Institute of Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON, M5S 3G9, Canada.
Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON, M5S 3E1, Canada.
Adv Mater. 2024 Oct;36(41):e2403701. doi: 10.1002/adma.202403701. Epub 2024 Aug 15.
Targeting complementary pathways in diseases such as cancer can be achieved with co-delivery of small interfering ribonucleic acid (siRNA) and small molecule drugs; however, current formulation strategies are typically limited to one, but not both. Here, ionizable small molecule drugs and siRNA are co-formulated in drug-rich nanoparticles. Ionizable analogs of the selective estrogen receptor degrader fulvestrant self-assemble into colloidal drug aggregates and cause endosomal disruption, allowing co-delivery of siRNA against a non-druggable target. siRNA is encapsulated in lipid-stabilized, drug-rich colloidal nanoparticles where the ionizable lipid used in conventional lipid nanoparticles is replaced with an ionizable fulvestrant analog. The selection of an appropriate phospholipid and formulation buffer enables endocytosis and potent reporter gene knockdown in cancer cells. Importantly, siRNA targeting cyclin E1 is effectively delivered to drug-resistant breast cancer cells, demonstrating the utility of this approach. This strategy opens the possibility of using ionizable drugs to co-deliver RNA and ultimately improve therapeutic outcomes.
靶向癌症等疾病中的互补途径可以通过小干扰核糖核酸 (siRNA) 和小分子药物的共递送来实现；然而，目前的制剂策略通常仅限于一种，而不是两种。在这里，可离子化的小分子药物和 siRNA 共包封在富含药物的纳米颗粒中。选择性雌激素受体降解剂氟维司群的可离子化类似物自组装成胶体药物聚集体，并导致内体破坏，从而共递送针对不可成药靶点的 siRNA。siRNA 被包封在脂质稳定的富含药物的胶体纳米颗粒中，其中在传统脂质纳米颗粒中使用的可离子化脂质被可离子化的氟维司群类似物取代。选择合适的磷脂和制剂缓冲液可使内吞作用和癌症细胞中报告基因的有效敲低。重要的是，针对细胞周期蛋白 E1 的 siRNA 被有效递送至耐药乳腺癌细胞，证明了这种方法的实用性。这种策略为使用可离子化药物共递送 RNA 并最终改善治疗结果开辟了可能性。
