Peters Erica B, Karver Mark R, Sun Kui, Gillis David C, Biswas Suvendu, Clemons Tristan D, He Wenhan, Tsihlis Nick D, Stupp Samuel I, Kibbe Melina R
Department of Surgery, Division of Vascular Surgery and Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Simpson Querrey Institute, Northwestern University, Chicago, IL 60611, USA.
Adv Ther (Weinh). 2021 Sep;4(9). doi: 10.1002/adtp.202100103. Epub 2021 Jul 23.
Atherosclerotic plaque remains the leading contributor to cardiovascular disease and requires invasive surgical procedures for its removal. Nanomedicine offers a minimally invasive approach to alleviate plaque burden by targeted therapeutic delivery. However, nanocarriers are limited without the ability to sense and respond to the diseased microenvironment. In this study, targeted self-assembled peptide amphiphile (PA) nanofibers were developed that cleave in response to biochemical cues expressed in atherosclerotic lesions-reactive oxygen species (ROS) and intracellular glutathione-to deliver a liver X receptor agonist (LXR) to enhance macrophage cholesterol efflux. The PAs released LXR in response to physiological levels of ROS and reducing agents and could be co-assembled with plaque-targeting PAs to form nanofibers. The resulting LXR PA nanofibers promoted cholesterol efflux from macrophages as well as LXR alone and with lower cytotoxicity. Further, the ApoA1-LXR PA nanofibers targeted plaque within an atherosclerotic mouse model and activated ATP-binding cassette A1 (ABCA1) expression as well as LXR alone with reduced liver toxicity. Taken together, these results demonstrate the potential of self-assembled PA nanofibers for controlled therapeutic delivery to the atherosclerotic niche.
动脉粥样硬化斑块仍然是心血管疾病的主要病因，需要通过侵入性外科手术来清除。纳米医学提供了一种微创方法，通过靶向治疗递送减轻斑块负担。然而，纳米载体如果没有感知和响应病变微环境的能力，其作用将受到限制。在本研究中，开发了靶向自组装肽两亲分子（PA）纳米纤维，其可响应动脉粥样硬化病变中表达的生化信号——活性氧（ROS）和细胞内谷胱甘肽——而裂解，从而递送肝脏X受体激动剂（LXR）以增强巨噬细胞胆固醇外流。PA可响应生理水平的ROS和还原剂释放LXR，并可与靶向斑块的PA共同组装形成纳米纤维。所得的LXR PA纳米纤维促进巨噬细胞胆固醇外流的能力与单独使用LXR时相当，且细胞毒性更低。此外，ApoA1-LXR PA纳米纤维在动脉粥样硬化小鼠模型中靶向斑块，并激活ATP结合盒A1（ABCA1）表达，其效果与单独使用LXR时相当，但肝脏毒性降低。综上所述，这些结果证明了自组装PA纳米纤维在向动脉粥样硬化微环境进行可控治疗递送方面的潜力。
