2015-08-012024-05-15https://scholars.lib.ntu.edu.tw/handle/123456789/665721摘要：奈米技術的發展對藥物釋放傳遞有著革命性的影響;奈米藥物系統(nanomedicine),正是納米 技術與醫藥技術整合下產生的新名詞,整合之下的研究工作也為各種棘手疾病疾的診斷和治療帶 來了前所未有的精準度和有效性。藉由藥物控制釋放的研究和應用的目標,提高藥物的療效、降 低和減少藥物的毒副作用、減少給藥次數等,進而減少病患的痛苦。藥物奈米載體 (nanocarrier) 技術是奈米藥物系統的重要發展方向之一,先進的藥物奈米載體已發展臻至可創造出多重組成的 藥物或藥物傳遞系統的時代,這些多功能載體的表面可以同時提供不同的表面化學和幾何形狀; 此外,新的製程技術,除了能夠精確控制載體的表面化學組成,大量生產的量化製程上也已經達 到上乘的水準。在另一方面,可供選擇掛載的藥物(或生物分子)也以多樣化的面貌呈現,包括抗 體,標靶型胜&#32957;分子,具標靶反應性的適合體(aptamer)和維生素,都整合應用在這些先進的多功 能載體之上,以多功能調節的思維來影響生物分佈和調節區域性的藥效濃度。奈米藥物系統的發 展至今仍非完美,面臨的挑戰有: 以多功能的姿態攜帶足夠量的不同藥物,必須有效地跨各種生 理障礙,精準地到達病灶的位置;還必須降低治療疾病同時所使用藥物的毒性;藥物的藥性必須 長時間持續有效;更重要的是,關鍵的多種功能必須在複雜的生物環境中各司其職,而不產生相 互的影響下發揮適性、適量的功能。 在此計畫中,我們將利用生物相容性極佳的聚對二甲苯(parylene)為基材,透過電噴霧技術 (electrified jetting)來創建新穎的多功能奈米藥物載體。這些精確設計的納米載體可針對所需藥物 以及所標定的癌細胞來客製化挑選所需使用的表面化學特性(歸功於我們先前在功能性聚對二甲 苯的豐碩研究成果)。多功能的設計,使得我們的奈米載體有分別獨立控制的表面化學特性可掛 載特定生物分子於固定的位相空間中,並提供多重藥物乘載亦或是標把分子與藥物分子的同時掛 載;這些多重功能以及對藥物分子、生物分子的自由選擇度,將使得在對抗癌細胞的治療上能針 對「多重藥效」以及對「癌細胞標定的精確性」同時發揮功能。此計畫所開發之多功能奈米藥物 載體,能同時滿足當前藥物遞送的主要挑戰:多種藥物治療或是癌細胞標定診斷的複雜、多功能 結合。這些先進的多功能載體將有助於提供未來更具多重藥效癌症療法,並且可以將標靶抗癌藥 物的遞送機制更自由更廣泛地的擴展及應用。本研究計畫將透過以下三個具體目標來實現對癌症 的標定與治療: 目標 1:針對癌細胞標定與治療為設計導向來合成以聚對二甲苯為基材之多功能奈米藥物載體 目標 2:多功能奈米藥物載體的生物相容性驗證 目標 3:評估此多功能奈米藥物載體的作為癌症標靶治療系統之功效 多功能奈米藥物載體以仿生工程為技術設計藍圖,成就多功能鍵結要藥物分子、生物分子於不 同之特異未向空間,於對抗癌細胞的治療上同時提供了精確的標定以及局部多重藥物遞送等功 能,此研究計畫的成果,將有有助於國內新型抗癌標靶藥物的發展。<br> Abstract: anotechnology is making a significant impact on drug delivery. There is a growing interest in integrating nanotechnology with medicine, creating so-called nanomedicine aiming for disease diagnosis and treatment with unprecedented precision and efficacy. In the past few years, resources allocated to the development of nanomedicine increased dramatically, highlighting the importance of this evolving field. In drug delivery, nanomedicine is a recently developed term to describe nanometer sized (1–1000 nm). The nanomedicine technology has recently evolved into an era of multi-component drug or drug delivery systems for disease treatment, providing access to multifunctional particles with different surface chemistry and geometry. Moreover, new fabrication methods have been formulated that give desirable control over not only surface chemical composition, but also the capacity to produce large quantities of monodisperse multifunctional particles, as well as a range of biological targeting moieties, including antibodies, targeting peptides, aptamers and vitamins, have been conjugated to particles to modulate their biodistribution and to increase local therapeutic concentrations. The existing challenge of nanomedicine delivery for these multifunctional particles is to design vehicles that can carry sufficient drugs, efficiently cross various physiological barriers to reach disease sites, and cure diseases in a less toxic and sustained manner, and more importantly, a key promise of these more complicated nanoparticle systems to demonstrate the ability to perform multiple functions in biological systems. We herein using a novel nanotechnology approach based on functionalized poly-p-xylylenes, we will now design and characterize a unique set of multiphasic nanocarriers for targeted chemotherapy. We hypothesize that these precisely engineered nanocarriers will enable specific targeting to receptors over-expressed on carcinomas. When designing bi- or multiphasic nanocarriers, one has independent control over the surface chemistry and the coverage of immobilized biomolecules in each compartment. This freedom of design enables us to create nanoparticles that simultaneously address the major challenges of modern drug delivery: They can be designed to exhibit tumor-specific targeting, and complex binding kinetics of multiple drugs or diagnostic probes. Drug or sensor molecules are immobilized through orthogonal bioconjugations to properly selected chemical motifs from the library of functionalized poly-p-xylylenes, featuring a designable and optimized nanocarrier platform for a user-specific application. The advanced nanocarriers will be instrumental not only to future carcinoma therapies, but may comprise a substantial shift in the paradigm of targeted drug delivery affecting a wide range of cancers. Multicompartmental nanocarriers will accomplish simple and complex release profiles of a single drug or multiple drugs. This research proposal will test our hypothesis by designing, fabricating, and vigorously characterizing novel parylene-based, multivalency nanocarriers for cancer therapy and diagnosis through the following three specific aims: Aim 1: Design and synthesis of parylene-based, multivalency nanocarriers for cell targeted therapy and diagnostics Aim 2: Assessment of biocompatibility of multivalency nanocarriers Aim 3: Evaluation of efficacy of multivalency nanocarriers as cancer-targeting therapeutic system The resulting biomimetic materials will be designed to specifically bind to carcinoma cells and provide localized drug delivery, and if successful, will have the potential to induce a shift in paradigm with respect to drug targeting.米藥物系統聚對二甲苯電噴霧技術仿生工程技術標靶抗癌藥物NanomedicineFunctionalized paryleneElectrified jettingBiomimetic engineeringTargeted cancer therapy