Chemical Engineering Program, Department of Chemical and Environmental Engineering, University of Cincinnati , Cincinnati, Ohio 45221-0012, United States.
Department of Cancer Biology, College of Medicine University of Cincinnati , Cincinnati, Ohio 45267-0521, United States.
Mol Pharm. 2017 Dec 4;14(12):4551-4559. doi: 10.1021/acs.molpharmaceut.7b00669. Epub 2017 Nov 7.
There are an increasing number of studies showing the order of drug presentation plays a critical role in achieving optimal combination therapy. Here, a nanoparticle design is presented using ion pairing and drug-polymer conjugate for the sequential delivery of gefitinib (Gi) and doxorubicin (Dox) targeting epidermal growth factor receptor (EGFR) signaling applicable for the treatment of triple negative breast cancers. To realize this nanoparticle design, Gi complexed with dioleoyl phosphatidic acid (DOPA) via ion paring was loaded onto the nanoparticle made of Dox-conjugated poly(l-lactide)-block-polyethylene glycol (PLA-b-PEG) and with an encapsulation efficiency of ∼90%. The nanoparticle system exhibited a desired sequential release of Gi followed by Dox, as verified through release and cellular uptake studies. The nanoparticle system demonstrated approximate 4-fold and 3-fold increases in anticancer efficacy compared to a control group of Dox-PLA-PEG conjugate against MDA-MB-468 and A549 cell lines in terms of half maximal inhibitory concentration (IC50), respectively. High tumor accumulation of the nanoparticle system was also substantiated for potential in vivo applicability by noninvasive fluorescent imaging.
越来越多的研究表明，药物呈现顺序在实现最佳联合治疗方面起着关键作用。在这里，提出了一种使用离子对和药物-聚合物缀合物的纳米颗粒设计，用于顺序递送电疗（Gi）和阿霉素（Dox），针对表皮生长因子受体（EGFR）信号，适用于治疗三阴性乳腺癌。为了实现这种纳米颗粒设计，通过离子配对将 Gi 与二油酰磷脂酸（DOPA）复合，负载到由 Dox 缀合的聚（L-丙交酯）-嵌段-聚乙二醇（PLA-b-PEG）制成的纳米颗粒上，包封效率约为 90%。通过释放和细胞摄取研究验证了纳米颗粒系统表现出所需的 Gi 随后是 Dox 的顺序释放。与 Dox-PLA-PEG 缀合物的对照组相比，该纳米颗粒系统在 MDA-MB-468 和 A549 细胞系中，在半最大抑制浓度（IC50）方面，抗癌功效分别提高了约 4 倍和 3 倍。通过非侵入性荧光成像，还证实了纳米颗粒系统在高肿瘤积累方面具有潜在的体内适用性。
