College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea; Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada.
Formulation Research Lab. DONG-WHA PHARM. Research Institute, Yongin 17084, Republic of Korea.
J Control Release. 2020 Aug 10;324:55-68. doi: 10.1016/j.jconrel.2020.05.001. Epub 2020 May 4.
The aims of this study were to design different chain length fatty acid-conjugated albumin nanoparticles (ANPs) and evaluate their anticancer activity in the HCT116 human colorectal cancer xenograft mouse model. Doxorubicin hydrochloride (DOX·HCl) was chosen as a model drug. The different chain lengths of fatty acids (butyric acid; C4, and stearic acid; C18) in albumin conjugates exhibited different physicochemical properties and anticancer activity. Fatty acid-conjugated albumin aided the formation of self-assembled structures with an average size of approximately 200 nm and a negative charge when incubated with excess DOX in an aqueous solution. DOX-loaded long-chain C18-conjugated ANPs allowed efficient encapsulation of hydrophobic DOX into the core of the self-assembled structure, enabling higher drug loading, enhanced colloidal stability and controlled release behavior in PBS pH 7.4 medium as compared with free DOX·HCl or non-fatty acid conjugated ANPs. Furthermore, DOX-loaded fatty acid-conjugated ANPs showed an increased cellular uptake intensity and cytotoxic effects in vitro. In vivo, HCT116 xenograft model experiments confirmed that DOX-loaded C18-conjugated ANPs showed improved anticancer activity and reduced side effects compared with the DOX-treated groups. The long-chain fatty acid-conjugated ANPs synergistically activated the interaction with the free-fatty acid receptor (FFAR) on HCT116 colorectal cancer cells as compared with short-chain C4 or other non-conjugated ANPs. Specifically, DOX-loaded C18-conjugated NPs exhibited significant performance to overexpressed FFAR4 on HCT116 colorectal cancer cells. The fatty acid chain length in the fattigation-platform system could be a promising molecular moiety to improve targeting efficiency and drug accumulation in various cancer therapy.
本研究旨在设计不同链长脂肪酸修饰白蛋白纳米粒（ANPs），并在 HCT116 人结直肠癌细胞异种移植小鼠模型中评估其抗癌活性。盐酸多柔比星（DOX·HCl）被选为模型药物。白蛋白缀合物中不同链长的脂肪酸（丁酸；C4 和硬脂酸；C18）表现出不同的理化性质和抗癌活性。脂肪酸修饰的白蛋白有助于在水溶液中与过量 DOX 孵育时形成平均大小约为 200nm 的自组装结构，带负电荷。载 DOX 的长链 C18 修饰的 ANPs 能够将疏水性 DOX 高效包封到自组装结构的核心内，与游离 DOX·HCl 或非脂肪酸修饰的 ANPs 相比，载药纳米粒具有更高的载药量、增强的胶体稳定性和在 PBS pH7.4 介质中的控制释放行为。此外，载 DOX 的脂肪酸修饰的 ANPs 在体外显示出增强的细胞摄取强度和细胞毒性作用。在体内，HCT116 异种移植模型实验证实，与 DOX 处理组相比，载 DOX 的 C18 修饰的 ANPs 显示出改善的抗癌活性和降低的副作用。与短链 C4 或其他非修饰的 ANPs 相比，长链脂肪酸修饰的 ANPs 协同激活了与 HCT116 结直肠癌细胞上游离脂肪酸受体（FFAR）的相互作用。具体来说，载 DOX 的 C18 修饰的 NPs 对 HCT116 结直肠癌细胞上过表达的 FFAR4 表现出显著的作用。在fattigation 平台系统中，脂肪酸链长可以作为一种有前途的分子部分，以提高各种癌症治疗中的靶向效率和药物积累。
