Metal-Free Radical Dendrimers as MRI Contrast Agents for Glioblastoma Diagnosis : Ex Vivo and In Vivo Approaches
| Autor: | Songbai Zhang, Vega Lloveras, Silvia Lope-Piedrafita, Pilar Calero-Pérez, Shuang Wu, Ana Paula Candiota, José Vidal-Gancedo |
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| Přispěvatelé: | Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Generalitat de Catalunya, Centro de Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina (España), European Commission, Zhang, Songbai, Lloveras, Vega, Lope Piedrafita, Silvia, Candiota, Ana Paula |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Popis: | 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 T1 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 ex vivo and in vivo 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 vivo. 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 in vivo. This work was supported by Ministerio de Ciencia e Innovación MICINN (PID2019-105622RB-I00, CTQ2017-90596-REDT, Severo Ochoa FUNMAT-FIP-2018, and FUNFUTURE-FIP-2020 projects), CSIC (Intramural CSIC project 201760E080), and Generalitat de Catalunya (2017 SGR918). ICMAB acknowledges Spanish MICINN through the Severo Ochoa Centres of Excellence Programme Grants SEV-2015-0496 and CEX2019-000917-S. The work was also funded by Centro de Investigación Biomédica en Red – Bioingeniería, Biomateriales y Nanomedicina, an initiative of the Instituto de Salud Carlos III (Spain) cofunded by EU Fondo Europeo de Desarrollo Regional (FEDER). A.P.C. received funding from the ATTRACT project funded by the EC under Grant Agreement 777222 and the MICINN grant TRIBUTE (PID2020-113058GB-I00/AEI/10.13039/501100011033). With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S). |
| Databáze: | OpenAIRE |
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