Pineiro-Alonso Laura, Rubio-Prego Inés, López-Estévez Ana M, Garrido-Gil Pablo, Valenzuela Rita, Labandeira-García José L, Aguiar Pablo, Rodríguez-Pérez Ana I, Alonso María J
Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, Santiago de Compostela, Spain.
Drug Deliv Transl Res. 2025 Sep 2. doi: 10.1007/s13346-025-01957-y.
Monoclonal antibodies (mAbs) are promising therapeutic agents for neurological disorders due to their high specificity. However, their clinical application is significantly hindered by their poor transport across the blood-brain barrier (BBB) and their limited diffusion within the brain parenchyma. While significant efforts have been oriented to tackle the first barrier, the challenge of efficient brain diffusion remains largely underexplored. To address this, we have developed and evaluated two structurally distinct nanosystems for mAb delivery to the brain: PEGylated polyglutamic acid nanocapsules (PGA-PEG NCs) and PGAC14-based nanoassemblies (PGAC14 NAs). Both formulations encapsulated efficiently the model mAb bevacizumab (BVZ) while they exhibited different physicochemical properties. Namely, PGA-PEG NCs displayed a size of 80 nm and a neutral zeta potential, whereas PGAC14 NAs featured an ultra-small size of 40 nm and a negative surface charge. After assessing their diffusion capacity using immunofluorescence, we concluded that PGAC14 NAs exhibited the highest brain diffusion together with a favorable neuroinflammatory profile. This was likely driven by their small size and negative charge, along with a selective ability to interact with and deliver BVZ intracellularly to neuronal cells upon intraparenchymal administration. These findings provide key insights into optimizing nanocarrier design for improved mAb delivery to the brain.
单克隆抗体（mAb）因其高特异性而有望成为治疗神经系统疾病的药物。然而，其临床应用受到血脑屏障（BBB）转运能力差以及在脑实质内扩散受限的显著阻碍。尽管人们已付出巨大努力来攻克第一个障碍，但高效脑内扩散的挑战在很大程度上仍未得到充分探索。为解决这一问题，我们开发并评估了两种结构不同的用于将mAb递送至脑内的纳米系统：聚乙二醇化聚谷氨酸纳米胶囊（PGA-PEG NCs）和基于PGAC14的纳米聚集体（PGAC14 NAs）。两种制剂均能有效包封模型单克隆抗体贝伐单抗（BVZ），同时它们表现出不同的物理化学性质。具体而言，PGA-PEG NCs的粒径为80 nm，zeta电位呈中性，而PGAC14 NAs的粒径超小，为40 nm，表面带负电荷。在使用免疫荧光评估它们的扩散能力后，我们得出结论，PGAC14 NAs表现出最高的脑内扩散能力以及良好的神经炎症特征。这可能是由其小尺寸和负电荷驱动的，同时还具有在脑实质内给药后与BVZ相互作用并将其细胞内递送至神经元细胞的选择性能力。这些发现为优化纳米载体设计以改善mAb向脑内的递送提供了关键见解。
