70年代前，骨肉瘤治療主要仰賴手術切除與化療，但預後不佳且部位在四肢的患者往往都需截肢。自1976年發明在術前施行新佐劑化療(neoadjuvant chemotherapy)後，不僅總體預後大幅改善，且患者肢體大都得以保留。但仍有三到四成原本無癌轉移的患者後續發生轉移而導致存活率降低。即便在積極手術與化療下，全期(all SEER stages)綜合五年存活率仍僅約六成，因而亟需開創性新療法的介入。骨肉瘤的局部增生擴展乃至遠端轉移都會造成種種併發症，尤其是腫瘤導致的神經壓迫，會嚴重降低病人的生活功能與品質。故骨肉瘤的原發性疾病本身與次發性的壓迫性神經病變都是當今重要的臨床課題，本研究探討兩種奈米材料的治療潛力。針對前者我們使用鐵核金殼的奈米粒子，在研究中我們發現其對於骨肉瘤細胞相對於正常組織的選擇性毒殺能力，且與化療藥物合併使用具有加成效果，我們更深入探討了這種選擇性毒殺的分子機轉，發現與溶脢體酸化、粒線體膜電位喪失、自由基與氧化壓力累積、細胞凋亡等相關。針對後者，我們則探討在壓迫性神經病變中，不同濃度與分子量的透明質酸形成之骨架對於神經再生的影響。我們發現高分子量的透明質酸對於神經再生與功能復元的助益高過低分子量的透明質酸，且即便是低分子量的透明質酸，也具有促進神經修復再生的優勢。奈米粒子與透明質酸在許多研究中因其高度的化學可修飾性都被用於攜帶藥物之載體。而本研究則發現這些奈米材料顯著的內源性藥理作用及相關分子機制，相信針對癌細胞具有選擇性的奈米材料結合再生醫學的聯合開發，必能提供未來癌症患者在治療與術後重建更加完整的臨床解決方案。

Surgical resection combined with adjuvant chemotherapy was the major treatment of choice for osteosarcoma in the 1970s. The general prognosis was poor then, and amputation was required for most patients with limb osteosarcoma. The neoadjuvant chemotherapy introduced in 1976 to perform chemotherapy before surgical resection has greatly improved the prognosis and limb preservation. However, there were still 30~40% non-metastatic patients developed distant metastasis subsequently and compromised the overall survival. The 5-year survival rate of osteosarcoma of all SEER (Surveillance, Epidemiology, and End Results) stages combined was only around 60%, signifying the unmet needs of developing novel effective therapeutics. Complications of osteosarcoma arise from local tumor growth and distant metastasis where tumor-induced compression neuropathy is a highly disabling clinical issue that greatly impairs the function and quality of life of the patient. Treating osteosarcoma per se together with effective prevention or management of tumor-induced compression neuropathy thus becomes an important clinical challenge. In this study, we investigated the therapeutic potential of nano-scale engineering for both anti-cancer therapy and neural regeneration. We synthesized a zerovalent iron-core gold-shell nanoparticle (ZVI@Au) and discovered its selective cytotoxicity to osteosarcoma cells in comparison to non-malignant mesenchymal cells. The ZVI@Au also presented synergistic efficacy when combined with traditional chemotherapeutic agents for osteosarcoma treatment in vitro. The molecular mechanism of the selective cytotoxicity was further explored and involved lysosomal acidification, mitochondrial membrane potential loss, accumulation of intracellular free radical and oxidative stress, as well as induction of programmed cell death in cancer cells. We also investigated hyaluronan (HA) of different concentrations and molecular weights and compared their efficacy in vivo. We found that higher molecular-weight (MW) HA facilitated neural regeneration and restored neurobehavioral functions superior to lower MW HA. In addition, even the lower MW HA presented significant benefits compared to the control group. In most publications, the roles of nanomaterials have been mainly focused on serving as an effective carrier of therapeutics for both gold- or iron- based metallic nanoparticles (NP) and HA owing to their high biocompatibility and biochemical modifiability. The significance of this thesis was the change in the concept of using NP, which serves as an active pharmaceutical entity while preserving their nano-scale advantages, e.g., targeting tumor lesion by enhanced permeation and retention (EPR) effect. We believe that integration of anti-cancer nano-therapy and effective nano-scale regenerative medicine will open a new chapter to provide a total solution in the future translational medicine for current untreatable or challenging malignancies.

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