Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences, Dr. H. S. Gour University, Sagar, India.
Drug Deliv. 2010 Nov;17(8):561-72. doi: 10.3109/10717544.2010.500635.
The present investigation was aimed to develop and explore the prospective of engineered PLGA nanoparticles as vehicles for targeted delivery of 5-fluorouracil (5-FU). Nanoparticles of 5-FU-loaded hyaluronic acid-poly(ethylene glycol)-poly(lactide-co-glycolide) (HA-PEG-PLGA-FU) copolymer were prepared and characterized by FTIR, NMR, transmission electron microscopy, particle size analysis, DSC, and X-ray diffractometer measurement studies. The nanoparticulate formulation was evaluated for in vitro release, hemolytic toxicity, and hematological toxicity. Cytotoxicity studies were performed on Ehrlich ascites tumor (EAT) cell lines using MTT cell proliferation assay. Biodistribution studies of 99m Tc labeled formulation were conducted on EAT-bearing mice. The in vivo tumor inhibition study was also performed after i.v. administration of HA-PEG-PLGA-FU nanoparticles. The HA conjugated formulation was found to be less hemolytic but more cytotoxic as compared to free drug. The hematological data suggested that HA-PEG-PLGA-FU formulation was less immunogenic compared to plain drug. The tissue distribution studies displayed that HA-PEG-PLGA-FU were able to deliver a higher concentration of 5-FU in the tumor mass. In addition, the HA-PEG-PLGA-FU nanoparticles reduced tumor volume significantly in comparison with 5-FU. Thus, it was concluded that the conjugation of HA imparts targetability to the formulation, and enhanced permeation and retention effect ruled out its access to the non-tumor tissues, at the same time favored selective entry in tumors, thereby reducing the side-effects both in vitro and in vivo.
本研究旨在开发并探索载有 5-氟尿嘧啶（5-FU）的工程 PLGA 纳米粒子作为靶向给药载体的潜力。通过傅里叶变换红外光谱（FTIR）、核磁共振（NMR）、透射电子显微镜（TEM）、粒径分析、差示扫描量热法（DSC）和 X 射线衍射仪（XRD）测量研究，对载有 5-FU 的透明质酸-聚乙二醇-聚（乳酸-共-乙醇酸）（HA-PEG-PLGA-FU）共聚物纳米粒子进行了制备和表征。对纳米粒制剂进行了体外释放、溶血毒性和血液毒性评价。采用 MTT 细胞增殖测定法，在艾氏腹水瘤（EAT）细胞系上进行了细胞毒性研究。对荷 EAT 小鼠进行了 99mTc 标记制剂的生物分布研究。静脉注射 HA-PEG-PLGA-FU 纳米粒子后，还进行了体内肿瘤抑制研究。与游离药物相比，连接透明质酸的制剂溶血作用较弱，但细胞毒性较强。血液学数据表明，与普通药物相比，HA-PEG-PLGA-FU 制剂的免疫原性较低。组织分布研究显示，HA-PEG-PLGA-FU 能够将更高浓度的 5-FU 递送至肿瘤组织中。此外，与 5-FU 相比，HA-PEG-PLGA-FU 纳米粒子显著降低了肿瘤体积。因此，可以得出结论，透明质酸的结合赋予了制剂靶向性，同时增强了渗透和保留效应，阻止了其进入非肿瘤组织，同时有利于选择性进入肿瘤，从而减少了体外和体内的副作用。
