摘要
本文旨在为胃癌术前经内镜注射局部化疗研制一种具有良好稳定性、高药物含量和显著肿瘤细胞靶向性的叶酸修饰磷脂包被紫杉醇纳米晶(PTX NC@FA)。以“从小到大”法继以超声法制备PTX NC@FA,考察其颗粒形态、粒径分布、ζ-电位、药物含量、叶酸修饰磷脂(FA-DSPE-PEG_(2000))含量、晶型特征、稳定性、体外释放行为、对人胃癌细胞株SGC-7901的细胞毒性及在裸鼠SGC-7901皮下肿瘤模型两种不同肿瘤大小(瘤体积100 mm^(3)或300 mm^(3))情况下单次瘤旁给药的缩瘤效果。动物实验经复旦大学药学院实验动物伦理委员会批准。结果表明,PTX NC@FA呈短棒状,平均粒径为175.3±2.5 nm(多分散指数0.17±0.02),ζ-电位为-2.5±0.2 mV,PTX含量为(28.23±0.74)%(w/w),FA-DSPE-PEG_(2000)含量为(4.40±0.60)%(w/w),在磷酸盐缓冲液或含血清磷酸盐缓冲液中均能稳定至少4天,可在96 h内缓慢释放药物。PTX NC@FA对SGC-7901细胞的IC_(50)显著低于无叶酸修饰纳米晶。单次瘤旁注射(20 mg·kg^(-1))后,PTX NC@FA抑瘤效果显著优于无叶酸修饰纳米晶和市售紫杉醇注射液(Taxol)。荷小肿瘤体积裸鼠(100 mm^(3))给药12天后,PTX NC@FA组7只动物肿瘤均完全消失,抑瘤率100%。荷大肿瘤体积裸鼠(300 mm^(3))给药12天后,PTX NC@FA组7只动物中的3只肿瘤完全消失,剩余4只瘤体亦缩小,抑瘤率约90%。结果提示,PTX NC@FA具有良好应用潜力,有望用于术前缩小肿瘤,增加保胃机会,提高患者的术后生存质量。
This paper aims to develop folic acid-modified paclitaxel nanocrystals(PTX NC@FA)with good stability,high drug loading and tumor cell targeting for endoscopic injection for preoperative local chemotherapy of gastric cancer.PTX NC@FA was prepared by the"bottom-up"followed by ultrasonic to study its morphology,particle size,ζ-potential,drug loading,folic acid-modified phospholipid(FA-DSPE-PEG_(2000))content,crystalline characteristics,stability,in vitro release,cytotoxicity against human gastric cancer cell line SGC-7901,and anti-tumor effect in two different tumor sizes(tumor volume 100 mm^(3) or 300 mm^(3))after single peri-tumor injection in a murine subcutaneous SGC-7901 tumor model.Animal experiments were approved by the Experimental Animal Ethics Committee of the School of Pharmacy,Fudan University.The resulting PTX NC@FA was of short rod-like shape,average particle size 175.3±2.5 nm(PDI 0.17±0.02),ζ-potential-2.5±0.2 mV,PTX loading(28.23±0.74)%(w/w)and FA-DSPE-PEG_(2000) content(4.40±0.60)%(w/w).The size of the PTX NC@FA remained unchanged for 4 days in phosphate buffer with or without serum.Cellular growth inhibition effect on SGC-7901 showed the superiority of PTX NC@FA over nanocrystals without FA modification.PTX NC@FA inhibited tumor growth more efficiently than both nanocrystals without FA modification and commercially available paclitaxel injection(Taxol)12 days after peri-tumor injection.For model tumor with the volume of 100 mm^(3),tumors of all animals in the PTX NC@FA group disappeared completely.For model tumor with the volume of 300 mm3,tumors of 3 animals in the PTX NC@FA group completely disappeared and tumors of the rest 4 animals also became significantly smaller with a tumor volume inhibition rate of 90%.PTX NC@FA showed good potential for preoperative chemo‐therapy of increase the chances of function preserving gastrectomy and improve the quality of life of patients.
作者
王俊
黄广建
刘瑜
陆伟跃
WANG Jun;HUANG Guang-jian;LIU Yu;LU Wei-yue(Key Laboratory of Smart Drug Delivery,Ministry of Education,School of Pharmacy,Fudan University,Shanghai 201203,China;Department of General Surgery,Huashan Hospital,Fudan University,Shanghai 200040,China)
出处
《药学学报》
CAS
CSCD
北大核心
2022年第1期233-241,I0007,共10页
Acta Pharmaceutica Sinica
基金
国家自然科学基金资助项目(81573361).
关键词
紫杉醇
纳米晶
叶酸化磷脂
胃癌
瘤旁注射
术前化疗
paclitaxel
nanocrystal
folic acid-modified phospholipid
gastric cancer
peritumoral injection
preoperative chemotherapy
