Costagliola di Polidoro Angela, Zambito Giorgia, Haeck Joost, Mezzanotte Laura, Lamfers Martine, Netti Paolo Antonio, Torino Enza
Department of Chemical, Materials and Production Engineering (DICMaPI), University of Naples Federico II, 80125 Naples, Italy.
Fondazione Istituto Italiano di Tecnologia, IIT, 80125 Naples, Italy.
Cancers (Basel). 2021 Jan 28;13(3):503. doi: 10.3390/cancers13030503.
Glioblastoma multiforme (GBM) has a mean survival of only 15 months. Tumour heterogeneity and blood-brain barrier (BBB) mainly hinder the transport of active agents, leading to late diagnosis, ineffective therapy and inaccurate follow-up. The use of hydrogel nanoparticles, particularly hyaluronic acid as naturally occurring polymer of the extracellular matrix (ECM), has great potential in improving the transport of drug molecules and, furthermore, in facilitatating the early diagnosis by the effect of hydrodenticity enabling the T boosting of Gadolinium chelates for MRI. Here, crosslinked hyaluronic acid nanoparticles encapsulating gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and the chemotherapeutic agent irinotecan (Thera-cHANPs) are proposed as theranostic nanovectors, with improved MRI capacities. Irinotecan was selected since currently repurposed as an alternative compound to the poorly effective temozolomide (TMZ), generally approved as the gold standard in GBM clinical care. Also, active crossing and targeting are achieved by theranostic cHANPs decorated with angiopep-2 (Thera-ANG-cHANPs), a dual-targeting peptide interacting with low density lipoprotein receptor related protein-1(LRP-1) receptors overexpressed by both endothelial cells of the BBB and glioma cells. Results showed preserving the hydrodenticity effect in the advanced formulation and internalization by the active peptide-mediated uptake of Thera-cHANPs in U87 and GS-102 cells. Moreover, Thera-ANG-cHANPs proved to reduce ironotecan time response, showing a significant cytotoxic effect in 24 h instead of 48 h.
多形性胶质母细胞瘤（GBM）的平均生存期仅为15个月。肿瘤异质性和血脑屏障（BBB）主要阻碍活性剂的运输，导致诊断延迟、治疗无效和随访不准确。水凝胶纳米颗粒的使用，特别是透明质酸作为细胞外基质（ECM）的天然聚合物，在改善药物分子运输方面具有巨大潜力，此外，通过水合作用促进钆螯合物的T增强用于MRI，有助于早期诊断。在此，提出了包裹钆二乙烯三胺五乙酸（Gd-DTPA）和化疗药物伊立替康的交联透明质酸纳米颗粒（Thera-cHANPs）作为具有改善MRI能力的治疗诊断纳米载体。选择伊立替康是因为它目前被重新用作效果不佳的替莫唑胺（TMZ）的替代化合物，TMZ通常被批准为GBM临床护理的金标准。此外，通过用血管肽-2修饰的治疗诊断cHANPs（Thera-ANG-cHANPs）实现主动穿越和靶向，血管肽-2是一种双靶向肽，可与血脑屏障内皮细胞和胶质瘤细胞过度表达的低密度脂蛋白受体相关蛋白-1（LRP-1）受体相互作用。结果表明，在先进制剂中保留了水合作用效果，并且通过活性肽介导的Thera-cHANPs在U87和GS-102细胞中的摄取实现了内化。此外，Thera-ANG-cHANPs被证明可缩短伊立替康的反应时间，在24小时而非48小时内显示出显著的细胞毒性作用。
