- 學位論文
血清白蛋白奈米製劑攜帶SN-38應用於三陰性乳癌之前導測試
A Pilot Study of SN-38 Entrapped Serum Albumin Nanoparticles to Triple Negative Breast Cancer
摘要
三陰性乳癌(Triple negative breast cancer)是所有乳癌中預後較不佳的亞型，並且市面上尚未有批准針對三陰性乳癌之藥物，因此三陰性乳癌在臨床治療上有迫切尋求突破之必要。白蛋白(Albumin)是具有藥物傳遞系統開發潛力的材料，因為白蛋白源於生物體，在相同物種的前提下，白蛋白預期會展現出高度生物相容性，加上白蛋白具有攜帶親水性或親油性物質的能力，使得成白蛋白為製作藥物傳遞系統的理想材料。若使用白蛋白加以製成奈米藥物傳遞系統，即便不用主動標靶加以修飾，此奈米顆粒也預期藉由滲透與滯留效應(Enhanced permeability and retention effect)累積於目標組織中。SN-38是具有高度細胞毒殺性之半合成物質，是臨床廣泛使用的化療藥-愛萊諾迪肯(Irinotecan)之活化態代謝物，但由於愛萊諾迪肯餘生體內轉換成SN-38的轉換率不佳，使得活化態的SN-38成為研究重點。綜合上述分析，促成了我們初步評估白蛋白奈米製劑攜帶SN-38 應用於三陰性乳癌的可行性。在本篇研究結果中，我們建立了白蛋白奈米顆粒攜帶SN-38的製程，並且進一步分析此奈米顆粒的物理性質、體外安全性、細胞毒殺性以及藥物動力學。研究結果顯示，我們可以控制白蛋的奈米顆粒於適當的大小範圍，並且於細胞實驗中發現，使用此製程的空白白蛋白奈米顆粒對細胞沒有毒性。反之，攜帶SN-38的白蛋白奈米顆粒具有與SN-38溶液相當的抗癌細胞效果。於藥物動力學實驗中發現，攜帶SN-38的白蛋白奈米顆粒，並無增進排除半衰期，但有累積於臟器的趨勢。總體而言，本篇研究為白蛋白製劑的前期研究，以牛血清白蛋白(Bovine serum albumin)作為製備材料。近期我們將著手於以人源白蛋白(Human serum albumin)並加以改善製程，以利更進一步評估其藥動及藥效學。
並列摘要
TNBC (Triple negative breast cancer) is a breast cancer with subtypes, and reported to be more aggressive and with worse prognosis compared to non-TNBC. Treatment for TNBC is an unmet clinical need, because no specific treatment for TNBC has been approved. Albumin has been regarded as promising drug delivery material due to the compatibility in living organism and its capacity to carry both hydrophobic and hydrophilic substances. By fabricating albumin into nanoparticles, they possibly exhibit passive target effect to tumor by enhanced permeability and retention (EPR) effect in vivo instead of circulating aimlessly. SN-38, also known as 7-ethyl-10-hydroxy-camptothecin, is an active metabolite of irinotecan that has been extensively used in clinical, and yet requires high dosage due to its low convert ratio to SN-38. The excessive irinotecan results in fatal adverse effects. Replacing irinotecan with SN-38 may be the solution. Importantly, SN-38 has been reported to exhibit higher cytotoxic effect compared to irinotecan. In this study, we formulated SN-38 entrapped albumin nanoparticles with the aim to TNBC. To answer the feasibility of SN-38 entrapped albumin nanoparticles (sBSANP), we attempted to setup a preparation for albumin nanoparticles with proper sizes, and further evaluated the physical properties, safety, cytotoxicity, and pharmacokinetics. The albumin nanoparticles without SN-38 (BSANP) showed no toxicity to both TNBC & non-TNBC cancer cell lines (MDA-MB-468, MCF-7) and healthy cell line (Hs68). For sBSANP, it showed no alteration regarding the high potency of SN-38 against MDA-MB-468, and exhibited IC50 as low as 2.01 ± 0.67 nM. For in vivo study, the sBSANP did not exhibit extended elimination half-life, but showed significant accumulation in specific organs. This study is a pilot study to pave the way for albumin-based drug delivery, we believe the SN-38 entrapped albumin nanoparticles are the potential solution to TNBC.