本研究中，我們製備出具有磁效應仿紅血球形狀的扁平結構奈米載體，利用血液動力學機制與粒子形狀效應，可將載體自發性有效累積於肺部進行腫瘤治療，而該載體可在微酸性環境與磁場作用下產生大量高分子奈米粒子達到腫瘤穿透與藥物遞送目的。在過去，肺癌常面臨藥物難以準確抵達肺部而造成治療上的困難；因此，我們根據血液動力學的邊際效應機制，設計一個扁平狀的多孔性奈米載體，期許其能在血液的流動中，貼齊血管壁運動進而成功累積至肺部。而此多孔性奈米載體的鑑定，透過電子顯微鏡(SEM和TEM)、X光繞射分析儀及超導量子干涉儀可以得知為一具有超順磁性的仿紅血球扁平體。此外，多孔性奈米載體可以夾帶大量具治療功效的高分子複合物(阿黴素-高分子)，其乃利用高度生物相容性、低毒性的聚麩胺酸(poly-l-glutamic acid (PGA))為主鏈，支鏈修飾具有酸鹼應答性的腙鍵(hydrazone bonds)和阿黴素形成共價鍵結，當奈米高分子粒子運輸到腫瘤微酸環境時，腙鍵遇到氫離子而發生斷鍵，釋放出阿黴素分子，累積至腫瘤後進而引發細胞凋亡。而這部分實驗已在體外試驗得到驗證，阿黴素-高分子粒子在pH值5.9和6.7時比起生物體pH值7.4時，其藥物釋放率分別提升57%和39%；而為能達到有效的釋放，我們施予高週波熱處理，當多孔性奈米粒子成功累積至肺部時，我們給予體外高週波，刺激孔洞內藥物釋放，除此之外，從孔洞中釋放出來的阿黴素-高分子粒子遇到水相環境中，長碳鏈端聚麩胺酸會自聚集成奈米小球，而其大小大約70-80奈米符合高滲透長滯留效應，而累積至肺部腫瘤處。而細胞毒殺和動物實驗結果顯示，修飾過後的阿黴素-高分子粒子有較低細胞毒殺特性且心肌細胞受損程度也有明顯的下降。而在動物實驗上，我們將黑色素瘤細胞B16F10以尾靜脈注射之方式打入小黑鼠體內，以建立肺癌模型；在動物實驗上已觀察到，在打入腫瘤細胞後第11天，可發現老鼠肺部有明顯的一顆顆黑色素瘤，隨著時間拉長至14天，其肺部的表面黑色素瘤已占70-80%，而在第17-18天時，老鼠會因為呼吸困難而死亡，而將其肺部解剖可觀察到肺部已完全被黑色素瘤攻佔，整個肺部變得結實。而當對老鼠以尾靜脈方式施予攜帶阿黴素-高分子載體並搭配2分鐘之高週波刺激釋放，可發現到老鼠的存活天數，從原本的17-18天，延長至27-29天。因此，經由仿紅血球扁平體搭載阿黴素-高分子粒子為一個有潛力的藥物傳輸平台，且能透過高週波刺激釋放來提高治療效果，期許能在腫瘤治療或其他生醫領域上有更多方面性應用。

Delivery of drug and energy within responsive carriers that effectively target and accumulate in cancer cells promise to mitigate side effects and to enhance the uniquely therapeutic efficacy demanded for personalized medicine. To achieve this goal, however, these carriers which are usually piled up at the tumors periphery near the blood vessels must simultaneously overcome the challenges in low tumor penetration and transport sufficient cargos to the deep tumor to eradicate whole cancer cells. Here, we report an erythrocyte-like silica nanosponges on magnetic nanosheet that doubles as a magneto-thermal agent and high cargo payload platform, which releases a burst of polydox (pDox) and intense heat upon high-frequency magnetic field (HFMF). Last but not least, pDox encapsulated into mesoporous silica not only prolonged drug circulation in vivo but also served as MF-generated nanoparticles for tumor penetration. To form this functional pDox, it was synthesized by covalently conjugating Dox to the poly-l-glutamic acid (PGA) by a pH-sensitive hydrazone linker2. Poly-l-glutamic acid (PGA) possessing unique physicochemical properties is considered for biocompatibility, biodegradability, and non-immunogenicity3. Furthermore, pH-sensitive linker between Dox and PGA is cleaved in the acidic environment of tumor tissue, yielding high intra-cellular concentrations of activated Dox for deep tumor therapy. This sophisticated erythrocyte-like magnetic mesoporous nanogenerator is an excellent delivery platform for penetrated, MF-responsive, and combined chemo-thermotherapy to facilitate tumor treatment and for use in other biological applications.

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