Department of Chemical Engineering & Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON, M5S 3E5, Canada.
Institute of Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON, M5S 3G9, Canada.
Adv Sci (Weinh). 2023 May;10(13):e2300311. doi: 10.1002/advs.202300311. Epub 2023 Mar 11.
Colloidal drug aggregates enable the design of drug-rich nanoparticles; however, the efficacy of stabilized colloidal drug aggregates is limited by entrapment in the endo-lysosomal pathway. Although ionizable drugs are used to elicit lysosomal escape, this approach is hindered by toxicity associated with phospholipidosis. It is hypothesized that tuning the pK of the drug would enable endosomal disruption while avoiding phospholipidosis and minimizing toxicity. To test this idea, 12 analogs of the nonionizable colloidal drug fulvestrant are synthesized with ionizable groups to enable pH-dependent endosomal disruption while maintaining bioactivity. Lipid-stabilized fulvestrant analog colloids are endocytosed by cancer cells, and the pK of these ionizable colloids influenced the mechanism of endosomal and lysosomal disruption. Four fulvestrant analogs-those with pK values between 5.1 and 5.7-disrupted endo-lysosomes without measurable phospholipidosis. Thus, by manipulating the pK of colloid-forming drugs, a tunable and generalizable strategy for endosomal disruption is established.
胶态药物聚集体使富含药物的纳米颗粒的设计成为可能；然而，稳定的胶态药物聚集体的疗效受到内体溶酶体途径中被捕获的限制。尽管可离子化的药物被用于引发溶酶体逃逸，但这种方法受到与磷脂病相关的毒性的阻碍。据推测，调整药物的 pK 值可以在避免磷脂病和最小化毒性的同时实现内体破坏。为了验证这一想法，合成了 12 种非离子化胶态药物氟维司群的类似物，这些类似物带有可离子化的基团，以实现 pH 依赖性的内体破坏，同时保持生物活性。脂质稳定的氟维司群类似物胶体被癌细胞内吞，这些可离子化胶体的 pK 值影响内体和溶酶体破坏的机制。四种氟维司群类似物——pK 值在 5.1 到 5.7 之间的类似物——在没有可测量的磷脂病的情况下破坏了内体溶酶体。因此，通过操纵胶态形成药物的 pK 值，建立了一种可调节和可推广的内体破坏策略。
