚环氧乙烷为亲水端，不同的聚甲基丙烯酸酯为疏水端的两嵌段聚合物胶束都可以被超声扰动。然而，形成胶束疏水内核的聚甲基丙烯酸酯的化学结构影响胶束破坏和染料释放的程度。特别是，PEO-b-PIBMA（聚（ 1-（异丁氧基）乙基甲基丙烯酸酯） ）和PEO-b-PTHPMA（聚（2-四氢吡喃基甲基丙烯酸酯） ）的疏水端具有不稳定的酯键侧基，因此在超声作用下更容易酯键水解。他们的胶束也更容易 被超声扰动，从而更快的释放尼罗红。相比之下，PEO-b-PMMA（聚甲基丙烯酸甲酯）的聚甲基丙烯酸酯链段比较稳定。因此相对于其他胶束，PEO-b-PMMA胶束在超声下更稳定，释放染料的速度也相对较慢。根据超声辐照前后胶束水溶液的红外光谱显示，PEO-b-PIBMA和PEO-b-PTHPMA在超声辐照下发生了水解反应，但是PEO-b-PMMA没有发生化学反应。在高频率HIFU辐照下，BCP的化学结构对胶束反应的影响展现了设计和发展应用超声-敏感BCP胶束的新视角。 在第一个研究课题的基础上，在第二个研究课题中，我们展示了一种可以放大HIFU在水溶液中对BCP胶束破坏效果的新方法。通过在形成胶束内核的温敏性聚合物中引入少量的超声不稳定共聚单体，由于超声诱导共聚体极性的变化从而增加温敏性聚合物的最低临界溶液温度（LCST）。这使得在没有改变溶液温度的情况下，BCP溶于水，并进一步导致BCP胶束的瓦解。为了证明这种新机制的可行性，我们合成并研究了二嵌段共聚物PEO-b-P(MEO2MA-co-THPMA) （MEO2MA 代表2-（2-甲氧基乙氧基）乙基甲基丙烯酸酯）。当T > LCST时，无规的热敏嵌段共聚物P(MEO2MA-co-THPMA)是疏水的。选择THPMA是因为在第一个研究课题里，相比于其他结构的单体，它对于HIFU的辐照更敏感，具有更大的反应活性。我们发现， 通过HIFU的辐照确实可以增加P(MEO2MA-co-THPMA)链段的LCST，导致BCP胶束在温度不变的情况下瓦解。13C NMR 提供了关于超声诱导THPMA基团水解和由于超声诱导使疏水的THPMA共聚单元转变成亲水的MAA从而使LCST增加进一步导致胶束瓦解的关键证据。这种超声改变LCST的方法具有普遍意义，可以被用来探索在BCP设计中其他的超声不稳定基团。通过把超声诱导效应转换成胶束内核的温敏性变化，这项研究展示了一种全新的SR-BCP胶束的放大和控制机制。 在这篇论文中所展示的第三个研究课题是设计一个具有特定目的的合理的BCP结构。即允许在使用最少的刺激响应官能团的情况下，BCP胶束可以在两种刺激下瓦解。这种BCP结构的展示可以使我们更深入的了解如何使BCP胶束对刺激敏感。为此，我们设计并合成了新的两亲性ABC型三嵌段共聚物，即聚（环氧乙烷） - 二硫化物 - 聚苯乙烯 - 邻 - 硝基苄基 - 聚（ 2 - （二甲基氨基）乙基甲基丙烯酸酯） (PEO-S-S-PS-ONB-PDMAEMA)。它在PEO和PS嵌段之间具有可还原裂解的二硫键，在PS和PDMAEMA嵌段之间具有可光裂解的ONB基团。我们证实，对于使具有最少数量的刺激-反应官能团（每条分子链上仅有两个）的BCP胶束可以同时在还原剂二硫苏糖醇 （DDT）水溶液中和紫外光照下发生响应，此设计是一种行之有效的策略。我们研究发现，这种三嵌段共聚物胶束可以以不同的方式被破坏。当只施加一种刺激时，无论是还原裂解PEO链段，或是光裂解PDMAEMA链段，都只有一种亲水链从胶束外壳被移走，这都只能导致胶束分散有限的不稳定。虽然一些胶束之间发生了团聚，但是分散体系总体上基本保持稳定。与之相对的，在两种刺激同时作用的情况下，PEO和PDMAEMA链段的同时断裂使聚合物的两亲性消失，从而导致聚合物严重的聚集。此外， 在两种刺激不同的施加情况下，通过在胶束中装载疏水尼罗红的方式，结果显示染料的荧光在水中的淬灭与胶束被破坏的不同程度有关。