Li Bin, Chu Feng, Lu Qian, Wang Yiqing, Lane Lucas A
Department of Biomedical Engineering, College of Engineering and Applied Sciences, Nanjing University, Jiangsu Province 210093, China; Department of Biochemistry and Cell Biology, Guanxi University of Science and Technology, Guangxi Province 545000, China.
Department of Biomedical Engineering, College of Engineering and Applied Sciences, Nanjing University, Jiangsu Province 210093, China.
Acta Biomater. 2021 Feb;121:527-540. doi: 10.1016/j.actbio.2020.11.047. Epub 2020 Dec 5.
In efforts to achieve minimal systemic toxicity and high tumor delivery efficiencies in cancer therapy, various nanomedicine formulations having stealth polymer coatings have been developed for minimizing immune cell uptake and off-target macrophage phagocyte system (MPS) organ accumulation. Despite an initial reduction in immune cell uptake, stealth nanoparticles still initiate an antibody immune response. This response acts on subsequent administrations in treatment regimens resulting in accelerated blood clearance of particles into MPS organs, particularly the liver, where they are retained for prolonged periods. Consequently, doses after the first administration in treatment regimens have diminished tumor accumulation and increased MPS toxicity. Here, we present a strategy reducing antibody responses to each dose in a treatment regimen by alternating between polyethylene-glycol and polymethyloxazoline polymers as the nanoparticle coating between administrations. In a weekly dosing regimen, we find that the first dose of particles having either coating display similar favorable pharmacokinetics and biodistributions, thus allowing the polymers to be used interchangeably. However, when maintaining the same coating in subsequent administrations, we find that particles are in circulation at the height of the antibody immune response resulting in 50-60% decreases of circulation half-lives and tumor accumulation along with 50% increases in liver accumulation. By alternating the polymers used in the nanoparticle coating between administrations, we find each dose maintains favorable in vivo behaviors at the height of the antibody immune response to the previous administration. Furthermore, our strategy increases the clearance of particles uptaken by macrophages and hepatocytes, resulting in marked decreases in hepatotoxicity.
为了在癌症治疗中实现最小的全身毒性和高肿瘤递送效率，人们开发了各种具有隐形聚合物涂层的纳米药物制剂，以尽量减少免疫细胞摄取和非靶向巨噬细胞吞噬系统（MPS）器官积累。尽管最初免疫细胞摄取有所减少，但隐形纳米颗粒仍会引发抗体免疫反应。这种反应作用于治疗方案中的后续给药，导致颗粒加速经血液清除进入MPS器官，特别是肝脏，在那里它们会被长时间保留。因此，治疗方案中首次给药后的剂量会使肿瘤积累减少，MPS毒性增加。在此，我们提出一种策略，通过在给药之间交替使用聚乙二醇和聚甲基恶唑啉聚合物作为纳米颗粒涂层，来降低治疗方案中每次剂量引发的抗体反应。在每周给药方案中，我们发现具有任何一种涂层的颗粒的首次剂量都显示出相似的良好药代动力学和生物分布，因此这些聚合物可以互换使用。然而，在后续给药中保持相同涂层时，我们发现颗粒在抗体免疫反应高峰期仍在循环，导致循环半衰期和肿瘤积累减少50 - 60%，同时肝脏积累增加50%。通过在给药之间交替使用纳米颗粒涂层中使用的聚合物，我们发现每次剂量在对前一次给药的抗体免疫反应高峰期都保持良好的体内行为。此外，我们的策略增加了被巨噬细胞和肝细胞摄取的颗粒的清除率，导致肝毒性显著降低。
