肝癌(Hepatocellular carcinoma，HCC )是全球第六大常見的癌症，在台灣佔惡性腫瘤患者死亡率第 二名。肝癌動脈栓塞療法(Transcatheter Arterial Embolization，TAE)是肝癌無法切除時使用的局部療 法，能大幅提升肝炎患者的存活率。本研究欲提升TAE 療法的成效，以微生物多醣體Gellan gum 為 基材，製備標靶性微粒作為肝癌動脈栓塞劑。Gellan gum 因具有好的生物相容性、血液相容性、緩 慢降解速度、易控制微粒大小、具傳輸藥物的能力、容易改質以及材料成本較低等特性，具有開發 成標靶性肝癌動脈栓塞劑之潛力。計畫第一年製備標靶性Gellan gum/sHA-PEI 微粒作為doxorubicin 的載體，doxorubicin 是一種廣泛使用的肝癌治療藥物、低分子量玻尿酸(sHA)具有與癌細胞結合的能 力、PEI(Polyetherimide)可利用其正電荷性吸附doxorubicin，並透過細胞吞噬作用協助藥物進入細胞。 計畫第二年製備標靶性Gellan gum/graphene-PEI-sHA 微粒作為microRNA 的載體。石墨烯(grapherene) 具有保護microRNA 穩定性的功能，並協助microRNA 以物理穿透方式進入細胞、sHA 具有與癌細 胞結合的能力，PEI 可利用其正電性吸附microRNA。microRNA 參與癌細胞轉錄調控，是癌症療法 的新策略也是未來的趨勢。計畫第三年，針對台灣及亞洲地區B 型肝癌高發生率及死亡率，本研究 利用Gellan gum/graphene-PEI-sHA 微粒傳輸miR-198、miR-122 進入Hep3B 肝癌細胞，研究其改變 癌細胞生理之分子生物學機制，並透過動物實驗評估Gellan gum 標靶治療微粒之效能以及生物相容性。
Hepatocellular carcinoma (HCC) represents the sixth most common cancer in the world and the second in the mortality of cancer in Taiwan. Transcatheter Arterial Embolization (TAE) is the most commonly used locoregional therapy worldwide for patients with unresectable liver cancer and has been shown to provide substantial survival benefit in a subset of patients with unresectable hepatocellular carcinoma. In this study we arm to elevate the therapeutic efficacy of TAE and development of targeted TAE therapy technology for liver cancer. Gellan gum-based microspheres will prepare by the water-in-oil emulsion solvent diffusion method for use as targeted embolic agent for TAE. Gellan gum have the potential to be an embolic agent for TAE because of the following characteristics: suitable biocompatibility, hemocompatibility, slow degradation rate, predictable sizing, ability to elute a drug and biological agents, easily functionalize by introducing chemical modification and affordable. The first year of implementation in this study, we will fabricate the Gellan gum/sHA-PEI microspheres as the embolic agent and drug carrier for doxorubicin. Doxorubicin is one of the most commonly used chemotherapeutic agents to treat HCC；sHA (low molecular weight hyaluronate) have the ability to target cancer cells；PEI (Polyetherimide) with high cationic charge density can load doxorubicin efficiently and facilitate drug entry inside the cell through endocytosis. Second year, we will prepare Gellan gum/graphene-PEI-sHA microspheres as the biological agents carrier for microRNA. MicroRNA (miRNA) are involved primarily in post-transcriptional regulation of cancer cell gene expression. Regulating miRNA could be a promising strategy for cancer therapy in the future. In this carrier system, graphene with the function to prevent miRNA degradation by ribonuclease and physically penetrate the cell membrane. The function of sHA, PEI as just mentioned. Third year, we focus on study the effectiveness therapy of HBV-related HCC because of the high incidence in Taiwan and Asia. We use Gellan gum/graphene-PEI-sHA microspheres as vector carrier for miR-198, miR-122 transfection in Hep3B cells. Mechanisms and role of miR-198, miR-122 regulation in cancer onset and progression will be confirmed. We will also evaluate gellan gum-based microspheres as potential embolic agent for use in TAE of hepatocellular carcinoma in vivo.
