Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People's Republic of China.
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People's Republic of China.
Int J Nanomedicine. 2021 Oct 27;16:7269-7281. doi: 10.2147/IJN.S331578. eCollection 2021.
Small molecule modified antitumor drug conjugate nanoparticles have the advantages of high drug loading, simple synthesis and preparation, and better biocompatibility. Due to the large demand for exogenous α-linolenic acid (ALA) by tumor cells, we synthesized α-linolenic acid-paclitaxel conjugate (ALA-PTX) and prepared α-linolenic acid-paclitaxel conjugate nanoparticles (ALA-PTX NPs), in order to obtain better tumor cellular uptake and antitumor activity in vitro and in vivo.
We synthesized and characterized ALA-PTX, and then prepared and characterized ALA-PTX NPs. The cellular uptake, uptake pathways, intracellular behavior, in vitro and in vivo antitumor activity of ALA-PTX NPs were evaluated.
The size of ALA-PTX NPs was approximately 110.7±1.7 nm. The drug loading was approximately 90% (w/w) with CrEL-free and organic solvent-free characteristics. The cellular uptake of ALA-PTX NPs was significantly higher than that of PTX injection by MCF-7, MCF-7/ADR and HepG2 cells. In these three cell lines, the cellular uptake of ALA-PTX NPs at 6h was approximately 1.5-2.6 times higher than that of PTX injection. ALA-PTX NPs were ingested through clathrin-mediated endocytosis, then transferred to lysosomes, and could dissolve in cells to play an antitumor activity. The in vitro and in vivo antitumor activity of ALA-PTX NPs was confirmed in MCF-7/ADR and HepG2 cell models and tumor-bearing nude mouse models.
ALA-PTX NPs developed in our study could provide a new method for the preparation of nano-delivery systems suitable for antitumor therapy that could increase tumor cellular uptake and enhance antitumor activity.
小分子修饰的抗肿瘤药物偶联纳米粒具有载药量大、合成及制备简单、生物相容性好等优点。由于肿瘤细胞对外源 α-亚麻酸（ALA）的需求量较大，我们合成了 α-亚麻酸-紫杉醇偶联物（ALA-PTX），并制备了 α-亚麻酸-紫杉醇偶联纳米粒（ALA-PTX NPs），以期获得更好的肿瘤细胞摄取和体内外抗肿瘤活性。
我们合成并表征了 ALA-PTX，然后制备并表征了 ALA-PTX NPs。评价了 ALA-PTX NPs 的细胞摄取、摄取途径、细胞内行为、体外和体内抗肿瘤活性。
ALA-PTX NPs 的粒径约为 110.7±1.7nm。载药量约为 90%（w/w），具有无 CrEL 和有机溶剂的特点。ALA-PTX NPs 在 MCF-7、MCF-7/ADR 和 HepG2 细胞中的细胞摄取明显高于 PTX 注射液。在这三种细胞系中，ALA-PTX NPs 在 6h 的细胞摄取量比 PTX 注射液高 1.5-2.6 倍。ALA-PTX NPs 通过网格蛋白介导的内吞作用被摄取，然后转移到溶酶体中，并能在细胞内溶解发挥抗肿瘤活性。在 MCF-7/ADR 和 HepG2 细胞模型和荷瘤裸鼠模型中证实了 ALA-PTX NPs 的体外和体内抗肿瘤活性。
本研究中开发的 ALA-PTX NPs 为制备适合抗肿瘤治疗的纳米递药系统提供了一种新方法，可增加肿瘤细胞摄取，增强抗肿瘤活性。
