製備多壁奈米碳管搭載超順磁性氧化鐵作為化療藥物Oxaliplatin 之奈米藥物載體並評估其藥物釋放及核磁共振顯影之能力

Abstract

近年來科學家致力於將奈米碳管應用於癌症治療上並且已獲得許多重要的學術研究資料。而我的研究主題為製備多壁奈米碳管搭載超順磁性氧化鐵作為化療藥物oxaliplatin之奈米藥物載體並評估其藥物釋放及核磁共振顯影之能力。 本研究為了使化療藥物oxaliplatin達到延緩釋放的效果，將oxaliplatin封裝於具管狀結構且經功能性修飾的多壁奈米碳管中。其超順磁性和副產物的純化可由氧化鐵/碳管的複合物製備中以熱處理達成，且為了有更好的親水性質與生物可相容性我們進一步的修飾分子量3400，末端為胺基的聚乙二醇。其oxaliplatin在我們的載體上的承載率為40.2%，並且由於修飾聚乙二醇之故，oxa@magmwnts-PEG3.4k具有延緩藥物釋放的能力。在藥物釋放實驗之中，12小時之內只有36.25%的藥物釋出，而在144小時候則為55.48%的平衡釋放率。且我們可由體外實驗中針對大腸直腸癌細胞株HCT116的細胞毒性、細胞凋亡假說、Pt-DNA加成物的定量研究中可進一步驗證延緩藥物釋放的效果。而在體內實驗中對皮下種植腫瘤的SCID品系小鼠，以一周兩次尾靜脈注射方式給予兩個禮拜的oxa@magmwnts-PEG3.4k (5mg/kg)腫瘤抑制療程，我們發現其具有腫瘤生長抑制的效果。此對比於給予臨床化療藥物歐力普Oxalip，治療過程並不會導致小鼠死亡。此外，我們通過分析oxaliplatin和碳管載體的組織分布，驗證這樣新穎的oxa@magmwnts-PEG3.4k是通過增強滲透與滯留效應(EPR Effect)的被動性累積於腫瘤組織內來達到藥物釋放和治療的效果。且由實驗結果我們推論使用奈米藥物載體搭載之化療藥物，其藥物的代謝效率較不受小鼠的個體差異化的影響。並且藉由給予單次注射後觀察不同時間點腫瘤T2影像的衰退情形，確認奈米藥物載體在腫瘤位置的分布情形。

Researchers in recent years have put a lot of efforts on the development of carbon nanotube in the field of cancer therapy. In order to achieve the goal of sustained drug release, oxaliplatin was encapsulated into multi-walled carbon nanotubes which were modified by SPIOs and PEGylated for drug delivery. Superparamagnetic property and purifications of iron oxide/MWNTs composites were achieved by annealing treatment during fabrication process; the better hydrophilicity and bio-compatibility were also accomplished subsequently after the modification of the composites with PEG3.4k. Drug content of oxaliplatin in mamgnwts-PEG3.4k is about 40.2%. The oxa@magmwnts-PEG3.4k presented the ability of sustained release that there was only 36.25% of loaded oxaliplatin leaked within 12hrs and 55.48% of them were last over 144hrs. In vitro, the cytotoxicity experiments were further verified by apoptosis assay. Pt-DNA quantification on HCT116 cells showed that the ability of sustained release last to 96hrs. In vivo, oxa@magmwtns-PEG3.4k (10mg/kg) were intravenously injected to subcutaneously seeding tumors of SCID mice suppressed the tumor growth. Moreover, the oxa@magmwnt-PEG3.4k didn’t lead to the lethal of mice during treatment, but Oxalip did. The EPR effect of this novel nanomedicine was verified by investigating the bio-distribution of the drug and carriers, and the potential of magnetic resonance imaging of modified nanotubes was also investigated, too.