Chemical Biology, Molecular Medicine Division, Rajiv Gandhi Centre for Biotechnology, Poojappura, Thiruvananthapuram, Kerala, India.
Int J Nanomedicine. 2011;6:1685-97. doi: 10.2147/IJN.S20165. Epub 2011 Aug 17.
Nanoscaled devices have great potential for drug delivery applications due to their small size. In the present study, we report for the first time the preparation and evaluation of antitumor efficacy of 5-fluorouracil (5-FU)-entrapped poly (D, L-lactic-co-glycolic acid) (PLGA) nanoparticles with dependence on the lactide/glycolide combination of PLGA. 5-FU-loaded PLGA nanoparticles with two different monomer combinations, 50-50 and 90-10 were synthesized using a modified double emulsion method, and their biological evaluation was done in glioma (U87MG) and breast adenocarcinoma (MCF7) cell lines. 5-FU-entrapped PLGA 50-50 nanoparticles showed smaller size with a high encapsulation efficiency of 66%, which was equivalent to that of PLGA 90-10 nanoparticles. Physicochemical characterization of nanoparticles using differential scanning calorimetry and X-ray diffraction suggested the presence of 5-FU in molecular dispersion form. In vitro release studies showed the prolonged and sustained release of 5-FU from nanoparticles with both the PLGA combinations, where PLGA 50-50 nanoparticles showed faster release. Nanoparticles with PLGA 50-50 combination exhibited better cytotoxicity than free drug in a dose- and time-dependent manner against both the tumor cell lines. The enhanced efficiency of PLGA 50-50 nanoparticles to induce apoptosis was indicated by acridine orange/ethidium bromide staining. Cell cycle perturbations studied using flow cytometer showed better S-phase arrest by nanoparticles in comparison with free 5-FU. All the results indicate that PLGA 50-50 nanoparticles possess better antitumor efficacy than PLGA 90-10 nanoparticles and free 5-FU. Since, studies have shown that long-term exposure of ailing tissues to moderate drug concentrations is more favorable than regular administration of higher concentration of the drug; our results clearly indicate the potential of 5-FU-loaded PLGA nanoparticles with dependence on carrier combination as controlled release formulation to multiplex the therapeutic effect of cancer chemotherapy.
由于其体积小，纳米级设备在药物输送应用中具有巨大的潜力。在本研究中，我们首次报道了依赖于 PLGA 的丙交酯/乙交酯组合制备和评价载 5-氟尿嘧啶（5-FU）的聚（D，L-丙交酯-共-乙交酯）（PLGA）纳米粒的抗肿瘤功效。使用改良的双重乳液法合成了两种不同单体组合的 5-FU 负载 PLGA 纳米粒，50-50 和 90-10，并在神经胶质瘤（U87MG）和乳腺癌（MCF7）细胞系中进行了生物评价。5-FU 负载的 PLGA 50-50 纳米粒粒径较小，包封效率为 66%，与 PLGA 90-10 纳米粒相当。使用差示扫描量热法和 X 射线衍射对纳米粒进行的物理化学特性分析表明，5-FU 以分子分散形式存在。体外释放研究表明，两种 PLGA 组合的纳米粒均能延长和持续释放 5-FU，其中 PLGA 50-50 纳米粒释放更快。PLGA 50-50 组合的纳米粒在剂量和时间依赖性方面对两种肿瘤细胞系均表现出比游离药物更好的细胞毒性。吖啶橙/溴化乙锭染色表明，PLGA 50-50 纳米粒诱导细胞凋亡的效率更高。用流式细胞仪研究细胞周期扰动表明，与游离 5-FU 相比，纳米粒可更好地阻滞 S 期。所有结果均表明，PLGA 50-50 纳米粒的抗肿瘤功效优于 PLGA 90-10 纳米粒和游离 5-FU。由于研究表明，与常规给予更高浓度的药物相比，使患病组织长期暴露于适度药物浓度下更有利；我们的结果清楚地表明，依赖于载体组合的载 5-FU 的 PLGA 纳米粒作为控释制剂具有作为癌症化疗的多效治疗效果的潜力。
