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.

中文翻译：

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吉非替尼和阿霉素在靶向联合化疗中的延迟序贯联合分娩。

越来越多的研究表明，药物呈递的顺序在实现最佳组合治疗中起着至关重要的作用。在这里，提出了一种使用离子对和药物-聚合物共轭物的纳米颗粒设计方案，用于依次递送适用于治疗三阴性乳腺癌的靶向表皮生长因子受体（EGFR）的吉非替尼（Gi）和阿霉素（Dox）信号。为了实现这种纳米颗粒设计，将通过离子配对与二油酰磷脂酸（DOPA）络合的Gi负载到由Dox共轭聚（l-丙交酯）-嵌段-聚乙二醇（PLA- b）制成的纳米颗粒上-PEG），封装效率约为90％。通过释放和细胞摄取研究证实，纳米粒子系统表现出所需的Gi继之以Dox的顺序释放。与对照组的Dox-PLA-PEG缀合物针对MDA-MB-468和A549细胞系的对照组相比，纳米颗粒系统的抗癌效力提高了约4倍和3倍，分别是半数最大抑制浓度（IC50） 。通过无创荧光成像，还证实了纳米颗粒系统的高肿瘤蓄积性对于潜在的体内适用性。