Metal-Free Radical Dendrimers as MRI Contrast Agents for Glioblastoma Diagnosis: Ex Vivo and In Vivo Approaches

Abstract

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 .

Fluorinated Human Serum Albumin as Potential 19F Magnetic Resonance Imaging Probe

“…However, rapid radical reduction reactions in vivo and low relaxivity, both limit area progress. The earlier stages’ results of the proposed construction show high perspectives for these CAs in the future [ 16 , 19 ]. Another approach is a multinuclear MRI called nonproton MRI [ 20 ].…”

Autocatalytic photoinduced oxidative dehydrogenation of pyrido[2,3-d]pyrimidin-7(8H)-ones: synthesis of C5–C6 unsaturated systems with concomitant formation of a long-lived radical

“…At this point of the mechanistic study, we decided to use electron paramagnetic resonance (EPR) spectroscopy, a specific technique to characterize radicals, 17,18 to gain more insight into the radicals involved in this process. The experiment carried out consisted of recording the EPR spectrum of a sample of the dehydrogenation of 11a (R 5 = R 6 = H) to 12a, at a concentration of 25 mg mL −1 in DMSO-d 6 after 15 min of irradiation at 450 nm with bubbling of air.…”

Image‐guided diagnosis and treatment of glioblastoma

“…Although optical methods have been used for the accurate diagnosis of GBM, MR, a commonly used clinical detection method, has high accuracy and excellent performance in identifying small lesions. For example, MR image‐guided GBM diagnosis has recently been reported, with MR agents based on superparamagnetic iron oxide particles 128 and paramagnetic organic PROXYL radicals 129 staying longer at the tumor site. In addition, PET, as an advanced clinical examination imaging technology in the field of nuclear medicine, is also of great significance for the development of effective GBM imaging platforms.…”