利用斑馬魚腫瘤模型評估搭載阿黴素之氧化還原應答矽-金 奈米藥物載體於抑癌及改善藥物副作用之成效

Abstract

儘管現今醫學的進步，癌症仍位居十大死因之首，死亡率居高不下。化學治療為最常見之癌症治療方式，然而其藥物非專一性使得病患常受嚴重的副作用影響，可容許的投藥劑量因而受限，也降低了治療效果。相較於傳統化療直接施打藥物的方式，使用藥物奈米載體搭載抗癌藥物可藉由選擇性辨識分子的修飾使抗癌藥物更精確的定位投遞到癌細胞的位置，降低藥物對人體產生的副作用，並提升治療的效果。Doxorubicin是一種已知對多種癌症皆有治癒效果的化療用藥，但由於對心臟具不可逆的累積性傷害因而限制了此藥物的使用。本研究發展一新穎矽金奈米複合藥物載體Tf-DOX-ReSi-Au NPs，具雙硫鍵可針對氧化還原應答的矽材料(redox-responsive silica, ReSi)修飾於金奈米粒子(13 nm)表面；藉由電荷吸引方式將艾黴素(Doxorubicin, DOX)搭載於矽金奈米材料；而於載體外吸附之運鐵蛋白(Transferrin, Tf), 由於其受器在癌細胞表面高度表現，並具良好的親和性，可作為專一辨識分子，提高對癌細胞治療的選擇性。藥物的釋放藉由癌細胞內高濃度之穀胱甘肽將載體上之雙硫鍵還原，造成交聯結構破壞，誘發藥物釋放進而達到治療效果。本研究中並建立了斑馬魚癌症動物模型，評估奈米藥物載體於生物體內之生物相容性。Tf-DOX-ReSi-Au NPs相較於原本的free DOX有較佳的抑制癌細胞生長效果；同時，藉由雷射共聚焦顯微鏡(confocal laser scanning microscopy)所建立的斑馬魚3D心臟模型，研究結果顯示，奈米複合材料Tf-DOX-ReSi-Au NP 相較於free DOX，對心臟功能不具顯著毒性以及副作用。

Despite the advancement in medicine, cancer still ranked first in the top ten causes of death. Chemotherapy has been the most common strategy to treat cancer. However, its non-specificity led to severe side effects in patients, as a result, the tolerant dosage was limited and the therapeutic effect could be reduced. The drug-loaded nanocarriers thus were employed to enable targeted delivery by selective ligand functionalization, improving the therapeutic efficacy. Doxorubicin is a well-known anti-cancer drug which is effective to several types of carcinoma but with severe and irreversible cardiotoxicity thereby hindering its usage. In this study, we developed a novel silica-gold nanocomposite Tf-DOX-ReSi-Au NPs in which the disulfide-linked redox-responsive silica (ReSi) was functionalized on the surface of gold nanoparticles (Au NPs, 13 nm), followed by the electrostatic adsorption of doxorubicin (DOX). Transferrin (Tf) served as selective ligand with high affinity to its receptor expressed predominantly in carcinomas. The release of DOX was then triggered upon high concentration of glutathione stimuli to reduce the disulfide bond embedded in the nanocomposite. The zebrafish tumor model was established in the study to evaluate the biocompatibility of nanocomposite in vivo. Tf-DOX-ReSi-Au NPs has found to be more effective in the inhibition of tumor growth than that of free DOX. Moreover, using the laser scanning confocal microscope, a 3D zebrafish heart model was constructed to investigate the cardiovascular functions after free drug and the nanocomposites treatment. Tf-DOX-ReSi-Au NPs revealed insignificant cardiotoxicity and side effects compared with that in free DOX.