開發以聚己內酯薄膜為基礎之長效型藥物釋放系統

Abstract

為了建立能夠治療惡性肋膜積水且以聚己內酯薄膜為基礎的長效藥物釋放系統，因此在膜中混參由溶劑置換法所形成的奈米粒子來發展出此系統達到長時間穩定釋放抗癌藥物：順鉑。在體外實驗中發現奈米粒子釋放藥物時間遠比含藥膜的釋放天期長，且在細胞毒殺實驗也發現奈米粒子的毒性較小，推測結果是因為藥物釋放相較於含藥膜較為緩慢。另外，在抑制腫瘤生長的動物實驗也發現同時含藥和奈米粒子的薄膜在十八天後可以看到比含藥水溶液和一般含藥膜有較好的抑制生長情形。本研究也利用大鼠腹腔沾黏實驗觀察用氯化鈉作為致孔劑的多孔膜和有混參奈米粒子的膜的沾黏情況，結果發現兩者的沾黏情形沒有顯著差異，也都比表面較為緻密的膜的沾黏效果好，而根據掃描電子顯微鏡發現其原因可能是奈米粒子會造成膜的表面結構多孔化，促進沾黏反應。與預期相同，混參有奈米粒子的聚己內酯膜可以被用作兩階段藥物釋放系統。實驗結果顯示，此系統可以控制粒子內的藥物接在膜內藥物之後釋放，這說明了此系統有機會取代目前臨床治療惡性肋膜積水的給藥方式成為新的可以同時進行肋膜沾黏和體內釋放藥物的產品。

To develop a sustained drug delivery system based on PCL membrane, promoting pleural adhesion, for the treatment of malignant pleural effusion (MPE), cisplatin (CDDP)-encapsulated PLGA nanoparticles (PLGA/CDDP NPs) were fabricated via solvent displacement method for the purpose of prolonging drug delivery. The PCL membrane incorporating CDDP and PLGA/CDDP NPs (PLGA/CDDP NP-PCL/CDDP membrane) was investigated under the in vitro and in vivo conditions with the comparison of PCL membrane incorporating CDDP (PCL/CDDP membrane) and free CDDP in solution form. As nanoscale drug carriers, the PLGA/CDDP NPs released the drug in a long-term manner for a longer period than PCL/CDDP membrane and were also less cytotoxic than free CDDP and PCL/CDDP membrane which probably due to the slower release of CDDP from NPs. The tumor-suppressing ability was observed that PLGA/CDDP NP-PCL/CDDP membrane could successfully inhibit the tumor growth after 17days because of the sustained release of CDDP in tumor-bearing mice, as shown by changes in tumor volumes, body weights, and survival trends. Histological analysis of tumor sections on Day 21 also showed that PLGA/CDDP NP-PCL/CDDP membrane had an obvious anti-tumor effect than other treatments. In addition, there was no significant difference of abdominal adhesion effect between the PLGA NP-PCL membrane and the porous PCL membrane probably because PCL membrane blended with PLGA NPs also had the porous surface structure facilitating the adhesion response without influencing the living conditions of rats. As expected, PLGA NP-PCL membrane system can also be used as two-step drug delivery system serving as a promising new treatment for MPE.