新型光敏剂3^(2)-(4-甲氧基苯基)-15^(2)-天冬氨酸-二氢卟吩e6的药代动力学及组织分布特征  

Pharmacokinetics and tissue distribution characteristics of the novel photosensitizer 3^(2)-(4-methoxyphenyl)-15^(2)-aspartyl-chlorin e6

作　　者：王柳 董伊 曹雷 孙玉明[2] 李悦青 赵伟杰 WANG Liu;DONG Yi;CAO Lei;SUN Yuming;LI Yueqing;ZHAO Weijie(College of Chemical Engineering, Faculty of Chemical, Environment and Biological Science and Technology, Dalian University of Technology, Dalian 116024, China;Chemical Analysis and Research Center, Dalian University of Technology, Dalian 116024, China;State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China)

机构地区：[1]大连理工大学化工与环境生命学部化工学院,辽宁大连116024 [2]大连理工大学化学分析测试中心,辽宁大连116024 [3]大连理工大学精细化工国家重点实验室,辽宁大连116024

出　　处：《色谱》2021年第12期1291-1297,共7页Chinese Journal of Chromatography

基　　金：国家科技支撑计划重点项目(2015BAD17B05).

摘　　要：二氢卟吩类衍生物3^(2)-(4-甲氧基苯基)-15^(2)-天冬氨酸-二氢卟吩e6(DYSP-C34)是从程海湖螺旋藻中提取并合成的新型光敏剂。研究DYSP-C34在生物体内的药代动力学及组织分布过程对光动力疗法(PDT)的有效性和安全性至关重要。该文运用高效液相色谱-紫外(HPLC-UV)检测技术,建立了大鼠血浆中DYSP-C34的检测方法。采用沉淀蛋白-液液萃取法处理血浆和组织样品,采用Unitary C_(18)色谱柱(250 mm×4.6 mm,5μm)分离,流动相为甲醇-5 mmol/L四丁基磷酸氢铵缓冲盐溶液(70∶30,v/v),流速为1.0 mL/min,进样量为20μL,检测波长为400 nm,柱温为40℃。实验结果表明,大鼠血浆药物质量浓度在1~200μg/mL范围内线性良好,判定系数(r2)为0.9941。在低、中、高(8、40、120μg/mL)3个添加水平下的提取回收率分别为74.39%、69.71%和65.89%,日内和日间相对标准偏差(RSD)均在5%以内。运用此方法测定静脉注射DYSP-C34(16 mg/kg)后大鼠血浆中以及荷瘤小鼠组织中的药物浓度,采用DAS 2.0计算出药物半衰期t_(1/2z)为6.98 h,药-时曲线下面积AUC(0-∞)为1025.01 h\5mg/L,平均驻留时间MRT_((0-∞))为9.19 h。DYSP-C34在荷瘤小鼠体内的分布结果显示,DYSP-C34可以在肿瘤组织中蓄积,并具有一定的滞留作用。综上,该文建立了大鼠血浆中DYSP-C34的HPLC-UV测定方法,并进行了方法学验证,此方法简便、快速,结果准确。阐明了DYSP-C34在静脉给药方式下大鼠体内药代动力学和荷瘤小鼠组织中的分布特征,对临床合理用药和药效学研究具有重要意义。Photodynamic therapy(PDT)has garnered immense research interest.PDT can directly kill the cells via a combination of photosensitizer,light,and molecular oxygen.It has emerged as a promising therapeutic option for cancer treatment owing to its advantages such as minimized systemic toxicity,minimal invasiveness,high therapeutic efficacy,and potential for developing antitumor immunity.The novel photosensitizer 3^(2)-(4-methoxyphenyl)-15^(2)-aspartyl-chlorin e6(DYSP-C34)was synthesized by introducing a 3^(2)-aryl substitution and amino acid substituent of the Chenghai chlorin(CHC).Briefly,3^(2)-(4-methoxyphenyl)substitution was achieved via olefin metathesis reactions.The aspartic acid side chain was introduced regioselectively at C-15^(2),followed by hydrolysis to yield the target DYSP-C34.CHC with the same chemical structure as chlorin e6 was prepared from chlorophyll a,which was extracted from Spirulina powders derived from Chenghai Lake in the Yunnan province of China.This strategy successfully endowed the resultant photosensitizer with better cellular permeability and increased water solubility.In addition,the photodynamic antitumor effects of PDT largely depend on the dose of photosensitizer used,time between photosensitizer administration and light exposure,and possibly other still poorly known variables.Determination of optimal conditions for PDT requires a coordinated interdisciplinary effort.Therefore,the pharmacokinetics and tissue distribution of DYSP-C34 in vivo are critical for the efficacy and safety of PDT.Herein,a high performance liquid chromatography-ultraviolet(HPLC-UV)detection method was established for the determination of the new photosensitizer DYSP-C34 in rat plasma.The sample preparation involved a protein-precipitation and liquid-liquid extraction method.Methanol was used to precipitate proteins and chloroform was used to extract chlorins.Then,DYSP-C34 was separated on a Unitary C18 column(250 mm×4.6 mm,5μm)with a mobile phase comprising methanol and 5 mmol/L tetrabutylammonium phosphate

关 键 词：高效液相色谱-紫外检测 药代动力学 组织分布 光敏剂 二氢卟吩类 荷瘤小鼠 

分 类 号：O658[理学—分析化学]