Institut de Ciència de Materials de Barcelona, ICMAB-CSIC; Campus UAB, 08193 Bellaterra, Spain.
CIBER de Bioingeniería, Biomateriales y Nanomedicina, Instituto de Salud Carlos III, Campus UAB, 08913 Bellaterra, Spain.
Biomacromolecules. 2022 Jul 11;23(7):2767-2777. doi: 10.1021/acs.biomac.2c00088. Epub 2022 Jun 24.
Simultaneously being a nonradiative and noninvasive technique makes magnetic resonance imaging (MRI) one of the highly required imaging approaches for the early diagnosis and follow-up of tumors, specifically for brain cancer. Paramagnetic gadolinium (Gd)-based contrast agents (CAs) are the most widely used ones in brain MRI acquisitions with special interest when assessing blood-brain barrier (BBB) integrity, a characteristic of high-grade tumors. However, alternatives to Gd-based contrast agents (CAs) are highly required to overcome their established toxicity. Organic radicals anchored on a dendrimer macromolecule surface (radical dendrimers) are promising alternatives since they also exhibit paramagnetic properties and can act as CAs like Gd-based CAs while being organic species (mitigating concerns about toxic metal accumulation). Here, we studied the third generation of a water-soluble family of poly(phosphorhydrazone) radical dendrimers, with 48 PROXYL radical units anchored on their branches, exploring their potential of and contrast enhancement in brain tumors (in particular, of immunocompetent, orthotopic GL261 murine glioblastoma (GB)). Remarkably, this radical species provides suitable contrast enhancement on murine GL261 GB tumors, which was comparable to that of commercial Gd-based CAs (at standard dose 0.1 mmol/kg), even at its 4 times lower administered dose (0.025 mmol/kg). Importantly, no signs of toxicity were detected . In addition, it showed a selective accumulation in brain tumor tissues, exhibiting longer retention within the tumor, which allows performing imaging acquisition over longer time frames (≥2.5 h) as opposed to Gd chelates. Finally, we observed high stability of the radicals in biological media, on the order of hours instead of minutes, characteristic of the isolated radicals. All of these features allow us to suggest that the G3-Tyr-PROXYL-ONa radical dendrimer could be a viable alternative to metal-based MRI contrast agents, particularly on MRI analysis of GB, representing, to the best of our knowledge, the first case of organic radical species used for this purpose and one of the very few examples of these types of radical species working as MRI CAs .
同时作为一种非放射性和非侵入性技术，磁共振成像（MRI）成为肿瘤早期诊断和随访的首选成像方法之一，特别是脑癌。顺磁钆（Gd）基造影剂（CA）是脑 MRI 采集最广泛使用的造影剂，特别是在评估血脑屏障（BBB）完整性时，这是高级别肿瘤的一个特征。然而，为了克服 Gd 基 CA 的既定毒性，非常需要替代 Gd 基 CA 的方法。锚定在树枝状大分子表面的有机自由基（自由基树枝状大分子）是很有前途的替代品，因为它们也表现出顺磁性质，可以像 Gd 基 CA 一样作为 CA 发挥作用，同时又是有机物质（减轻对有毒金属积累的担忧）。在这里，我们研究了第三代水溶性聚（膦酰肼）自由基树枝状大分子，其支链上锚定了 48 个 PROXYL 自由基单元，探索了它们在脑肿瘤（特别是免疫活性、原位 GL261 鼠胶质母细胞瘤（GB））中的潜在和磁共振增强作用。值得注意的是，这种自由基物种可以为鼠 GL261GB 肿瘤提供合适的对比增强，与商业 Gd 基 CA（在标准剂量 0.1mmol/kg 时）相当，即使在其低 4 倍的给药剂量（0.025mmol/kg）时也是如此。重要的是，没有发现毒性迹象。此外，它在脑肿瘤组织中表现出选择性积累，在肿瘤内保留时间更长，这允许在更长的时间框架内（≥2.5h）进行成像采集，而不是 Gd 螯合物。最后，我们观察到自由基在生物介质中的高稳定性，为小时量级，而不是分钟量级，这是孤立自由基的特征。所有这些特征都表明，G3-Tyr-PROXYL-ONa 自由基树枝状大分子可能是金属基 MRI 造影剂的可行替代品，特别是在 MRI 对 GB 的分析中，据我们所知，这是首次将有机自由基用于此目的，也是少数几种此类自由基作为 MRI CA 发挥作用的例子之一。
