Dendrimers as Innovative Radiopharmaceuticals in Cancer Radionanotherapy

Radiotherapy is one of the most commonly used cancer treatments, with an estimate of 40% success that could be improved further if more efficient targeting and retention of radiation at the tumor site were achieved. This review focuses on the use of dendrimers in radionanotherapy, an emerging technology aimed to improve the efficiency of radiotherapy by implementing nanovectorization, an already established praxis in drug delivery and diagnosis. The labeling of dendrimers with radionuclides also aims to reduce the dose of radiolabeled materials and, hence, their toxicity and tumor resistance. Examples of radiolabeled dendrimers with alpha, beta, and Auger electron emitters are commented, along with the use of dendrimers in boron neutron capture therapy (BNCT). The conjugation of radiolabeled dendrimers to monoclonal antibodies for a more efficient targeting and the application of dendrimers in gene delivery radiotherapy are also coveredThis work was financially supported by the Spanish Government (CTQ2015-69021-R, CTQ2012-34790) and the Xunta de Galicia (GRC2014/040) and by the “Institut National de la Santé et de la Recherche Médicale” (INSERM), by the “Axe Vectorisation and Radiothérapies” and the “Réseau Gliome Grand Ouest” (ReGGO) of the“Cancéropôle Grand-Ouest”. The coauthors of this manuscript are also members of the LabEx IRON “Innovative Radiopharmaceuticals in Oncologyand Neurology” as part of the french government program “Investissements d’Avenir”. F.L. thanks the European Commission, Education, Audiovisual and Cultural Executive Agency (EACEA) for an Erasmus Mundus Grant under the NanoFar Joint Doctoral ProgramS

Potentiel des dendrimères comme outil d'applications théranostiques

A new oncologic strategy, based on the integration of nanovectorized radiotherapy and locoregional delivery, was evaluated for the treatment and imaging of glioblastomas, the most common and lethal type of primary brain tumors. Gallic acidtriethylene glycol (GATG) dendrimers were the nanovectors of choice to deliver the radiotherapeutic 188Re and paramagnetic nuclei Gd3+, with a minimally invasive stereotactic injection, directly depositing the radiotherapeutic dose to the tumor site in a F98 rat glioma model. Intravenous injection was used to further investigate the pharmacokinetics, throughout body distribution and clearance profiles of these dendrimers. Molecular weight and architecture had an important role on the in vivo behavior of the dendrimers. Their use as nanovectors prevented the fast brain clearance of the radionuclide alone, and prolonged the confinement of the internal radiation at the tumor site.Une nouvelle stratégie oncologique, basée sur l’intégration de la radiothérapie nanovectorisée et l’administration loco-régionale, a été évaluée pour le traitement et l’imagerie du glioblastome, le type le plus commun des tumeurs cérébrales primaires. Les dendrimères Gallic Acid-Triethylène Glycol (GATG) sont des nanovecteurs de choix pour délivrer simultanément l’agent thérapeutique (le radioisotope 188Re par son rayonnement béta a été retenu) et l’agent diagnostique (le gadolinium est un agent paramagnétique utilisé en Imagerie par Résonance Magnétique (IRM)). Leur évaluation a été réalisée par administration locorégionale par stéréotaxie sur un modèle de rat F 98. Les données pharmaco-cinétiques ont été également obtenues après injection intraveineuse permettant d’apprécier les propriétés des différents dendrimères synthétisés. Leur apport en terme de confinement au site d’injection représente un avantage majeur de ce nouveau type de radiopharmaceutiques

Radical dendrimers based on biocompatible oligoethylene glycol dendrimers as contrast agents for MRI

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.This research was funded by the Spanish Government (PID2019-105622RB-I00, MAT2016-80826-R, CTQ2017-90596-REDT and Severo Ochoa FUNMAT-FIP-2018 (J.V.) and SAF-2014-60138-R and RTI2018-093831-B-I00 (M.R.), CSIC (intramural 201760E080 project), CIBER BBN (CB06/01/0033, CB06/01/0074 and intramural ORDECA project) and Generalitat de Catalunya (2017-SGR-918 and 2017-SGR-1439). ICMAB acknowledges Spanish MINECO through the Severo Ochoa Centres of Excellence Programme Grant SEV- 2015-0496.Peer reviewe

Redox-Active PTM Radical Dendrimers as Promising Multifunctional Molecular Switches

Nowadays there is a great interest in using individual molecules as nanometer-scale switches and logic devices, with the aim of reaching higher power and smaller size. Demonstrating that one molecular switch can be turned on and off at room temperature simply by applying a current to a neighboring molecule has interesting implications. Herein, we report the synthesis, characterization, and behavior of three generations of polyphosphorhydrazone dendrimers, fully functionalized with 6, 12, and 24 redox-active perchlorotriphenylmethyl (PTM) radicals in the periphery, capable of undergoing an electrochemical reversible switching by multielectron reduction and oxidation. An electrical input was used to trigger the physical properties of these radical dendrimers in a reversible way, modifying their optical, magnetic, and electronic properties. Our Gn(PTM• )x radical dendrimers are paramagnetic, exhibit an absorbance band at 386 nm, and have a red fluorescence emission, if in the radical state. When they are switched to their anion state, these dendrimers convert to diamagnetic species with a maximum absorbance band at ca. 520 nm and no fluorescence emission. Due to two different molecular states, the switch undergoes a reversible and important color change, from light brown for G0(PTM• )6 and bright yellow for G1(PTM• )12 and G2(PTM• )24 dendrimers, when in the radical state, to either a deep wine color for G0(PTM−)6 or purple colors for G1(PTM−)12 and G2(PTM−)24 dendrimers, when in the anion state. Furthermore, there exists a viable opportunity to control the exact number of electrons transferred during the switching process, which could lead not only to a two-state but also to a multistate switch in the near future. This is the first molecular switch based on organic radical dendrimers, to our best knowledge. Moreover, these species can act as electron accumulative molecules able to accept and release up to 24 electrons per molecule at very accessible potentials and in a reversible way.This work was supported by DGICT-MINECO (MAT2016- 80826-R and CTQ2017-90596-REDT), AGAUR (2017 SGR 918), Intramural CSIC project (201760E080), and Severo Ochoa FUNMAT-FIP-2018. ICMAB acknowledges Spanish MINECO through the Severo Ochoa Centres of Excellence Programme Grant SEV- 2015-0496.Peer reviewe

Fully Water-Soluble Polyphosphorhydrazone-Based Radical Dendrimers Functionalized with Tyr-PROXYL Radicals as Metal-Free MRI T1 Contrast Agents

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 GnTyr-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 r1 relaxivity, ca. four times higher (13 mM−1 s −1 ) than the gold-standard Gd-DTPA used in clinics. Furthermore, the r1 and r2 relaxivity per unit of radical showed an increase with the increase in generation of dendrimers.This work was supported by DGICT-MINECO (MAT2016- 80826-R and CTQ2017-90596-REDT), AGAUR (2017 SGR 918), Intramural CSIC project (201760E080), and Severo Ochoa FUNMAT-FIP-2018. ICMAB acknowledges Spanish MINECO through the Severo Ochoa Centres of Excellence Programme Grant SEV- 2015-0496 and Luiz F. Pinto his Juan de la Cierva grant. We thank Dr. Silvia Lope from the MRI facility of the Universitat Autonoma de Barcelona and Dr. Ana ̀ Paula Candiota (GABRMN-UAB) for the ex vivo MRI preliminar studies, Amable Bernabé (Zetasizer facility at the ICTS “NANBIOSIS” Unit 6 of CIBER-BBN, ICMAB), and Judith Oró (TEM ICMAB facility). Songbai Zhang acknowledges his China Scholarship Council (CSC) Scholarship.Peer reviewe