SURG-03. LAYER-BY-LAYER CORE-SHELL NANOPARTICLES FOR THE DELIVERY OF HDAC INHIBITORS TO THE CENTRAL NERVOUS SYSTEM
SURG-03. LAYER-BY-LAYER CORE-SHELL NANOPARTICLES FOR THE DELIVERY OF HDAC INHIBITORS TO THE CENTRAL NERVOUS SYSTEM
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DOI：
10.1093/neuonc/noad073.279
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发表时间：
2023-06-12
期刊：
影响因子：
15.9
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中科院分区：
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弥漫性中线胶质瘤 (DMG) 给儿科癌症护理带来了独特的挑战。 DMG 的位置通常使肿瘤无法手术，而放射只能产生暂时的效果。 DMG 治疗中一种有前景的方法是组蛋白脱乙酰酶 (HDAC) 抑制剂。然而，由于血脑屏障（BBB）通透性低且在肿瘤组织中的积累较差，HDAC抑制剂难以递送至原发性中枢神经系统（CNS）肿瘤。 DMG 的 BBB 渗透性尤其受到限制，因为 DMG 保持相对完整的 BBB。为了克服这些递送挑战，我们开发了一种新的聚合物-脂质核-壳纳米制剂，用于将 HDAC 抑制剂递送到中枢神经系统，不依赖聚乙二醇 (PEG) 来实现胶体稳定性。去除 PEG 可以进行表面电荷操作，生成带电纳米颗粒，能够与交替带电的聚电解质进行逐层组装。该模块化平台允许添加靶向部分，以增强 HDAC 抑制剂核壳纳米粒子穿过 BBB 并进入 DMG 细胞的递送。将 HDAC 抑制剂帕比司他和 quisinostat 装入由聚丙交酯乙交酯 (PLGA) 核和磷脂壳组成的核壳纳米颗粒中。使用动态光散射和透射电子显微镜对纳米颗粒进行表征，显示出有利于体内递送的特性（帕比司他纳米颗粒直径 91.6 ± 1.0 nm，多分散指数 0.115 ± 0.013）。使用高效液相色谱研究了层状和非层状核壳纳米颗粒中 HDAC 抑制剂的释放。纳米胶囊药物的脱乙酰活性在体外患者衍生的 DMG 神经球模型中得到证实。目前正在对非荷瘤小鼠静脉注射载药纳米颗粒后的中枢神经系统药代动力学参数进行研究，包括脑脊液和脑组织中封装药物的浓度。未来的研究将调查核壳 HDAC 抑制剂纳米粒子在原位 DMG 荷瘤小鼠中的脑生物分布，比较静脉内和局部递送策略。
Diffuse midline gliomas (DMGs) present unique challenges in pediatric cancer care. The location of DMGs often renders the tumor inoperable and radiation produces only a temporary effect. One promising approach in DMG treatment is histone deacetylase (HDAC) inhibitors. However, HDAC inhibitors are difficult to deliver to primary central nervous system (CNS) tumors because of low blood-brain barrier (BBB) permeability and poor accumulation in tumor tissues. The BBB permeability is particularly restricting for DMGs, which maintain a relatively intact BBB. To overcome these delivery challenges, we developed a new polymer-lipid core-shell nanoformulation for the delivery of HDAC inhibitors to the CNS that does not rely on polyethylene glycol (PEG) for colloidal stability. Removing PEG allows for surface charge manipulation to generate charged nanoparticles amenable to layer-by-layer assembly with alternately charged polyelectrolytes. This modular platform allows the addition of targeting moieties to enhance the delivery of HDAC inhibitor core-shell nanoparticles across the BBB and into DMG cells. HDAC inhibitors panobinostat and quisinostat were loaded into core-shell nanoparticles comprised of a poly(lactide-co-glycolide) (PLGA) core and a phospholipid shell. Nanoparticles were characterized using dynamic light scattering and transmission electron microscopy exhibiting favorable properties for in vivo delivery (panobinostat nanoparticle diameter 91.6 ± 1.0 nm, polydispersity index 0.115 ± 0.013). The release of HDAC inhibitors from layered and unlayered core-shell nanoparticles was investigated using high-performance liquid chromatography. The deacetylating activity of nanoencapsulated agents was confirmed in vitro in patient-derived DMG neurosphere models. CNS pharmacokinetic parameters are currently being investigated after intravenous delivery of drug-loaded nanoparticles in non-tumor-bearing mice, including cerebrospinal fluid and brain tissue concentrations of the encapsulated agents. Future studies will investigate brain biodistribution of core-shell HDAC inhibitor nanoparticles in orthotopic DMG tumor-bearing mice, comparing intravenous and local delivery strategies.