Groult Hugo, Carregal-Romero Susana, Castejón David, Azkargorta Mikel, Miguel-Coello Ana-Beatriz, Pulagam Krishna Reddy, Gómez-Vallejo Vanessa, Cousin Rémi, Muñoz-Caffarel María, Lawrie Charles H, Llop Jordi, Piot Jean-Marie, Elortza Felix, Maugard Thierry, Ruiz-Cabello Jesús, Fruitier-Arnaudin Ingrid
BCBS team (Biotechnologies et Chimie des Bioressources pour la Santé), LIENSs Laboratory (Littoral environment et Sociétés), UMR CNRS 7266, University of La Rochelle, La Rochelle, France.
CIC biomaGUNE and Basque Research and Technology Alliance (BRTA), Donostia-San Sebastián, Gipuzkoa, Spain.
Nanoscale. 2021 Jan 21;13(2):842-861. doi: 10.1039/d0nr06378a.
The positive contrast of extremely small iron oxide nanoparticles (ESIONP) in magnetic resonance imaging (MRI) rejuvenates this class of metal nanoparticles (NP).Yet, the current synthesis often lacks the possibility of adjusting the core size (while it is a key element for ESIONP-based MRI contrast behaviour), and also involved multiple complex steps before obtaining a ready-to-use probe for medical applications. In this study, we faced these challenges by applying heparin oligosaccharides (HO) of different lengths as coatings for the preparation of HEP-ESIONP with a one-pot microwave method. We demonstrated that the HO length could control the core size during the synthesis to achieve optimal positive MRI contrast, and that HEP-ESIONP were endowed directly with anticoagulant properties and/or a specific antitumor activity, according to the HO used. Relevantly, positron emission tomography (PET)-based in vivo biodistribution study conducted with 68Ga core-doped HEP-ESIONP analogues revealed significant changes in the probe behaviours, the shortening of HO promoting a shift from hepatic to renal clearance. The different conformations of HO coatings and a thorough in vitro characterisation of the probes' protein coronas provided insight into this crucial impact of HO length on opsonization-mediated immune response and elimination. Overall, we were able to identify a precise HO length to get an ESIONP probe showing prolonged vascular lifetime and moderate accumulation in a tumor xenograft, balanced with a low uptake by non-specific organs and favourable urinary clearance. This probe met all prerequisites for advanced theranostic medical applications with a dual MRI/PET hot spot capability and potential antitumor activity.
磁共振成像（MRI）中极小的氧化铁纳米颗粒（ESIONP）的阳性对比使这类金属纳米颗粒（NP）重焕生机。然而，目前的合成方法往往缺乏调整核心尺寸的可能性（而核心尺寸是基于ESIONP的MRI对比行为的关键要素），并且在获得可用于医疗应用的即用型探针之前还涉及多个复杂步骤。在本研究中，我们通过应用不同长度的肝素寡糖（HO）作为涂层，采用一锅法微波法制备HEP-ESIONP来应对这些挑战。我们证明，HO的长度可以在合成过程中控制核心尺寸，以实现最佳的阳性MRI对比，并且根据所使用的HO，HEP-ESIONP直接具有抗凝血特性和/或特定的抗肿瘤活性。相关地，用68Ga核心掺杂的HEP-ESIONP类似物进行的基于正电子发射断层扫描（PET）的体内生物分布研究揭示了探针行为的显著变化，HO的缩短促进了从肝脏清除到肾脏清除的转变。HO涂层的不同构象以及对探针蛋白冠的全面体外表征，为HO长度对调理素介导的免疫反应和清除的这一关键影响提供了深入了解。总体而言，我们能够确定一个精确的HO长度，以获得一种ESIONP探针，该探针在肿瘤异种移植中显示出延长的血管寿命和适度的积累，与非特异性器官的低摄取和有利的尿液清除相平衡。该探针满足了具有双重MRI/PET热点能力和潜在抗肿瘤活性的先进治疗诊断医学应用的所有先决条件。
