Glioblastoma (GBM) is one of the most malignant tumors with poor prognosis and outcomes. Although smaller particle size can lead to higher blood-brain barrier (BBB)-permeability of the nanomaterials, most of the reported BBB-crossable nanomaterials for targeted GBM therapy are larger than 24 nm. To realize theranostics of GBM, co-loading of therapeutic and diagnostic agents on the same nanomaterials further results in larger particle size. In this study, we developed a kind of novel BBB-transportable nanomaterials smaller than 14 nm for high-efficiency theranostics of GBM (i.e., high contrast magnetic resonance imaging (MRI) and radiosensitization of GBM). Typically, poly(acrylic acid) (PAA) stabilized extremely small gadolinium oxide nanoparticles with modification of reductive bovine serum albumin (ES-GON-rBSA) was synthesized in water phase, resulting in excellent water-dispersibility. RGD dimer (RGD2, Glu-{Cyclo[Arg-Gly-Asp-(D-Phe)-Lys]}2) and lactoferrin (LF) were then conjugated to the ES-GON-rBSA to obtain composite nanoparticle ES-GON-rBSA-LF-RGD2 with extraordinary relaxivities (r1 = 60.8 mM-1 s-1, r2/r1 = 1.1). The maximum signal enhancement (ΔSNR) for T1-weighted MRI of tumors reached up to 423 ± 42% at 12 h post-injection of ES-GON-rBSA-LF-RGD2, which is much higher than commercial Gd-chelates (<80%). ES-GON-rBSA-LF-RGD2 exhibited high biocompatibility and can transport across the in vitro BBB model and the in vivo BBB of mice due to its small particle size (dh = 13.4 nm) and LF receptor mediated transcytosis. Orthotopic GBM studies reinforce that ES-GON-rBSA3-LF-RGD2 can accumulate in the orthotopic GBM and enhance the radiation therapy of GBM as an effective radiosensitizing agent.

中文翻译：

---

小型氧化oxide基纳米颗粒，用于原位胶质母细胞瘤的高效治疗。

胶质母细胞瘤（GBM）是预后和预后不良的最恶性肿瘤之一。尽管较小的粒径可以导致纳米材料具有更高的血脑屏障（BBB）渗透性，但用于靶向GBM治疗的大多数已报道的BBB可交叉纳米材料都大于24 nm。为了实现GBM的分子论，在相同的纳米材料上共同装载治疗剂和诊断剂会导致更大的粒径。在这项研究中，我们开发了一种新型的小于14 nm的BBB可运输纳米材料，用于GBM的高效诊断学（即高对比度磁共振成像（MRI）和GBM的放射增敏）。通常，在水相中合成具有还原牛血清白蛋白（ES-GON-rBSA）修饰的聚丙烯酸（PAA）稳定的极小的氧化oxide纳米颗粒，导致优异的水分散性。然后将RGD二聚体（RGD2，Glu- {Cyclo [Arg-Gly-Asp-（D-Phe）-Lys]} 2）和乳铁蛋白（LF）偶联至ES-GON-rBSA，以获得复合纳米粒子ES-GON- rBSA-LF-RGD2具有出色的弛豫性（r1 = 60.8 mM-1 s-1，r2 / r1 = 1.1）。ES-GON-rBSA-LF-RGD2注射后12小时，T1加权MRI肿瘤的最大信号增强（ΔSNR）达到423±42％，远高于商业Gd螯合物（<80 ％）。ES-GON-rBSA-LF-RGD2具有很高的生物相容性，并且由于其小粒径（dh = 13.4 nm）和LF受体介导的胞吞作用，可以在小鼠的体外BBB模型和体内BBB中转运。