Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology, ICTP-CSIC, Juan de la Cierva, 3, 28006, Madrid, Spain.
Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Madrid, Spain.
J Mater Sci Mater Med. 2017 Aug 31;28(10):152. doi: 10.1007/s10856-017-5963-y.
Active targeting not only of a specific cell but also a specific organelle maximizes the therapeutic activity minimizing adverse side effects in healthy tissues. The present work describes the synthesis, characterization, and in vitro biological activity of active targeting nanoparticles (NP) for cancer therapy based on α-tocopheryl succinate (α-TOS), a well-known mitocan, that selectively induces apoptosis of cancer cells and proliferalting endothelial cells. Human epidermal growth factor receptor 2 (HER2) targeting peptide LTVSPWY (PEP) and triphenylphosphonium lipophilic cation (TPP) were conjugated to a previously optimized RAFT block copolymer that formed self-assembled NP of appropriate size for this application and low polydispersity by self-organized precipitation method. PEP and TPP were included in order to target not only HER2 positive cancer cells, but also the mitochondria of these cancer cells, respectively. The in vitro experiments demonstrated the faster incorporation of the active-targeting NP and the higher accumulation of TPP-bearing NP in the mitochondria of MDA-MB-453 HER2 positive cancer cells compared to non-decorated NP. Moreover, the encapsulation of additional α-TOS in the hydrophobic core of the NP was achieved with high efficiencies. The loaded NP presented higher cytotoxicity than unloaded NP but preserved their selectivity against cancer cells in a range of tested concentrations.
主动靶向不仅针对特定的细胞，而且还针对特定的细胞器，最大限度地提高治疗活性，最大限度地减少健康组织的不良反应。本工作描述了基于 α-生育酚琥珀酸酯（α-TOS）的主动靶向纳米颗粒（NP）的合成、表征和体外生物学活性，α-TOS 是一种众所周知的线粒体靶向剂，可选择性诱导癌细胞凋亡和增殖的内皮细胞。人表皮生长因子受体 2（HER2）靶向肽 LTVSPWY（PEP）和三苯基膦亲脂阳离子（TPP）与先前优化的 RAFT 嵌段共聚物缀合，该嵌段共聚物通过自组织沉淀法形成适用于该应用的适当大小且低多分散性的自组装 NP。PEP 和 TPP 被包含在内，目的不仅是为了靶向 HER2 阳性癌细胞，还为了靶向这些癌细胞的线粒体。体外实验表明，与非修饰 NP 相比，主动靶向 NP 更快地被细胞摄取，并且携带 TPP 的 NP 更易在 MDA-MB-453 HER2 阳性癌细胞的线粒体中积累。此外，还可以以高效率将额外的 α-TOS 封装在 NP 的疏水性核心内。负载 NP 比未负载 NP 具有更高的细胞毒性，但在测试浓度范围内对癌细胞仍保持其选择性。
