Fischell Department of Bioengineering, School of Engineering, University of Maryland, College Park, Maryland, USA.
Nanomedicine. 2012 Jul;8(5):731-9. doi: 10.1016/j.nano.2011.08.014. Epub 2011 Sep 9.
Enzyme replacement therapies for lysosomal storage disorders are often hindered by suboptimal biodistribution of recombinant enzymes after systemic injection. This is the case for Pompe disease caused by acid α-glucosidase (GAA) deficiency, leading to excess glycogen storage throughout the body, mainly the liver and striated muscle. Targeting intercellular adhesion molecule-1 (ICAM-1), a protein involved in inflammation and overexpressed on most cells under pathological conditions, provides broad biodistribution and lysosomal transport of therapeutic cargoes. To improve its delivery, we coupled GAA to polymer nanocarriers (NCs; ∼180 nm) coated with an antibody specific to ICAM-1. Fluorescence microscopy showed specific targeting of anti-ICAM/GAA NCs to cells, with efficient internalization and lysosomal transport, enhancing glycogen degradation over nontargeted GAA. Radioisotope tracing in mice demonstrated enhanced GAA accumulation in all organs, including Pompe targets. Along with improved delivery of Niemann-Pick and Fabry enzymes, previously described, these results indicate that ICAM-1 targeting holds promise as a broad platform for lysosomal enzyme delivery.
In this study, ICAM-1 targeted nanocarriers were used to deliver GAA (acid alpha glucosidase) into cells to address the specific enzyme deficiency in Pompe's disease. The results unequivocally demonstrate enhanced enzyme delivery over nontargeted GAA in a mice model.
溶酶体贮积症的酶替代疗法常因全身性注射后重组酶的生物分布不理想而受阻。这种情况发生在由酸性α-葡萄糖苷酶（GAA）缺乏引起的庞贝病中，导致全身（主要是肝脏和横纹肌）糖原过度储存。靶向细胞间黏附分子-1（ICAM-1），一种在大多数细胞中过度表达的与炎症有关的蛋白质，可提供治疗性货物的广泛生物分布和溶酶体转运。为了改善其递送，我们将 GAA 与聚合物纳米载体（NC；∼180nm）偶联，这些 NC 用针对 ICAM-1 的抗体进行了涂层。荧光显微镜显示抗 ICAM/GAA NC 对细胞的特异性靶向，具有高效的内化和溶酶体转运，增强了糖原的降解，而非靶向 GAA。在小鼠中的放射性同位素示踪表明，所有器官（包括庞贝病靶点）中的 GAA 积累均增强。与之前描述的尼曼-匹克和法布瑞酶的改进递送一起，这些结果表明，ICAM-1 靶向具有作为溶酶体酶递送的广泛平台的潜力。
在这项研究中，使用 ICAM-1 靶向纳米载体将 GAA（酸性α-葡萄糖苷酶）递送入细胞，以解决庞贝病中特定的酶缺乏问题。结果明确证明，在小鼠模型中，与非靶向 GAA 相比，酶的递送得到了增强。
