2013-01-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/659120摘要：近年來新的藥物傳遞和基因治療方式對一些已存在的錯綜複雜疾病，打開一個新的遠景。例如遺傳性疾病如裘馨氏肌肉病變或是囊性纖維變性、癌症、血管或代謝方面等疾病。除了對引起，調控或治療疾病之特定基因的研究方面有相當大的進展外。為了能安全且更有效治療疾病，新治療的方向著重在能安全且有效地傳遞這些治療用基因。目前已有幾種治療策略被使用來將藥物或基因傳遞進細胞內。例如利用病毒將基因帶入細胞內，而非病毒方式則是利用合成的載體，或是利用外力來加強物質的進到細胞內的量。因為利用病毒會造成細胞產生病變、造成細胞毒性等副作用，或是產生一些不可預期的免疫反應等。因此目前認為非病毒式的方法是比較安全的。目前普遍使用之非病毒式方法 (電轉，微注射或是基因槍等)在使用上會有一些限制，然而利用超音波的方式若能在基因轉殖效率及細胞生存上取得一個平衡，則較沒有使用上的問題。超音波讓物質進入細胞內的現象稱為超音波導入（sonoporation），這是利用空泡作用（cavitation）來讓細胞膜產生暫時性的通透變化，以讓物質進入到細胞內。超音波具有相當多的特點，例如他是非侵入式的，能讓病人有較高的耐受性(在活體應用方面)，經濟效益高，並且可以在體內達到專一位置的精確聚焦等特性，因此可作為一個理想的傳遞系統。然而，當其應用在活體實驗時也產生一些技術上的問題，其中最重要的是低轉殖效率。而造成這些問題的原因，主要是由於對超音波導入的基本機制目前尚未真正很明瞭。因此，若是能對機制更加了解，將可提供科學上和產業應用上有更進一步的突破。本計畫SonInCaRe 的主要目標是想藉由橫向整合建立一個包含台灣與法國兩方的團隊，由基礎物理研究、數學模擬、細胞實驗開始，利用超音波導入可穩定再現及受到控制的觀點，去設計、執行及驗証在一定空間及程度上受到控制的超音波導入方法，最後用活體實驗來驗證我麼調控空泡作用加強基因轉殖的成果。<br> Abstract: Drug delivery and gene therapy have recently opened a potentially newperspective for managing an array of complicated diseases that may havesubstantial societal dimensions. Among the possible applications, theadministration of a therapeutic gene or drug can help in treating pathologieslike monogenic hereditary diseases (mucoviscidose or Duchenne myopathy),cancers, vascular and metabolic diseases. In addition to considerable advancesin the identification of the specific genes involved in causing, regulating andcuring diseases, new therapeutic modalities have to be found to efficientlydeliver these genes in order to treat diseases safely and efficiently. Severalstrategies have been designed for drug or gene delivery into cells. Viralmethods consist in using virus to transfer genes into the cells, while nonviralmethods rest upon the use of either synthetic vectors to penetrate the cells orexternal energetic source to enhance molecule uptake. Because of thelimitations of viral methods like cytopathy, cytotoxicity and an unpredictableimmune response, nonviral methods are considered to be safer thanviral-mediated molecule for a therapeutic use. Common nonviral methods(electroporation, microinjection or gene gun) present limitations thatultrasound could remove at the condition to obtain a better balance betweentransfection efficiency and cell viability. The phenomenon of ultrasoundenhancement of molecule uptake, known as sonoporation, is based on thetemporarily increase of cell membrane permeability and the poration of cellmembrane, allowing molecules transfer. Ultrasound thus reveals manyattributes of an ideal transfer system, as it is non-invasive, well-tolerated bythe patients (for in-vivo applications), cost-effective and can achievesite-specific transfer of ultrasound energy within the body as ultrasound can befocused with a millimeter precision. Nevertheless, the transfection efficienciesof sonoporation are lower than those of other methods, and many technicalproblems arise when they are applied in-vivo. These limitations are generallythought to be due to the lack of fundamental understanding of the mechanismsinvolved in sonoporation. Thus a better knowledge of sonoporationmechanisms would provide a significant breakthrough with scientific andindustrial applications.The aim of our project SonInCaRe is to set up a transverse field group(biologists, physicists, in-vivo clinical applications specialists) to design,implement and validate a spatially- and level-controlled sonoporationsystem applied to the in-vitro and in-vivo transfection of cells, with theperspectives of a reproducible and under control sonoporation.From this description, the fundamental mechanisms underlyingsonoporation will be studied through different approaches (numerical,theoretical and experimental). Different sonoporation devices will beimplemented for in-vitro and in-vivo applications on various animal tumormodels in collaboration with Taiwanese teams. Particularly, our partnershipwith TransDerma Systems will result in an industrial application of a subcutaneous sonoporation device.超音波導入空泡作用基因轉殖超音波Drug DeliverySonoporationCell MembraneTransfectionUltrasound,Cavitation