奈米藥物傳輸系統除了增強療效及降低藥物副作用外，更著重在提升生物相容性與多功能性。使用天然的分子作為藥物載體，可減少免疫反應及肝臟代謝的負擔。另外，功能性藥物載體則可整合標靶(Target therapy)、磁控(Magnetic guidance)、刺激釋放及合併治療(熱療、化療及免疫療法等…)來增強療效。在此研究中，開發一種蛋白質奈米磁性殼核膠囊，其中，以血液中重要的成分血清白蛋白作為藥物載體的基材(本研究中使用牛血清蛋白(Bovine serum albumin (BSA))，增強載體的生物相容性。為了使得藥物載體達到奈米化，我們先以熱裂解法合成油相的奈米氧化鐵(Iron Oxide Nanoparticles (IOP))，並藉由BSA作為水相界面活性劑乳化製成，達到一步驟水/油/水(Water-in-oil-in-water)的奈米穩定結構，並在本結構中，可直接穩定包覆氧化鐵奈米粒子。由於包覆磁性粒子，因此可藉由高週波(High frequency magnetic filed, HFMF)驅動載體生熱，達到熱療的目的。另外，由於蛋白質結構易受酸鹼與熱影響，本研究中也發現，在不同環境下，載體會產生聚集現象(Aggregation transition)，期盼未來能夠有機會使用在自發性腫瘤標靶治療上。

Combination therapy is a very powerful approach to fight cancer disease that not only induce cancer cell death but also modulates the complex tumor microenvironment. Except for choice of multiple therapy combination, the more difficulty is how to take co-treatment to reach the synergistic therapeutic effects in a simple way.
In this study, we provide a new class of nano-hollow-capsules that can achieve magneto-thermal- and chemo- therapy in one system to kill cancerous cells effectively. The design is prepared by single-emulsion that assemble bovine serum albumin (BSA) and iron oxide nanoparticles (IOPs) into one BSA-based magnetic capsules (BSA@IOP capsule). Such hollow capsules with nanoscale enable carrying both hydrophobic and hydrophilic drugs spontaneously. The BSA@IOP capsule is anticipated accumulate in tumor directly through enhanced permeability and retention effect (EPR effect). Subsequently, IOPs of BSA@IOP capsule were actuated by high frequency magnetic field (HFMF), causing temperature rise of microenvironment and lead to bovine serum albumin (BSA) denature, which makes drug release, capsules collapse adhesion together. In this chemo-thermotherapy approach, thermotherapy is active in treating local cancer at the primary site and chemotherapy is effective in secondary treating.
These nano-hollow-capsules are bio-degradable and bio-eliminable after drug release had been triggered. These results demonstrate that the BSA@IOP capsule is an excellent new delivery platform for local, on-demand, magneto-responsive, pH-responsive combined chemotherapy/hyperthermia for tumor treatments and other biomedical applications.

中文摘要..........................................................1
Abstract.........................................................2
Table of Content.................................................3
Abbreviations....................................................6
Chapter 1 Introduction & literature review.......................7
1.1 Application of nanoparticles in medicine..................7
1.2 Revolution in drug delivery systems.......................7
1.3 Bio-mimetic drug carrier..................................8
1.4 Natural bio-nanoparticles as drug delivery vehicles.......9
1.5 Magnetic drug delivery system for cancer therapy.........10
1.6 Hollow structure nano-capsule............................11
Chapter 2 Materials and experimental methods....................13
2.1 Materials................................................13
2.2 Apparatus................................................14
2.3 Methods..................................................15
2.3.1 Synthesis of iron oxide particles (IOP)...................15
2.3.2 Evaluation of Hydrophilic-Lipophilic Balance (HLB) Value of Surfactants (Bovine Serum Albumin, BSA).........................16
2.3.3 Preparation of BSA@IOP capsule............................17
2.3.4 Characterization..........................................18
2.3.5 Magnetic thermal heating effect of nanocapsules...........19
2.4 In vitro study..............................................19
2.5 Cellular uptake of BSA@IOP capsules.........................20
2.6 Cell cytotoxicity and compatibility of BSA@IOP capsule......21
Chapter 3 Results and discussions...............................22
3.1 Iron oxide characterization..............................22
3.2 Hydrophilic-lipophilic balance value of bovine serum albumin.........................................................23
3.3 Temperature sensitivity..................................27
3.4 Cell uptake..............................................28
Chapter 4 Conclusions...........................................30
Reference.......................................................31

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