The finding of alternative imaging probes to Gadolinium (Gd) and other metal based contrast agents (CA) is crucial to overcome their established toxicity. Herein we describe the synthesis and characterization of an entirely organic metal-free magnetic resonance imaging (MRI) contrast agent based on polyphosphorhydrazone (PPH) dendrimers, fully functionalized with up to 48 organic nitroxide radical units. We propose an innovative synthetic procedure based on the use of an amino acid linker (Tyr) coupled to each dendrimer′s branch that permits the anchoring of the radicals and at the same time makes possible the control over their water solubility. We demonstrate that the negatively charged resulting PPH Gn-Tyr-PROXYL (n = 0–3) radical dendrimers are excellent candidates to be used as MRI contrast agents, suited for biomedical applications as they show high water solubility, no aggregation problems, and low cytotoxicity, as well as good stability in highly reducing environments. It is achieved a remarkable r 1 relaxivity, ca. four times higher (13 mM–1 s–1) than the gold-standard Gd-DTPA used in clinics. Furthermore, the r 1 and r 2 relaxivity per unit of radical showed an increase with the increase in generation of dendrimers.

Finding alternatives to gadolinium (Gd)-based contrast agents (CA) with the same or even better paramagnetic properties is crucial to overcome their established toxicity. Herein we describe the synthesis and characterization of entirely organic metal-free paramagnetic macromolecules based on biocompatible oligoethylene glycol dendrimers fully functionalized with 5 and 20 organic radicals (OEG Gn-PROXYL (n = 0, 1) radical dendrimers) with the aim to be used as magnetic resonance imaging (MRI) contrast agents. Conferring high water solubility on such systems is often a concern, especially in large generation dendrimers. Our approach to overcome such an issue in this study is by synthesizing dendrimers with highly water-soluble branches themselves. In this work, we show that the highly water-soluble OEG Gn-PROXYL (n = 0, 1) radical dendrimers obtained showed properties that convert them in good candidates to be studied as contrast agents for MRI applications like diagnosis and follow-up of infectious diseases, among others. Importantly, with the first generation radical dendrimer, a similar r1 relaxivity value (3.4 mM−1s−1) in comparison to gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) used in clinics (3.2 mM−1s−1, r.t. 7T) has been obtained, and it has been shown to not be cytotoxic, avoiding the toxicity risks associated with the unwanted accumulation of Gd in the body.

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 T 1 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 .

The spin−spin interactions between unpaired electrons in organic (poly)radicals, especially nitroxides, are largely investigated and are of crucial importance for their applications in areas such as organic magnetism, molecular charge transfer, or multiple spin labeling in structural biology. Recently, 2,2,6,6-tetramethylpiperidinyloxyl and polymers functionalized with nitroxides have been described as successful redox mediators in several electrochemical applications; however, the study of spin−spin interaction effect in such an area is absent. This communication reports the preparation of a novel family of discrete polynitroxide molecules, with the same number of radical units but different arrangements to study the effect of intramolecular spin−spin interactions on their electrochemical potential and their use as oxidation redox mediators in a Li−oxygen battery. We find that the intensity of interactions, as measured by the d 1 /d electron paramagnetic resonance parameter, progressively lowers the reduction potential. This allows us to tune the charging potential of the battery, optimizing its energy efficiency.

Dual or multimodal imaging probes have emerged as powerful tools that improve detection sensitivity and accuracy in disease diagnosis by imaging techniques. Two imaging techniques that are complementary and do not use ionizing radiation are magnetic resonance imaging (MRI) and optical fluorescence imaging (OFI). Herein, we prepared metal-free organic species based on dendrimers with magnetic and fluorescent properties as proof-of-concept of bimodal probes for potential MRI and OFI applications. We used oligo(styryl)benzene (OSB) dendrimers core that are fluorescent on their own, and TEMPO organic radicals anchored on their surfaces, as the magnetic component. In this way, we synthesized six radical dendrimers and characterized them by FT-IR, 1H NMR, UV-Vis, MALDI-TOF, SEC, EPR, fluorimetry, and in vitro MRI. Importantly, it was demonstrated that the new dendrimers present two properties: on one hand, they are paramagnetic and show the ability to generate contrast by MRI in vitro, and, on the other hand, they also show fluoresce emission. This is a remarkable result since it is one of the very few cases of macromolecules with bimodal magnetic and fluorescent properties using organic radicals as the magnetic probe.