CD44是一種透明質酸受體，參與胞外基質在癌化訊息傳導上的調控進而在癌症的生成扮演重要角色。口腔癌相關研究發現CD44在癌細胞生長、存活與轉移等現象皆有所參與。而它也是個眾所皆知的癌幹細胞標記。最近的研究指出CD44結合其配體或抗體後能進行核易位，並形成轉錄複合而參與癌細胞轉化癌幹細胞表型之重編程。因此，CD44內化路徑或能作為一選擇性運輸之”分子特洛伊木馬”達到細胞與次細胞層次標靶癌細胞的方法。本研究中，我們應用CD44內化途徑實現同步熱療/化療的新型複合靶向治療，此靶向分子探針包括核苷酸修飾的磁奈米粒子，可增強癌細胞標靶的抗CD44抗體 (Hermes-3) 以及小分子抗癌藥物5-FU。當此奈米探針標靶癌細胞並受到射頻磁場擾動時，可造成奈米粒子升溫並破壞其與搭載物間的氫鍵而達到同步化藥物釋放與熱療的目地。在細胞實驗的結果中我們發現口腔癌細胞的CD44內化程度比正常細胞顯著。而抗體修飾確實可以專一性提高癌細胞攝取奈米粒子的能力。利用穿透式電子顯微鏡，我們也發現經過抗體修飾的奈米粒子可以被運輸到細胞核或是接近細胞核。接著我們合併射頻與此標靶奈米粒子可以造成細胞傷害並與射頻處理時間成正比。在動物實驗中也顯示只需要一劑量的磁性標靶奈米粒子並搭配15分鐘的射頻處理可以造成腫瘤體積下降。從病理切片的結果中發現腫瘤組織確實有自溶死亡的現象並且伴隨磁性奈米粒子的浸潤但主要器官中並沒有發現顯著的病理現象。最後在生物分布實驗中發現，有經過射頻處理的組別，其奈米粒子可被延長其在腫瘤中時間。另一方面，我們也觀察到只有熱療處理的組別在經過一個禮拜後並沒有抑制腫瘤生長，這也說明了5-FU在這療程中或許扮演重要角色。根據以上結果，我們認為利用腫瘤細胞傳遞CD44內化途徑的方式來運輸藥物或許是個理想的靶向治療策略。而透過奈米粒子整合局部熱療並搭配化療可以達到顯著的治療效果。

CD44 is a receptor for hyaluronic acid, and often involved in tumor formation through extracellular matrix (ECM) mediated oncogenic signaling. CD44 plays multiple roles in oral squamous cell carcinoma (OSCC) progression including tumor growth, survival, and metastasis. CD44 is also well known to be an important cancer stem-like cells (CSLCs) marker. Recent studies showed that CD44 could mediate nuclear translocation of its ligand or antibody and then turned on cancer reprogramming for stem-like phenotypic alterations. Thus CD44 pathway could serve as ‘Trojan Horse’ to shuffle selectively from tumor surface to the cytoplasm and the nucleus. In this study, we applied this internalization pathway to implement a novel multi-modal targeting-therapy that synchronized hyperthermia and chemotherapy. The oligonucleotides served to carry 5-FU non-covalently were modified on magnetite nanoparticles that selectively target cancer cell membrane via anti-CD44 monoclonal antibody. The complex was subsequently delivered to tumor cells where 5-FU was released upon radiofrequency (RF) mediated temperature raise that breaks hydrogen bond between the payload drug and the carrier oligonucleotides. In vitro studies discovered the internalization of CD44 in OSCC cells is significantly higher than the normal cells. Hermes-3 conjugation also could specifically enhance nanoparticles uptake in cancer cells but not in normal cells. TEM showed Hermes-3 conjugated nanoparticles were internalized and transported into or near the nucleus. We confirmed that combined RF and targeted nanoparticles could further augment cancer cell cytotoxicity in a time-dependent manner. In vivo evaluation showed only a single dose of i.v. injection of the magnetite nanoparticles (500 g/mL) could cause significant tumor regression when combined RF exposure. In the biodistribution result, we observed accumulation of nanoparticles in the tumor locale 24 hours after RF treatment. H&E staining showed massive autolysis of tumor cells with nanoparticle infiltration but the major organs showed no detectable pathological findings after treatment. On the other hand, we observe hyperthermia alone group showed minimal tumor growth inhibition 1 week after treatment. We suggest that 5-FU maybe play key roles in the augmented therapeutic efficacy. In summary, CD44 is an ideal marker for cancer-targeting therapy that required localized activation in the nucleus. Combined chemotherapy with localized hyperthermia through nanotechnology would significantly augment overall therapeutic efficacy in cancer therapy.

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