Fonseca Cristina, Simões Sérgio, Gaspar Rogério
Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3000, Coimbra, Portugal.
J Control Release. 2002 Oct 4;83(2):273-286. doi: 10.1016/s0168-3659(02)00212-2.
The main objective of this study was to develop a polymeric drug delivery system for paclitaxel, intended to be intravenously administered, capable of improving the therapeutic index of the drug and devoid of the adverse effects of Cremophor EL. To achieve this goal paclitaxel (Ptx)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Ptx-PLGA-Nps) were prepared by the interfacial deposition method. The influence of different experimental parameters on the incorporation efficiency of paclitaxel in the nanoparticles was evaluated. Our results demonstrate that the incorporation efficiency of paclitaxel in nanoparticles was mostly affected by the method of preparation of the organic phase and also by the organic phase/aqueous phase ratio. Our data indicate that the methodology of preparation allowed the formation of spherical nanometric (<200 nm), homogeneous and negatively charged particles which are suitable for intravenous administration. The release behaviour of paclitaxel from the developed Nps exhibited a biphasic pattern characterised by an initial fast release during the first 24 h, followed by a slower and continuous release. The in vitro anti-tumoral activity of Ptx-PLGA-Nps developed in this work was assessed using a human small cell lung cancer cell line (NCI-H69 SCLC) and compared to the in vitro anti-tumoral activity of the commercial formulation Taxol. The influence of Cremophor EL on cell viability was also investigated. Exposure of NCI-H69 cells to 25 microg/ml Taxol resulted in a steep decrease in cell viability. Our results demonstrate that incorporation of Ptx in nanoparticles strongly enhances the cytotoxic effect of the drug as compared to Taxol, this effect being more relevant for prolonged incubation times.
本研究的主要目的是开发一种用于紫杉醇的聚合物药物递送系统，旨在静脉给药，能够提高药物的治疗指数并避免聚氧乙烯蓖麻油（Cremophor EL）的不良反应。为实现这一目标，采用界面沉积法制备了负载紫杉醇（Ptx）的聚乳酸-羟基乙酸共聚物（PLGA）纳米颗粒（Ptx-PLGA-Nps）。评估了不同实验参数对纳米颗粒中紫杉醇包封效率的影响。我们的结果表明，纳米颗粒中紫杉醇的包封效率主要受有机相制备方法以及有机相/水相比例的影响。我们的数据表明，制备方法能够形成适合静脉给药的球形纳米级（<200 nm）、均匀且带负电荷的颗粒。所制备的纳米颗粒中紫杉醇的释放行为呈现出双相模式，其特征是在最初24小时内有一个快速的初始释放，随后是较慢且持续的释放。使用人小细胞肺癌细胞系（NCI-H69 SCLC）评估了本研究中制备的Ptx-PLGA-Nps的体外抗肿瘤活性，并与市售制剂紫杉醇的体外抗肿瘤活性进行了比较。还研究了聚氧乙烯蓖麻油对细胞活力的影响。将NCI-H69细胞暴露于25μg/ml紫杉醇会导致细胞活力急剧下降。我们的结果表明，与紫杉醇相比，将紫杉醇包封在纳米颗粒中可显著增强药物的细胞毒性作用，这种作用在延长孵育时间时更为明显。
