特洛伊木馬奈米載體 –多階段藥物釋放及傳遞系統應用於深層腫瘤組織之穿透

Abstract

在本研究中成功開發具有多階段釋放之複合式子母彈型載體─特洛伊木馬奈米膠囊。此種特殊的藥物傳輸系統是藉由整合雙重系統而形成，分別是次載體系統─Greece soldiers (GSs) 以及母體載體─特洛伊木馬奈米膠囊Trojan horse nanocapsules (THNCs)。次載體系統GS是由多孔隙中空氧化鐵奈米粒子 (PHMNP) 所組成，此種氧化鐵奈米粒子具備了相當特殊的結構，不僅有空心的結構，且其空心結構亦連通至表面的孔洞，這樣的結構賦予了PHMNP包覆疏水性或親水性之抗癌藥物的能力。在本研究中我們使用的是疏水性藥物─太平洋紫杉醇 (paclitaxel; PTX) 作為藥物模型。GS因為粒徑大約20 – 25 nm，因此不僅具備穿透至離血管較遠的腫瘤組織的能力，且又因為具有超順磁的特性，因此也可以作為核磁共振成像 (MRI) 的造影劑 (contrast agent)，以及擁有應用於磁熱療的潛能。另一方面，母體載體系統THNC則扮演在循環系統中輸送GSs的角色，其原理是利用一層雙性明膠 (amphiphilic gelatin; AmG) 之結構將一群GS進行包覆，進而形成約100 nm的奈米膠囊。又因為AmG具有對於基質金屬蛋白酶二型 (matrix metalloproteinase-2; MMP-2) 敏感性，當THNC遇到MMP-2時會被分解進而釋放出包覆在內的GS。而MMP-2又常常會在血管新生處或腫瘤邊緣過量表現，因此不僅具有被動標靶的價值，同時又能作為觸發THNC釋放GS之觸發機制。本研究也利用HeLa細胞株評估THNC以及GS在包覆藥物前後之細胞毒性，透過體外細胞實驗發現，THNC和GS不僅具備高生物相容性以及低細胞毒性。因此，我們認為此多階段釋放之複合式子母彈型載體─特洛伊木馬奈米膠囊具備了成為次代藥物傳輸系統之潛能。

In this study, multistage cluster-munition-like nanocapsules, Trojan horse nanocapsules (THNCs), were successfully designed. This idiosyncratic drug delivery system (DDS) integrated sub-carrier system and matrix-carrier system. Sub-carrier system, Greece soldiers (GSs), were designed to penetrate to the tumor parenchyma distant from blood vessels. GSs possesses outstanding advantages such as acting as MRI contrast agent and application on hyperthermia since the present of superparamagnetic nanoparticles. The unique hollow structure of PHMNP also allow GSs to encapsulate and deliver hydrophilic and hydrophobic anti-cancer drugs. We utilized a common anticancer drug, paclitaxel (PTX) to discuss the drug release behavior. On the other hand, matrix-carrier system, Trojan horse nanocapsules (THNCs), were programmed to deliver a group of GSs simultaneously with amphiphilic gelatin (AmG) layer. AmG can be digested by matrix metalloproteinase-2 (MMP-2) which is overexpressed at the edge of tumors and the sites of angiogenesis - regions the nanocarriers are possible to infiltrate. The cytotoxicity and the biocompatibility of GSs and THNCs were evaluated in vitro. The in vitro assessments were carried out by HeLa cell line to compare the cytotoxicity of nanocarriers and drug-loading nanocarriers. Both THNCs and GSs show low cytotoxicity and high biocompatibility. In summary, THNCs has great potential in biomedical applications including co-delivery, controlled release, passive targeted therapy and bioimaging.