癌症的多重抗藥性機轉一直是化學療法治療的主要障礙之一，其導致腫瘤的不斷復發及耐藥腫瘤的擴散。為了抑制多重抗藥性，過去幾年已開發出多種化學療劑。然而，由於這些藥物的多種嚴重不良反應，皆於臨床試驗中失敗。因此，近幾年來，發展出能夠減少化學療法的副作用且同時允許標靶藥物積存，並在目標部位發揮療效的多重療法，一直是研究人員的主要目標。本研究著重於對抗MDR的關鍵策略，主要將光敏感性金屬奈米粒子應用於藥物釋放，同時靶向傳遞不同的治療化合物。我們設計了三種不同的策略，能成功地減少異種移植MCF-7/ADR模型中的MDR腫瘤。首項實驗，我們利用殼聚醣（CTS），聚乙烯醇（PVA）和分支型聚乙烯亞胺（bPEI）的三聚物塗層，經靜電相互作用產生疏水性氧化鐵奈米顆粒，裝載孟加拉玫紅（RB）。此研究中，以bPEI 為一種光誘導開關，在bPEI的奈米平台中，以光氧化作用控制宿主分子（例如：RB）或客體分子（例如：紫杉醇）的釋放。在奈米平台中，親水性孟加拉玫紅(RB) 的包封，能避免了藥物的過早滲漏，並將其保留在耐藥性癌細胞中，自主地控制釋放光敏劑。同時，增強了其在細胞內藥物的分佈，以有效進行MDR癌症治療。 第二項研究中，揭示了適體於MDR癌症治療中，其靶向細胞特異性以及在細胞內遞送的重要性。透過使用熱和酸不穩定的亞甲基鍵，將化學治療藥物阿黴素（DOX）準確地綴合在適體AS1411的脫氧鳥苷殘基上，藉以產生藥物適體加合物（dsDDA）。 AuNS具有在近紅外線（NIR）區域的強吸收能力，並與dsDDA層組裝在一起。在近紅外線NIR照射下，dsDDA–AuNS能夠依需求釋放治療劑。此外，適體AS1411在藥物-細胞核相互作用中發揮了積極作用，增強了藥物在耐藥性乳腺癌細胞和腫瘤血管內皮細胞核中的積存。透過了在單一治療性的奈米藥物中進行之光熱化學療法，與單一療法相比，即使在等效藥物劑量少54倍的情況下，它也可以獲得顯著的抗腫瘤功效，進而減少心肌毒副作用。在最後一個研究中，我們特以裝飾鉑的金奈米星（Pt/Au-NS）作為貴金屬前藥。 Pt-AuNS是一種有效的光熱傳感器，可以強烈吸收近紅外線光 (NIR)。 經近紅外線光(NIR)照射後，誘發了有毒物質Pt和Au的釋放，進而對癌細胞作選擇性毒殺。作用機制，歸功於活性氧物質的產生，細胞內GSH的消耗和GPX4的失活，進而導致脂質代謝失調和脂質過氧化物的積累。這些發現，為開發金屬型藥物（例如Pt和Au）奠定了基礎，以誘導鐵死亡為潛在手段，有效治療耐藥性腫瘤。綜合上述，經由體內MCF-7/MDR異種移植腫瘤之臨床前研究結果表示，與單一治療相較之下，光響應性奈米載體顯著增強了對MDR腫瘤的光動力、化學、光熱、或受鐵療法的療效；同時減少傳統化學療法的生理副作用。這同時也暗示了，使用能夠按需求釋放和遞送藥物的金屬型奈米載體，可以在癌症治療中，有效加強藥物散布的實質效果。即便仍需進一步探討，這些臨床前研究已強烈表示，奈米藥物的形成為有改善MDR治療的潛在應用。

The incidence of multidrug resistance (MDR) is one of the main obstacles in the successful chemotherapeutic treatment of cancer, resulting in tumor recurrence and the expansion of drug-resistant tumors. To circumvent MDR, diverse chemotherapy agents have been developed in the last years; unfortunately, these have failed in clinical trials due to severe adverse effects. Hence, the research and development of multi-therapeutics, which can reduce the chemotherapy side effects, while also allowing targeted drug accumulation, and ensure sustained drug release at the target site, have been a primary goal of researchers over the past years. In this thesis, we focus on some pivotal strategies to combat MDR, by applying light stimuli-sensitive metal-based nanoparticles for drug release, and targeted co-delivery of different therapeutic compounds. We designed three different strategies to diminish MDR tumors successfully in xenograft MCF-7/ADR models. Firstly, we focused on exploiting hydrophobic iron oxide nanoparticles with a tripolymer coating of chitosan (CTS), poly(vinyl alcohol) (PVA), and branched polyethyleneimine (bPEI) for Rose Bengal (RB) loading, through electrostatic interaction. We identify bPEI as a photoinducible switch, the photooxidation process-induced controlled release of the host molecules (i.e., RB) or guest molecules (i.e., paclitaxel) from the bPEI-based nanoplatform. The encapsulation of the hydrophilic RB in the nanoplatform avoided premature drug efflux and enhanced drug retention in drug-resistance cancer cells, allowing the spatiotemporally controlled release of the photosensitizer; at the same time, enhanced its intracellular drug distribution for effective MDR cancer therapy. Our second study reveals the importance of aptamers to direct cell-specific targeting and intracellular delivery in MDR cancer therapy. The chemotherapeutic drug, doxorubicin (DOX), was precisely conjugated on deoxyguanosine residues of the AS1411 aptamer by employing heat and acid-labile methylene linkages to yield a drug-aptamer adduct (dsDDA). AuNS, with its strong absorption in the near-infrared (NIR) region, was assembled with a layer of dsDDA. Upon NIR irradiation, dsDDA–AuNS allowed the on-demand release of therapeutics. Moreover, AS1411 played an active role in drug cargo–nucleus interactions, enhancing drug accumulation in the nuclei of drug-resistant breast cancer cells, and tumor vascular endothelial cells. By delivering concerted photothermal-chemotherapy in a single therapeutic nano-agent, it allowed to obtain remarkable antitumor efficacy than individual treatment, even at a 54-fold less equivalent drug dose, thus preventing cardiomyopathy in vivo. Finally, in our last study, we characterized Pt-decorated gold nanostars (Pt/Au-NS) as noble metal prodrugs. Pt-AuNS are an efficient photothermal transducer that can strongly absorb NIR light. Upon NIR irradiation, triggered the release of toxic Pt and Au species to induce selective cytotoxic effects to cancer tumor cells. The mechanism of action is attributed to the ROS generation, intracellular GSH depletion, and GPX4 inactivation, resulting in dysregulated lipid metabolism and the accumulation of lipid ROS that executes ferroptosis. These findings lay the groundwork for exploiting metal-based medication (e.g., Pt and Au) as a potential means of inducing ferroptosis to treat drug-resistant cancer effectively. As mentioned above, the results obtained by in vivo MCF-7/MDR xenograft pre-clinical studies proposed that the nanoengineered light-switchable carriers significantly augment their photodynamic-, chemo-, photothermal-, or ferroptotic- therapy efficacy against MDR tumors as compared with individual treatments while diminishing the physiological adverse effects of traditional chemotherapy. It also implied that the substantial effects of enhanced drug distribution for efficient cancer therapy were achieved using metal-based nanocarriers capable of on-demand drug release and delivery. While there are challenges to be battled, these preclinical studies strongly suggest that nanomedicine formations have potential applications for improving the treatment of MDR.

Acknowledgment 2
Table of Figures 7
Table of Tables 10
摘要 11
Abstract 13
Chapter 1. Introduction 15
1.1 Multidrug resistance (MDR) in cancer 15
1.1.1 Drug influx and efflux 16
1.1.2 Inactivation of chemotherapeutic agents 17
1.1.3 Alterations in target molecules 18
1.1.4 Enhanced DNA repair 18
1.1.5 Growth factor signaling 18
1.1.6 Cell death inhibition 19
1.1.7 NF-κB activation pathway 20
1.1.8 Cancer cell heterogeneity 21
1.2 Status quo of monotherapy in MDR cancer 22
1.2.1 Inhibit or evade P-gp in MDR cancer treatment 22
1.2.2 Chemotherapy based on ferroptotic mechanism 28
1.2.3 Photodynamic therapy (PDT) 31
1.2.4 Photothermal therapy (PTT) 33
1.2.5 Pre-clinical and clinical challenges in monotherapy 36
1.3 Multimodal combination therapy for MDR cancer treatment 37
1.3.1 PDT-enhanced chemotherapy. 39
1.3.2 PTT enhanced chemotherapy 43
1.4 Scope of this study 46
Chapter 2. Materials and Experimental Methods 51
2.2 Chemicals 51
2.3. Buffers and cell medium 55
2..3.1. Deionized water (18.2 MΩ·cm). 55
2.3.2. Dulbecco’s phosphate-buffered saline (DPBS) buffer. 55
2.3.3. Phosphate-buffered saline buffer. 55
2.3.4. Washing Buffer. 55
2.3.5. Dulbecco’s Modified Eagle Medium 55
2.3.6. Modified Eagle Medium 55
2.4. Laboratory apparatus and equipment 55
2.5 Experimental methods 56
2.5.1 RB-Loaded MNCs system 56
2.5.2. dsDDA-AuNS system 63
2.5.3. Pt-AuNS system 72
Chapter 3. A Photosensitized Oxidation-Responsive Iron-Based Nanoplatform for Controlled Drug Release and Photodynamic Cancer Therapy 78
Abstract 79
3.1 Introduction to the study 81
3.2 Results and discussion 82
3.2.1 Preparation and characterization of MNCs 82
3.2.2 MNCs provides high loading efficiency of photosensitizers 86
3.3.3 On-demand ROS trigger release from bPEI 90
3.3.4 RB-MNCs can increase intracellular ROS upon laser irradiation 96
3.3.5 Intracellular ROS generations damage the endolysosome and induce cancer cell death. 100
3.2.6 RB:[ MNC's (c)] are efficient against multidrug-resistant tumors 105
Conclusions 111
Chapter 4. Anticancer Therapy Against Drug-Resistant Tumors via Simultaneous Targeting of Tumor Vasculature and Cancer Cells using Aptamer-Conjugated Gold Nanostars with Near-Infrared Light-Cleavable Drug Adducts 113
4.1 Abstract 114
4.2 Introduction to the study 116
4.3 Results and discussion 120
4.3.1 Synthesis and characterization of an aptamer-DOX adduct (dsDDA) 120
4.3.2 AuNS allows high functionality of dsDDA loading and enhanced colloidal stability 125
4.3.3 Controlled drug delivery is archived remotely in dsDDA-AuNS due to their vulnerability to high temperature and acidic pH. 128
4.3.4 dsDDA-AuNS have excellent specificity toward nucleolin-overexpressed cancer and tumor-associated endothelial cells over non-malignant cells. 133
4.3.5 A nuclear localization capability is essential for dsDDA-AuNS to combat drug resistance in cancer cells. 139
4.3.6 In a xenograft MDR model, impressive drug accumulation is accomplished at the tumor site using dsDDA-AuNS. 156
4.3.7 On-demand drug release and in vivo dsDDA-AuNS action against MDR tumor can be activated by NIR photothermally. 158
4.3.8 dsDDA-AuNS increases tumor eradication through a combination therapeutic effect on drug-resistant cancer tumor and endothelial tumor-associated cells. 161
4.4 Conclusion 166
Chapter 5. Near Infrared-Responsive Platinum-Gold Nanostars for Ferroptosis Therapy in Combating Cancer Drug Resistance 168
5.1 Abstract 168
5.2 Introduction to the study 171
5.3 Results and discussion 173
5.3.1 Synthesis and characterization of Pt-AuNS 173
5.3.2 Remote release of active metal species from Pt-AuNS using NIR irradiation 178
5.3.3 Induction of cancer cell death through ferroptosis with irradiated Pt-AuNS 181
5.3.4 Synergetic effects of Au (III) and Pt (II) on cell damage through ferroptosis 189
5.3.5 Roles of irradiated Pt-AuNS–mediated ferroptosis in GSH depletion and GPX4 inactivation 193
5.3.7 Pt-AuNS–induced selective ferroptotic cell death in drug-sensitive and drug-resistant breast cancer cells 194
5.3.8 NIR photothermal performance of Pt-AuNS in the MDR xenograft model 196
5.3.9 Inhibition of tumor growth with irradiated Pt-AuNS through combined PTT and ferroptosis therapy 200
5.4 Conclusion 204
Chapter 6. Conclusions and Further Remarks 206
References 209

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