應用細胞微陣列系統於篩選對腫瘤細胞有效之藥物組合

Abstract

藥物組合之協同作用已經在臨床被證實具有改善癌症治療、減低藥物使用量，進而達到減少副作用的效果。然而臨床所能取得的病人檢體與分離出之原發腫瘤(primary tumor)數量相當稀少，不宜使用傳統孔盤進行篩選。本研究開發出一種只需使用少量細胞即可進行一百種藥物組合快速篩選的細胞微陣列系統(ECMS)。ECMS包含了一個由聚二甲基矽氧烷 (PDMS) 與蓋玻片製成的膠體晶片，與一台能符合高通量需求的液體列印點膠器 (liquid dispenser) 。目前已經使用攝護腺癌與神經母細胞瘤細胞株完成概念驗證研究，結果顯示在我們的晶片系統中所得到之癌細胞對藥物的敏感性，和於96孔盤上所得並無顯著差異，表示ECMS的藥篩結果是絕對可信的。接著，我們利用ECMS篩選最佳化藥物組合，並將該最佳組合在異種移植小鼠中進行藥效的驗證。結果顯示最佳藥物組合在動物中的腫瘤抑制率和單一藥物相比有顯著的提升。此外，我們還展示了ECMS也可以應用於三維 (3D) 細胞球培養與三維細胞之藥物篩選。總合上述，本研究所研發之細胞微陣列系統在個人化醫療與新藥開發應有寶貴的價值與潛力。

Therapeutic synergism has been demonstrated with a potential to improve cancer treatments by screening of optimized drug combinations, reducing drug doses, and therefore attenuating side effects in patients. Here we present an elastomer cellular microarray system (ECMS) that can perform numerous drug screenings as well as requires few cells per assay. The ECMS includes an elastomer device – made with a polydimethylsiloxane (PDMS)-coated cover glass – and a robotic liquid dispenser, allowing to meet the high-throughput requirement in industries. Prostate and neuroblastoma cancer cell lines are utilized for our proof-of-conceptual study. Results show that drug sensitivities derived from our ECMS and conventional 96-well plates have no significant difference. In addition, the optimized drug combination evaluated from our system is further verified in xenograft tumor models. Remarkably, the tumor inhibition rate resulted from this optimized combination is significantly higher than other treatments adopted, i.e. single drug doses, indicating such screening approach by our in vitro platform could recapitulate the in vivo conditions. We demonstrate, furthermore, the ECMS could be employed and applied for applications of three-dimensional (3D) cell culture. Taken together, the ECMS developed herein should have an invaluable insight in the rapid identification of personalized medicine, achieving the new drug development on demand.