新合成抗癌化合物,PK-L1,及其固相脂質顆粒奈米化處方在小鼠體內分佈及其藥物動力學研究

Biodistribution and pharmacokinetic study of new synthetic anti-tumor compounds, PK-L1, and its solid lipid nanoparticle formulation in mice

劉雅婷(Ya-Ting Liu)

指導教授 ： 蔡義弘

高雄醫學大學/藥學院/臨床藥學研究所/碩士(2007年)

摘要

中文摘要
PK-L1（1-[4-(Furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone）為一具有抗腫瘤活性的新化合物，在人類前列腺癌細胞株(PC-3)經細胞凋亡產生直接的破壞作用，此外PK-L1在人類癌細胞株平均之GI50為0.025 ?嵱顯示強而廣效的細胞毒殺作用，對多數化療藥物而言往往在全身性高濃度之下產生嚴重之不良反應，因此化療製劑在組織之標的化為一重要的劑型開發目標。於本研究中對PK-L1首先建立良好之分析條件，以進行該成分在體內血中及組織中濃度的定量分析，經籂選後之高效液相層析條件為利用C18層析管柱，在移動相為40%氰甲烷與60%含1-pentasulfonate鈉鹽緩衝溶液(pH=3)下，以電化學檢測器(1.0V，20 nA)進行檢品之分析。該條件在線性範圍在10-2000 ng/mL，最低檢測濃度(LOD)為5 ng/mL。為達到PK-L1標的化之目的，本研究中利用Trimyristin、Gelucire 53/10、phosphatydylcholine，stearylamine及poloxamer188進行PK-L1之SLN劑型設計與開發，其平均粒徑大小為36.7 nm，並以溶液劑型為控制組分別以靜脈注射方式投予8.4 mg/kg之劑量於小鼠，進行PK-L1在動物體內之生體分佈評估與比較，由結果顯示PK-L1在SLN處方於小鼠體內之肺臟、肝臟及脾臟均顯著高於溶液劑之處方，且可達標的化之作用。

關鍵字

抗癌化合物 ； 固相脂質顆粒奈米化處方 ； 體內分佈 ； 藥物動力學

並列摘要

Abstract

PK-L1（1-[4-(Furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone） is a novel compound with anti-tumor activity. It was demonstrated that have direct disruption of tubulin polymerization followed by apoptosis in human prostate cancer PC-3 cell line. In the human cancer cell line, PK-L1 （a mean GI50 value of 0.025 ?嵱）also exhibited potent and board cytotoxicity. Through cancer chemotherapeutic agents are often administrated systemically in high concentration. Unfortunately, this system-wide application often has serious side effects. Base on this reason, specific-targeting tissue is an important for chemotherapy. In this study, we used high performance liquid chromatography to determine the drug content in blood and tissues of health ICR mice. A C18 250 mm×4mm column was used for the separation of analyte with a mobile phase consisting of 40% acetonitrile and 60% pH 3.0 of sodium 1-pentansulfonate solution at a flow rate of 1.0 mL/min. PK-L1 was detected by electrochemical detector at 1.0 V and 20 nA. Linear range of calibration curves was 10~2000 ng/mL, and the limit of detection (LOD) was 6 ng/mL. In order to targeting effect, the SLN formula containing Trimyristin、Gelucire 53/10、phosphatydylcholine，stearylamine and poloxamer188 was developed in this study. The biodistribution of PK-L1 in mice after single intravenous injection with PK-L1 solution and SLN formulation of 8.4 mg/kg were investigated. The tissue level of SLN formulation was higher than of the solution dosage form in lung, liver and spleen.

並列關鍵字

PK-L1 ； solid lipid nanoparticles ； trimyristin ； gelucire 53/10

參考文獻

伍、 參考文獻

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