Department of Biomedical Engineering, Malone Engineering Center, Yale University, New Haven, Connecticut 06510, USA.
Department of Pathology, Yale University, New Haven, Connecticut 06520, USA.
Nat Commun. 2017 May 19;8:15322. doi: 10.1038/ncomms15322.
Nanoparticles are of long-standing interest for the treatment of neurological diseases such as glioblastoma. Most past work focused on methods to introduce nanoparticles into the brain, suggesting that reaching the brain interstitium will be sufficient to ensure therapeutic efficacy. However, optimized nanoparticle design for drug delivery to the central nervous system is limited by our understanding of their cellular deposition in the brain. Here, we investigated the cellular fate of poly(lactic acid) nanoparticles presenting different surface chemistries, after administration by convection-enhanced delivery. We demonstrate that nanoparticles with 'stealth' properties mostly avoid internalization by all cell types, but internalization can be enhanced by functionalization with bio-adhesive end-groups. We also show that association rates measured in cultured cells predict the extent of internalization of nanoparticles in cell populations. Finally, evaluating therapeutic efficacy in an orthotopic model of glioblastoma highlights the need to balance significant uptake without inducing adverse toxicity.
纳米颗粒长期以来一直受到关注，可用于治疗神经退行性疾病，如神经胶质瘤。过去的大多数研究都集中在将纳米颗粒引入大脑的方法上，这表明进入脑间质将足以确保治疗效果。然而，用于向中枢神经系统递药的优化纳米颗粒设计受到我们对其在大脑中细胞沉积的理解的限制。在这里，我们研究了通过对流增强递送后具有不同表面化学性质的聚乳酸纳米颗粒的细胞命运。我们证明，具有“隐形”特性的纳米颗粒大多避免被所有细胞类型内化，但通过与生物粘附端基官能化可以增强内化。我们还表明，在培养细胞中测量的结合速率可以预测纳米颗粒在细胞群体中的内化程度。最后，在神经胶质瘤的原位模型中评估治疗效果突出表明需要在不引起不良反应的情况下平衡大量摄取。
