Zinger Assaf, Baudo Gherardo, Naoi Tomoyuki, Giordano Federica, Lenna Stefania, Massaro Matteo, Ewing April, Kim Ha Ram, Tasciotti Ennio, Yustein Jason T, Taraballi Francesca
Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, Texas 77030, United States.
Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, Texas 77030, United States.
ACS Appl Bio Mater. 2020 Oct 19;3(10):6737-6745. doi: 10.1021/acsabm.0c00685. Epub 2020 Sep 2.
Ponatinib (Pon) is a multi-tyrosine kinase inhibitor that demonstrated high efficiency for treating cancer. However, severe side effects caused by Pon off-targeting effects prevent its extensive use. Using our understanding into the mechanisms by which Pon is transported by bovine serum albumin in the blood, we have successfully encapsulated Pon into a biomimetic nanoparticle (NP). This lipid NP (i.e., "leukosomes") incorporates membrane proteins purified from activated leukocytes that enable immune evasion, and enhanced targeting of inflamed endothelium NPs have been characterized for their size, charge, and encapsulation efficiency. Membrane proteins enriched on the NP surface enabled modulation of Pon release. These NP formulations showed promising dose-response results on two different murine osteosarcoma cell lines, F420 and RF379. Our results indicate that our fabrication method is reproducible, nonuser-dependent, efficient in loading Pon, and applicable toward repurposing numerous therapeutic agents previously shelved due to toxicity profiles.
波纳替尼（Pon）是一种多酪氨酸激酶抑制剂，对癌症治疗显示出高效性。然而，波纳替尼的脱靶效应所导致的严重副作用阻碍了其广泛应用。基于我们对波纳替尼在血液中由牛血清白蛋白转运机制的理解，我们已成功地将波纳替尼封装到一种仿生纳米颗粒（NP）中。这种脂质纳米颗粒（即“白细胞体”）包含从活化白细胞中纯化的膜蛋白，这些膜蛋白能够实现免疫逃逸，并且增强了对炎症内皮的靶向性。纳米颗粒的大小、电荷和包封效率已得到表征。富集在纳米颗粒表面的膜蛋白能够调节波纳替尼的释放。这些纳米颗粒制剂在两种不同的小鼠骨肉瘤细胞系F420和RF379上显示出有前景的剂量反应结果。我们的结果表明，我们的制备方法具有可重复性、不依赖用户、在加载波纳替尼方面效率高，并且适用于将许多因毒性特征而先前搁置的治疗药物重新用于其他用途。
