Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China.
School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.
Int J Pharm. 2019 Feb 10;556:217-225. doi: 10.1016/j.ijpharm.2018.12.023. Epub 2018 Dec 14.
Nanocrystals has been constructed for insoluble drugs as a novel type of nanoscale drug delivery systems with high drug loading. How to prepare nanocrystals with good stability and tumor targeting capability is still challenging. This study was to modify paclitaxel nanocrystals with polyethylene glycol (PEG) for stabilization and RGD peptide for tumor targeting. Inspired by the structure of mussel's foot protein, polydopamine (PDA) was introduced to the drug delivery system for the modification of nanocrystals. Briefly, PDA was coated on the surface of nanocrystals to form a reaction platform for further PEGylation and RGD peptide conjugation. PEGylated nanocrystals with RGD peptide modification (NC@PDA-PEG-RGD) were prepared with near-spheroid shape, drug loading 45.12 ± 1.81% and a hydrodynamic diameter 419.9 ± 80.9 nm. The size of NC@PDA-PEG-RGD remained basically unchanged for at least 72 h in the presence of plasma while the size of unmodified nanocrystals (NC) increased and exceeded 1000 nm in 12 h. Cellular uptake and cellular growth inhibition experiments using the lung cancer cell line A549 demonstrated the superiority of NC@PDA-PEG-RGD over NC or PEGylated nanocrystals without RGD modification (NC@PDA-PEG). In A549 model tumor bearing-mice, NC@PDA-PEG-RGD showed significantly higher intratumor accumulation and slower tumor growth than NC@PDA-PEG or free paclitaxel. In summary, our study suggested the superiority of RGDmodified PEGylated paclitaxel nanocrystals as a lung cancer-targeted delivery system and the potential of PDA coating technique for targeting functionalization of nanocrystals.
纳米晶体已被构建为一种新型的纳米级药物传递系统，用于负载高浓度的难溶性药物。如何制备具有良好稳定性和肿瘤靶向能力的纳米晶体仍然具有挑战性。本研究旨在通过聚乙二醇（PEG）稳定化和 RGD 肽肿瘤靶向修饰紫杉醇纳米晶体。受贻贝足部蛋白结构的启发，本研究将聚多巴胺（PDA）引入药物传递系统，用于纳米晶体的修饰。简而言之，PDA 被涂覆在纳米晶体表面，形成用于进一步 PEG 化和 RGD 肽缀合的反应平台。通过 PEG 化和 RGD 肽修饰（NC@PDA-PEG-RGD）制备了近球形的纳米晶体，载药量为 45.12±1.81%，水动力学直径为 419.9±80.9nm。在存在血浆的情况下，NC@PDA-PEG-RGD 的粒径至少在 72 小时内基本保持不变，而未经修饰的纳米晶体（NC）的粒径在 12 小时内增加并超过 1000nm。使用肺癌细胞系 A549 进行的细胞摄取和细胞生长抑制实验表明，NC@PDA-PEG-RGD 优于 NC 或未经 RGD 修饰的 PEG 化纳米晶体（NC@PDA-PEG）。在 A549 荷瘤模型小鼠中，NC@PDA-PEG-RGD 显示出比 NC@PDA-PEG 或游离紫杉醇更高的肿瘤内积累和更缓慢的肿瘤生长。综上所述，本研究表明 RGD 修饰的 PEG 化紫杉醇纳米晶体作为肺癌靶向递药系统具有优越性，并且 PDA 涂层技术具有纳米晶体靶向功能化的潜力。
