National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China.
National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China.
Int J Pharm. 2024 Apr 10;654:123990. doi: 10.1016/j.ijpharm.2024.123990. Epub 2024 Mar 11.
The precise delivery of therapeutic agents to specific cell populations, including cancer cells, remains a target in modern medicine, to enhance treatment efficacy, while minimizing unintended side effects. This study presents a strategy utilizing bispecific antibodies for the targeted delivery of nucleic acid drugs to the surface of glucose-regulated protein 78 (GRP78)-overexpressing cancer cells. Strong binding affinity of the bispecific antibodies to GRP78-overexpressing cancer cells, including HEPG2 cells, confirmed the tumor-targeting potential of this platform. Functional analyses demonstrated the role of the bispecific antibodies in enhancing lipid nanoparticle (LNP) uptake, causing increased gene expression levels of nucleic acid drugs loaded within LNPs. In vivo imaging confirmed the potency of the bispecific-antibody-modified LNPs in delivering nucleic acid drugs to tumors and sustaining therapeutic expression levels. In vivo therapy results indicated that the bispecific antibodies improved the antitumor activity of PE38-loaded LNPs in tumors overexpressing surface GRP78. This study pioneered a bispecific-antibody-centered platform for the targeted delivery of nucleic acid drugs. The robust antigen-antibody binding affinity, tumor-selective interactions, enhanced cellular uptake, and proficient gene expression promise to advance precision therapeutics in oncology. Continued refinement and translation of this drug delivery strategy are important to unlock its full clinical potential.
精确地将治疗剂递送到特定的细胞群体，包括癌细胞，仍然是现代医学的一个目标，以提高治疗效果，同时最大限度地减少意外的副作用。本研究提出了一种利用双特异性抗体将核酸药物靶向递送到葡萄糖调节蛋白 78（GRP78）过表达癌细胞表面的策略。双特异性抗体与包括 HEPG2 细胞在内的 GRP78 过表达癌细胞具有很强的结合亲和力，证实了该平台的肿瘤靶向潜力。功能分析表明，双特异性抗体在增强脂质纳米颗粒（LNP）摄取方面发挥作用，导致 LNP 内负载的核酸药物的基因表达水平增加。体内成像证实了双特异性抗体修饰的 LNP 将核酸药物递送到肿瘤并维持治疗表达水平的能力。体内治疗结果表明，双特异性抗体提高了表面 GRP78 过表达肿瘤中负载 PE38 的 LNP 的抗肿瘤活性。本研究开创了一种基于双特异性抗体的核酸药物靶向递药平台。强大的抗原-抗体结合亲和力、肿瘤选择性相互作用、增强的细胞摄取和高效的基因表达有望推动肿瘤学中的精准治疗。继续改进和转化这种药物递送策略对于充分发挥其临床潜力非常重要。
