Department of Chemistry, University of Tennessee, 1420 Circle Drive, Knoxville, Tennessee 37996, United States.
Bioconjug Chem. 2021 Dec 15;32(12):2485-2496. doi: 10.1021/acs.bioconjchem.1c00425. Epub 2021 Dec 6.
Liposomes are effective nanocarriers due to their ability to encapsulate and deliver a wide variety of therapeutics. However, therapeutic potential would be improved by enhanced control over the release of drug cargo. Zinc ions provide exciting new targets for stimuli-responsive lipid design due to their overly abundant concentrations associated with diseased cells. Herein, we report zinc-triggered release of liposomal contents exploiting synthetic lipid switches designed to undergo conformational changes in the presence of this ion. Initially, Nile red leakage assays were conducted that validated successful dose-dependent triggering of release using zinc-responsive lipids (ZRLs). In addition, dynamic light scattering and confocal microscopy experiments showed that zinc treatment led to morphological changes in lipid nanoparticles only when ZRLs were present in formulations. Next, zinc-binding experiments conducted in a solution (NMR, MS) or membrane (zeta potential) context confirmed ZRL-Zn complexation. Finally, polar cargo release from liposomes was achieved. The results from these wide-ranging experiments using four different compounds indicated that zinc-responsive properties varied based on ZRL structure, providing insights into the structural requirements for activity. This work has established zinc-responsive liposomal platforms toward the development of clinical triggered release formulations.
脂质体由于其能够包裹和递送各种治疗药物的能力，是一种有效的纳米载体。然而，如果能够增强对药物货物释放的控制，那么其治疗潜力将会得到提高。锌离子为刺激响应性脂质设计提供了令人兴奋的新目标，因为它们与患病细胞相关的浓度过高。在此，我们报告了利用旨在在存在这种离子时发生构象变化的合成脂质开关来触发脂质体内容物的锌触发释放。最初，进行了尼罗红泄漏测定，该测定验证了使用锌响应性脂质（ZRL）进行的成功的剂量依赖性触发释放。此外，动态光散射和共焦显微镜实验表明，只有在制剂中存在 ZRL 时，锌处理才会导致脂质纳米颗粒的形态发生变化。接下来，在溶液（NMR、MS）或膜（ζ电位）环境中进行的锌结合实验证实了 ZRL-Zn 络合。最后，实现了从脂质体中释放极性货物。使用四种不同化合物进行的这些广泛实验的结果表明，锌响应特性基于 ZRL 结构而变化，为活性的结构要求提供了见解。这项工作已经建立了锌响应脂质体平台，以开发临床触发释放制剂。
