School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua 418000, China.
ACS Appl Mater Interfaces. 2021 Mar 31;13(12):14577-14586. doi: 10.1021/acsami.1c00184. Epub 2021 Mar 17.
In part because of their high drug loading, nanocrystals (NCs) have seen extensive use in drug delivery, particularly for insoluble or poorly soluble drugs. It remains a challenge, however, to prepare stable nanocrystals with tumor-targeting capability. Here, we designed a novel preparation of stable paclitaxel (PTX) nanocrystals with efficient active tumor-targeting properties. PTX NC was prepared using a bottom-up method and modified with both poly(ethylene glycol) (PEG) and folic acid (FA) derivatives using film hydration. The resulting PTX NC@lipid-PEG-FA had a rodlike shape, with hydrodynamic diameters and drug loading values of 201.90 ± 2.92 nm and 31.07 ± 3.41%, respectively. The size of the PTX NC@lipid-PEG-FA was unchanged after 168 h in the presence of plasma, whereas nonmodified paclitaxel nanocrystals (PTX NC) exceeded 600 nm within 12 h under the same conditions. Cellular uptake and cellular growth inhibition experiments in 4T1 breast cancer cells showed the superiority of PTX NC@lipid-PEG-FA over PTX NC or PEGylated paclitaxel nanocrystals without FA modification (PTX NC@lipid-PEG). A pharmacokinetic evaluation in rats revealed that PTX NC@lipid-PEG-FA significantly prolonged the circulation of PTX in the bloodstream, in comparison with PTX NC or Taxol. Tissue distribution and antitumor studies in 4T1 orthotopic breast cancer-bearing nude mice showed that PTX NC@lipid-PEG-FA significantly increased the intratumor accumulation of PTX and efficiently inhibited tumor growth, in comparison with PTX NC@lipid-PEG, PTX NC, or Taxol. In summary, PTX NC@lipid-PEG-FA showed good potential for breast cancer-targeted delivery for insoluble therapeutics.
部分由于其高载药量，纳米晶体（NCs）已广泛应用于药物传递，特别是对于不溶性或难溶性药物。然而，制备具有肿瘤靶向能力的稳定纳米晶体仍然是一个挑战。在这里，我们设计了一种新型的具有高效主动肿瘤靶向特性的稳定紫杉醇（PTX）纳米晶体的制备方法。PTX NC 采用自下而上的方法制备，并使用薄膜水合作用修饰聚乙二醇（PEG）和叶酸（FA）衍生物。所得 PTX NC@脂质-PEG-FA 呈棒状，水动力学直径和药物载药量分别为 201.90 ± 2.92nm 和 31.07 ± 3.41%。在存在血浆的情况下，PTX NC@脂质-PEG-FA 的尺寸在 168 小时内保持不变，而在相同条件下，未经修饰的紫杉醇纳米晶体（PTX NC）在 12 小时内超过 600nm。在 4T1 乳腺癌细胞中的细胞摄取和细胞生长抑制实验表明，PTX NC@脂质-PEG-FA 优于 PTX NC 或无 FA 修饰的 PEG 化紫杉醇纳米晶体（PTX NC@脂质-PEG）。在大鼠中的药代动力学评价表明，与 PTX NC 或 Taxol 相比，PTX NC@脂质-PEG-FA 显著延长了 PTX 在血液中的循环。在 4T1 原位乳腺癌荷瘤裸鼠中的组织分布和抗肿瘤研究表明，与 PTX NC@脂质-PEG、PTX NC 或 Taxol 相比，PTX NC@脂质-PEG-FA 显著增加了 PTX 在肿瘤中的蓄积，并有效地抑制了肿瘤生长。总之，PTX NC@脂质-PEG-FA 显示出对不溶性治疗药物的乳腺癌靶向递送的良好潜力。
