2015-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/651059摘要：癌症是屬於異質性疾病，常發生於人類各種的組織中，但這些癌症有不同的基因背景和病理成因。許多癌症病患在經過抗癌治療後，其腫瘤仍可能再復發，其原因就是產生多重藥物抗藥性。近年來奈米科技提供了有效的方法來偵測及治療早期癌症，因此分子影像和標靶治療在奈米醫藥占有重要角色。儘管奈米材料擁有優良的物化特性，但要發展這類藥物在臨床上所使用，細胞毒性仍舊是一個重大的課題。設計一個生物相容性好，並能有效在體內控制藥物釋放的奈米粒子，第一步驟就是需要做好奈米結構的表面修飾，基於這個原理，脂質及聚合物的材質所製備的奈米粒子，具有藥物發展之優勢。在過去幾年，我們發展出以膽固醇當做基底含的脂質奈米粒子，這些粒子在血清中，具有良好生物相容性和穩定度，可依此發展為多功能奈米載體，藉由包覆奈米鑽石、氧化鐵奈米粒子、量子點、矽奈米粒子，我們進一步發現這些殼核形式的奈米結構，不只具備了螢光及磁振造影的特性，也可具有非線性的光學特性。再者，利用磁性輔助作為標靶藥物遞送方式，使得包覆親脂性的抗癌藥物，能有效達到治療之組織。在本研究中，我們合成正電荷膽固醇所包覆的氧化鐵奈米粒子，用於有效遞送親脂藥物，如紫杉醇、依托泊苷及薑黃素等。葉酸等配體修飾之脂質，加上PEG-膽固醇，就可以快速形成具標靶作用之奈米載體。我們的目標就是設計出多功能性的奈米粒子， 以一次同時能有效傳遞多種藥物，這種策略提供了解決複合性抗藥性問題的契機。利用結合上玻尿酸或抗CD44 抗體的奈米粒子，有機會能根除較不活動的癌症幹細胞。不管是直接鍵結，或者利用靜電力方式，快速來連結配體、抗體、抗體的小片段在以膽固醇為基底的奈米載體上，運用這些策略來達到有效傳遞多重藥物的能力，提供了一個多樣化的技術平台，讓我們可得以發展更有效的癌症的奈米醫藥治療。<br> Abstract: Cancers are heterogeneous diseases which happen in various human tissues. Theirgenetic background and pathogenesis are different among cancers. After undergoingconventional anticancer therapies, cancer patients may suffer from the risk tumorrecurrence, which are more often resulted from multiple drug resistant (MDR)phenotypes. Recent advances in nanotechnology have provided effective strategies inearly cancer detection and effective treatment. Therefore, molecular imaging andtargeted therapy is the emerging field in nanomedicine. Despite of good physical andchemical properties, the cytotoxicity of these nanomaterials is the main issue forfurther development in clinical uses. Surface modification of nanostructures is thefirst step to design such biocompatible nanoparticles with controlled ability in vivo.For these reason, lipidic and polymeric nanoparticles have their advantages in medicalapplication. For the past few years, we have developed a simple yet versatileformulation of nanosized particles using all cholesterol-based lipid ingredients. Theyare biocompatible and behave the good stability in the serum, and could be furtherdeveloped for multifunctional and multimodal nanocarriers. By encapsulatingnanodiamonds, iron oxide nanoparticles, quantum dots, silica nanoparticles. Wefurther discovered these core-shell nanostructures not only have the fluorescent orresonance properties, but also have the strongest signals in the non-linear opticalimaging, microscopic analysis, MRI imaging, as well as for potential use inmagnet-assisted targeted delivery. With the encapsulation of hydrophobic anticancerdrugs and adjuvants, the co-delivery system could be achieved. In this study, wesynthesized the cationic cholesterol-based-Fe3O4 nanocarriers (GCC-Fe3O4) anddeveloped these nanocarriers for efficient drug delivery for Paclitaxol, Etoposide andcurcumin. By using the newly synthesized ligand-linked PEG-lipids, e.g.folate-PEG-cholesterol, the targeting nanocarriers could be easily formed. We aimedto design multifunctional nanoparticles for effective delivery of multiple drugs at onetime. This strategy provide us the opportunity to overcome the multiple drugresistance issues. The targeted forms of nanocarriers using hyalunonan or antibodiesagainst CD44 could contribute in eradicating the quiescent cancer stem-like cells. arealso focused in our project. The formulation involved direct conjugation orelectrostatic association of ligands, antibodies and antibody fragments to thecholesterol-based nanocarriers. Using these strategies for effective drug delivery withimaging capabilities, we will have a versatile platform that allows us to develop theeffective nanomedicines for human therapeutics.