Department of Biomedical Engineering, Yale University, New Haven, CT 06510, United States.
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States.
Biomaterials. 2019 May;201:87-98. doi: 10.1016/j.biomaterials.2019.02.016. Epub 2019 Feb 14.
Glioblastoma (GBM) is the most common and deadly form of malignant brain tumor in the United States, and current therapies fail to provide significant improvement in survival. Local delivery of nanoparticles is a promising therapeutic strategy that bypasses the blood-brain barrier, minimizes systemic toxicity, and enhances intracranial drug distribution and retention. Here, we developed nanoparticles loaded with agents that inhibit miR-21, an oncogenic microRNA (miRNA) that is strongly overexpressed in GBM compared to normal brain tissue. We synthesized, engineered, and characterized two different delivery systems. One was designed around an anti-miR-21 composed of RNA and employed a cationic poly(amine-co-ester) (PACE). The other was designed around an anti-miR-21 composed of peptide nucleic acid (PNA) and employed a block copolymer of poly(lactic acid) and hyperbranched polyglycerol (PLA-HPG). We show that both nanoparticle products facilitate efficient intracellular delivery and miR-21 suppression that leads to PTEN upregulation and apoptosis of human GBM cells. Further, when administered by convection-enhanced delivery (CED) to animals with intracranial gliomas, they both induced significant miR-21 knockdown and provided chemosensitization, resulting in improved survival when combined with chemotherapy. The challenges involved in optimizing the two delivery systems differed, and despite offering distinct advantages and limitations, results showed significant therapeutic efficacy with both methods of treatment. This study demonstrates the feasibility and promise of local administration of miR-21 inhibiting nanoparticles as an adjuvant therapy for GBM.
胶质母细胞瘤（GBM）是美国最常见和最致命的恶性脑肿瘤形式，目前的治疗方法未能显著提高患者的生存率。纳米颗粒的局部递送是一种很有前途的治疗策略，它可以绕过血脑屏障，最大限度地减少全身毒性，并增强颅内药物分布和保留。在这里，我们开发了负载能够抑制 miR-21 的纳米颗粒的制剂，miR-21 是一种致癌 miRNA，在 GBM 中与正常脑组织相比强烈过表达。我们合成、设计和表征了两种不同的递药系统。一种是围绕由 RNA 组成的抗 miR-21 设计的，并采用阳离子聚（胺-co-酯）（PACE）。另一种是围绕由肽核酸（PNA）组成的抗 miR-21 设计的，并采用聚乳酸和超支化聚甘油的嵌段共聚物（PLA-HPG）。我们表明，这两种纳米颗粒产品都能促进有效的细胞内递药和 miR-21 抑制，从而导致 PTEN 上调和人 GBM 细胞凋亡。此外，当通过对流增强递送（CED）递送至颅内神经胶质瘤动物时，它们都能诱导显著的 miR-21 敲低，并提供化学增敏作用，当与化疗联合使用时，可改善生存。优化这两种递药系统所涉及的挑战不同，尽管它们提供了明显的优势和局限性，但两种治疗方法的结果均显示出显著的治疗效果。这项研究证明了局部给予 miR-21 抑制纳米颗粒作为 GBM 辅助治疗的可行性和前景。
