多功能性奈米雙親性幾丁聚醣包覆雙藥系統 應用於癌症治療

Abstract

癌症是現今造成人類死亡的主要原因之一，然而肺癌又是眾多癌症之中發生率和致死率最高的，目前非小細胞肺癌治療方式仍以化學治療為主。若是長時間持續給予同一藥物容易使癌細胞產生多重抗藥性(MDR)是腫瘤轉移和治療失敗的主因。因此，開發能夠有效抑制多重抗藥性(MDR)的藥物系統為本研究的主軸。 我們透過奈米雙性幾丁聚醣(CHC)自組裝的特性來達到同時包覆二線抗癌藥健擇(dFdC)及去甲氧基薑黃素(DMC)， 形成具有高包藥率、生物相容性的藥物載體系統。在奈米載體外嫁接特定抗體能夠提供奈米粒子標靶效果，還能形成殼狀結構，進而減少藥物在血液循環中的釋放。除此之外，在這個設計中，我們能有效調控藥物濃度，使兩種藥物以特定比例同時到達癌細胞，以增加藥物的協同效應(synergetic effect)更有效的毒殺癌細胞。 在小鼠種植異位肺癌細胞(A549)的研究中。標靶雙藥奈米粒子比起純藥物，表現出優異的腫瘤抑制效果，另外，我們利用急毒性實驗的結果證實了標靶雙藥奈米粒子的生物安全性遠高過純藥物，並了解其藥物動力特性與體內分布情況。實驗結果充分表現出此設計無論在生物安全性和功效方面都有前瞻性的治療潛力。將在這個合併療法(combination therapy)盛行的時代扮演重要的角色 。

Multi-drug resistance (MDR) in cancer cells, is the main reason for tumor metastasis and invalid treatment. Thus, to develop an anti-MDR cancer therapy become the emergency work. This research established one multifunctional dual-drug delivery system with one-pot synthesis, which combined targeting, biodegradable and dual-drug encapsulation on one nanoparticle to inhibit MDR-pathway in caner stem cells. The second-line anti-cancer drug, gemcitabine (dFdC), and the Chinese herbal extract demethoxycurcumin (DMC) were chosen and loaded in biodegradable carboxymethyl-hexanoyl chitosan (CHC) nanoparticles modified with EGFR antibody, which is the biomarker on non-small cell lung cancer, A549. The CHC/dual-drug/anti-EGFR nanoparticle did out-standing IC50 and CI value on killing A549 compared with free dFdC and DMC combination, which meant the highly efficiency and synergy of this drug co-delivery system. In addition, CHC/dual-drug/anti-EGFR nanoparticle performed better treatment on A549 xenograft in mice than other experiment groups, indicating that this multifunctional nanocarrier may provide a new way for chemotherapy in cancer treatment.