Takasaki Advanced Radiation Research Institute (TARRI), National Institutes for Quantum and Radiological Science and Technology (QST), 1233 Watanuki-machi, Takasaki, Gunma, 370-1292, Japan.
Laboratory of Biomaterials, Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Kawara-cho Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Acta Biomater. 2021 Apr 15;125:290-299. doi: 10.1016/j.actbio.2021.02.016. Epub 2021 Feb 15.
Magnetic Resonance Imaging (MRI) contrast agents with rapid renal excretion that do not penetrate the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCFB) are preferred for safer and low-risk diagnosis. Gadolinium (Gd)-conjugated nanoparticles have been proposed for use as contrast agents; however, the particle size must range between 1 to 7 nm to ensure rapid renal excretion. In this study, three types of gelatin, dissolved in water at varying concentrations of 0.1-2 wt.%, were irradiated with 5 kGy γ-rays at 25°C under aerated conditions to produce ultra-small gelatin nanogels having an average particle size ranging between 6 ± 2 to 21 ± 4 nm. Ultra-small Gd-coordinated gelatin nanogels (GdGN) suitable for use as MRI contrast agents were produced using 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester (DOTA-NHS) and DOTA-butylamine as Gd ligand derivatives. Non-cytotoxicity and effective relaxivity of GdGN as a positive MRI contrast agent were verified using in vivo experiments. Rapid renal excretion of GdGN was observed in mice within 1 h with no accumulation in the liver. GdGN did not migrate across the BCFB in normal mice, thus emphasizing its safety as an MRI contrast agent. STATEMENT OF SIGNIFICANCE: The authors developed ultra-small sized gelatin nanogels as blood-brain-barrier impermeable contrast agents for magnetic resonance imaging (MRI). The authors used radiation crosslinking technique to ensure better integrity of the amino acids present in the gelatin nanogels while conjugating with gadolinium (Gd) to form gadolinium-coordinated gelatin nanogels (GdGN). The safety and efficacy of GdGN, as MRI contrast agents, were verified by in vivo studies. GdGN exhibited rapid renal excretion within 90 minutes and no passage across the barriers in the brain.
磁共振成像（MRI）对比剂具有快速的肾排泄功能，不会穿透血脑屏障（BBB）和血脑脊液屏障（BCFB），因此更安全、风险更低。已提出使用镧系元素（Gd）缀合的纳米粒子作为对比剂；然而，为了确保快速肾排泄，粒径必须在 1 至 7nm 之间。在这项研究中，三种明胶在 0.1-2wt.%的不同浓度下溶解在水中，在 25°C 下于有氧条件下用 5kGyγ射线辐照，产生平均粒径在 6±2 至 21±4nm 之间的超小型明胶纳米凝胶。使用 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸单-N-羟基琥珀酰亚胺酯（DOTA-NHS）和 DOTA-丁胺作为 Gd 配体衍生物，制备了适合用作 MRI 对比剂的超小型 Gd 配位明胶纳米凝胶（GdGN）。通过体内实验验证了 GdGN 作为正 MRI 对比剂的非细胞毒性和有效弛豫率。在小鼠体内观察到 GdGN 在 1 小时内快速从肾脏排泄，没有在肝脏中积累。在正常小鼠中，GdGN 不会穿过 BCFB，因此强调了其作为 MRI 对比剂的安全性。 意义声明：作者开发了超小型明胶纳米凝胶作为不透血脑屏障的磁共振成像（MRI）对比剂。作者使用辐射交联技术，在将镧系元素（Gd）与明胶纳米凝胶缀合形成镧系元素配位明胶纳米凝胶（GdGN）时，确保明胶纳米凝胶中存在的氨基酸具有更好的完整性。通过体内研究验证了 GdGN 作为 MRI 对比剂的安全性和有效性。GdGN 在 90 分钟内快速从肾脏排泄，并且没有穿过大脑中的屏障。
