Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei 230031, PR China.
Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei 230031, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei 230088, PR China.
Int J Pharm. 2021 Apr 15;599:120418. doi: 10.1016/j.ijpharm.2021.120418. Epub 2021 Feb 27.
Nanocrystals (NCs) enable the delivery of poorly water-soluble drugs with improved dissolution and bioavailability. However, their uncontrolled release and instability make targeted delivery challenging. Herein, a nano-in-nano delivery system composed of a drug nanocrystal core and liposome shell (NC@Lipo) is presented, which merges the advantages of drug nanocrystals (high drug loading) and liposomes (easy surface functionalization and high stability) for targeted delivery of hydrophobic drugs to tumors. CHMFL-ABL-053 (053), a hydrophobic drug candidate discovered by our group, was employed as a model drug to demonstrate the performance of NC@Lipo delivery system. Surface PEGylated (053-NC@PEG-Lipo) and folic acid-functionalized (053-NC@FA-Lipo) formulations were fabricated by wet ball milling combined with probe sonication. 053-NC@Lipo enabled high drug loading (up to 19.51%), considerably better colloidal stability, and longer circulation in vivo than 053-NC. Compared with free 053, 053-NC@PEG-Lipo and 053-NC@FA-Lipo exhibited higher tumor accumulation and considerably better in vivo antitumor efficacy in K562 xenograft mice with tumor growth inhibition rate (TGI) of up to 98%. Additionally, more effective tumor cell targeting in vitro and higher TGI in vivo were achieved with 053-NC@FA-Lipo. The NC@Lipo strategy may contribute to the targeted delivery of poorly water-soluble drugs with high drug loading, high stability, and tailorable surface, and has potential for the development of more efficient nanocrystal- and liposome-based formulations for commercial and clinical applications. It may also provide new opportunities for potential clinical application of candidate 053.
纳米晶体（NCs）使具有改善的溶解和生物利用度的难溶性药物得以递药。然而，它们的不受控制的释放和不稳定性使得靶向递药具有挑战性。在此，提出了一种由药物纳米晶体核和脂质体壳组成的纳米在纳米递药系统（NC@Lipo），它融合了药物纳米晶体（高载药量）和脂质体（易于表面功能化和高稳定性）的优势，用于将疏水性药物靶向递送至肿瘤。CHMFL-ABL-053（053）是我们小组发现的一种疏水候选药物，被用作模型药物来展示 NC@Lipo 递药系统的性能。通过湿球磨法结合探针超声法制备了表面聚乙二醇化（053-NC@PEG-Lipo）和叶酸功能化（053-NC@FA-Lipo）制剂。与 053-NC 相比，053-NC@Lipo 能够实现高载药量（高达 19.51%）、更好的胶体稳定性和更长的体内循环时间。与游离 053 相比，053-NC@PEG-Lipo 和 053-NC@FA-Lipo 在 K562 异种移植小鼠中表现出更高的肿瘤积累和更好的体内抗肿瘤疗效，肿瘤生长抑制率（TGI）高达 98%。此外，在体外具有更有效的肿瘤细胞靶向性和更高的体内 TGI。NC@Lipo 策略可能有助于具有高载药量、高稳定性和可定制表面的难溶性药物的靶向递药，并且具有开发更高效的基于纳米晶体和脂质体的制剂的潜力，用于商业和临床应用。它还可能为候选药物 053 的潜在临床应用提供新的机会。
