本研究主要為開發具備標靶性的光應答奈米傳輸系統應用於癌症治療。本研究中分別製備了具有光應答效應的有機奈米傳輸系統與無機奈米傳輸系統，並搭配光動力治療(photodynamic therapy, PDT)、光熱治療(photothermal therapy, PTT)及氣體治療(O2 / NO gas therapy)等策略，於兩種不同的腫瘤模型中進行研究。
由於外部光源的照射屬於非侵入式的治療策略，光應答奈米傳輸系統應用於癌症治療具備安全、療效好、效率高等優勢，光動力與光熱合併治療是癌症治療中常見的策略，然而腫瘤內的缺氧區與抗藥性使腫瘤無法根除仍是需要被克服的難題。為了克服此困境，本研究利用酯質分子二棕櫚酰磷脂酰膽鹼 (DPPC)、膽固醇 (Cholesterol)及具有酸鹼應答功能的N-Acetyl-Histidine modified D-α-tocopheryl poly(ethylene glycol) succinate (NAcHis-TPGS)作為材料並包覆能夠攜帶氧氣的Perfluorooctyl bromide (PFOB)液滴且搭載光熱藥物IR-780及光動力藥物mTHPC兩種藥物，製備出高分子脂質奈米粒子(PFOB@IMHNPs)。
由於PFOB@IMHNPs在腫瘤區域的酸性環境下，會產生表面電性轉變，促使此奈米粒子能更有效且準確地將光熱藥物IR-780及光動力藥物mTHPC運送至癌細胞內。而此奈米粒子對於小鼠前列腺癌細胞TRAMP-C1的毒性來自於紅外線照射IR-780藥物所引的光熱效應及紅外線照射mTHPC藥物，與PFOB所攜帶的氧氣作用後所造成的光動力效應。在小鼠體外及體內的影像中可以看到此奈米粒子在腫瘤處確實有較好的累積表現及光熱效果，且能有效地抑制腫瘤生長。另外，於免疫組織化學染色的影像中，呈現在腫瘤區域有更多的氧氣浸潤且避免了缺氧區域的產生。綜上所述，PFOB@IMHNPs為一具備標靶及功能性奈米光熱/光動力治療傳輸系統於癌症上之應用相當具有潛力。
於生理環境下的低溶解度、非特定位置的生物分布與高疏水性造成低擴散速率是一般化療藥物應用於癌症治療上無法有效抑制腫瘤生長的影響因素，而無機材料為主體的奈米粒子，因其可調控的光學性質、粒徑大小，以及水相中提高抗癌藥物的穩定性及分散性可克服此上述之困境，在癌症治療中搭配其他治療手段進行複合式的治療具有相當大的發展潛力。本研究中開發了搭載N, N′-Di-sec-butyl-N, N′-dinitroso-1,4-phenylenediamine (BNN6)藥物且可經由第二生物窗口紅外光(1000-1350 nm)激發的金複合量子點星狀奈米粒子(AuS@QDBNPEG NPs)，在1064 nm紅外光雷射的照射下，此能量將經由表面電漿共振效應使BNN6分解產生NO分子並使金奈米粒子產生高熱對小鼠乳癌細胞4T1產生細胞毒性。另外，此星狀金奈米粒子具備光熱及光聲成像的特性，便於診斷較深層的腫瘤。綜上所述，此具有診斷及治療功能且可經由第二生物窗口紅外光激發的金複合量子點星狀奈米粒子(AuS@QDBNPEG NPs)於癌症治療的臨床應用上具有潛力。

The development of a light sensitive combinatorial, targeted drug delivery system for cancer therapy is the main focus of this dissertation. Two different cancer models were explored using an external light stimulus-based nanoparticle therapeutic system, including organic and inorganic nanosystems, which exploits photodynamic (PD), photothermal (PT), and gas therapy techniques.
The light sensitive nanoparticles exhibit a safe, enhanced efficacy and effectiveness against cancer therapy by utilizing external stimuli based non-invasive therapeutic techniques. Combining photothermal and photodynamic therapy (PTT/PDT) has been proposed as a popular curative strategy for cancer progression. Drug resistance in solid tumors with hypoxic tumor areas is still a problem for efficient tumor elimination. To overcome this problem, DPPC (Dipalmitoyl phosphatidylcholine), cholesterol, and charge-switchable moiety N-acetyl histidine modified D--tocopheryl polyethylene glycol succinate (NAcHis-TPGS) molecules were assembled to form a lipid/polymer-based nanoparticle (organic nanoparticles). Perfluorooctyl bromide (PFOB), mTHPC (PDT agent), and IR780 (PTT agent) were all encased inside organic nanoparticles (PFOB@IMHNPs) at the same time. The NPs with switchable surface charges were capable of selectively co-delivering two NIR dyes, IR-780 for photothermal therapy and mTHPC for photodynamic therapy, in response to tumor extracellular acidity (pHe). Furthermore, the pH-responsive charge switch ability trait resulted in increased cellular uptake, indicating that PFOB@IMHNPs have a strong cellular target ability. The NIR-triggered hyperthermia and subsequent release of oxygen from PFOB, used for PDT alongside mTHPC, was used to induce cytotoxicity of PFOB@IMHNPs against prostate cancer cells (TRAMP-C1). Ex vivo and in vivo imaging after PFOB@IMHNPs injection revealed significant drug accumulation in tumor interstitium and an effective hyperthermia effect on tumor ablation. As a result, tumor growth inhibition in vivo showed that the PTT/PDT combination therapy can effectively reduce tumor growth profile. The immunohistochemical analysis of tumor sections revealed that, increased oxygen molecule penetration across the hypoxic zone of the tumor and prevention of hypoxia inside the tumor. The findings showed that PFOB@IMHNPs can be used as a nanoplatform for PTT/PDT combination tumor therapy using a dual-stimulus activated method.

By utilizing the PTT, PDT effect, the attractive optical and size tunability property of inorganic nanoparticles exhibited a large therapeutic efficacy and diagnosis capability in cancer therapy. Chemotherapy's cytotoxic efficacy is limited in cancer therapy due to poor drug solubility, non-specific biodistribution, and low diffusion rate. Combinatorial treatment techniques based on metallic nanosystems could circumvent these limitations. As a result, the appealing increased diffusivity nature of gas therapy, when combined with photothermal therapy (PTT), has shown a possible anti-cancer impact. By encapsulating a nitric oxide (NO) donor (N, N′-Di-sec-butyl-N, N′-dinitroso-1,4-phenylenediamine, (BNN6)) inside the quantum dot, unique near infrared-II sensitive plasmon-exciton gold nano star-quantum dot hybrid nanoparticles (AuS@QDBNPEG NPs) with high drug loading content are created (30 wt percent). AuS@QDBNPEG NPs produce a plasmon resonance energy transfer mediated NO generation and synergistic PTT effects in response to 1064 nm laser irradiation, resulting in robust killing of 4T1 (breast) cancer cells in vitro and in vivo. It also reduces the cancerous cell‘s antioxidant capacity by depleting cellular glutathione via the NO mediated oxidation process. The plasmon-exciton hybrid system's star-shaped gold core should improve photothermal/photoacoustic imaging, resulting in a novel paradigm of diagnostics and an effective gaseous-photothermal combinatorial therapy method for deep-seated cancers. The innovative multifunctional on-demand stimuli-responsive plasmon-exciton nano theranostics hybrid device activated in a second biological window is very attractive for clinical use.

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