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

PEG-dendritic block copolymers for biomedical applications

The incorporation of poly(ethylene glycol) (PEG) chains at the focal point of dendrimers results in customizable platforms where the careful selection of the PEG length, the nature of the peripheral groups, and the structure and generation of the dendritic block entail materials for specific applications in the biomedical field. In this focus article, the synthesis, properties, and biomedical applications of PEG-dendritic block copolymers are discussed with examples in drug and gene delivery, tissue repair, and diagnosisThis work was financially supported by the Spanish MICINN (CTQ2009-10963 and CTQ2009-14146-C02-02) and the Xunta de Galicia (10CSA209021PR and CN2011/037).S

Chitosan hydrophobic domains are favoured at low degree of acetylation and molecular weight

The aggregation of chitosan (CS) has been studied as a function of concentration, degree of acetylation (DA), and degree of polymerization (DP) by means of pyrene fluorescence and rheology. Fluorescence experiments show that aggregation of CS involves hydrophobic domains (HD) which are more favoured as lower the DA and DP. Consistent with these results, the viscosity of CS solutions decreases continuously on increasing DA, in the whole range of DP. These results, which rule out the participation of the acetyl groups in the HD, have been interpreted by the theory of hydrophobic polyelectrolytes in terms of the electrostatic energy of the aggregatesThis work was financially supported by the Spanish Government (CTQ2009-10963 and CTQ2009-14146-C02-02) and the Xunta de Galicia (10CSA209021PR and CN2011/037)S

Peripheral Functionalization of Dendrimers Regulates Internalization and Intracellular Trafficking in Living Cells

GATG (gallic acid-triethylene glycol) dendrimers represent appealing nanostructures for biomedical applications. The incorporation of specific ligands and targeting and imaging agents on their surface has resulted in promising tools in diagnosis and drug delivery. With the aim to further explore the versatility of GATG dendrimers in the biomedical field, in this work we study the effect of peripheral substitution on their uptake and intracellular trafficking in living cells. To this end, peripheral groups with different physicochemical properties and biological relevance have been installed on the surface of GATG dendrimers, and their interactions, uptake efficacy, and specificity for certain cell populations studied by confocal microscopy. Finally, this information was used to design a pH-sensitive drug delivery system for the selective release of cargo molecules inside cells after lysosomal localization. These results along with the easy functionalization and modular architecture of GATG dendrimers reveal these systems as promising nanotools in biomedicineThis work was financially supported by the Spanish MICINN (CTQ2009-10963 and CTQ2009-14146-C02-02) and the Xunta de Galicia (10CSA209021PR and CN2011/037). M.F.-V. thanks the Spanish Ministry of Education for a FPU fellowshipS

Disclosing an NMR-Invisible Fraction in Chitosan and PEGylated Copolymers and Its Role on the Determination of Degrees of Substitution

An unexpected 1H NMR invisible fraction (IF) for chitosan (CS) and CS-g-PEG is reported. The presence of this IF is remarkable considering that solution NMR is recognized as the method of choice for studying structural modifications in CS, including the degrees of acetylation (DA) and substitution (DS). In spite of IF figures as high as 50%, this IF does not interfere in the correct determination of the DA by 1H NMR, pointing to a homogeneous distribution of acetyl groups along the visible and invisible fractions. Quite in contrast, the IF negatively biases the determination of the DS in CS-g-PEG, with relative errors as high as 150% in a broad range of temperatures, pH values, and concentrations. This fact raises concerns about the accuracy of previously reported DS data for CS-g-PEG and many other CS copolymers. Efficient user-friendly conditions have been developed for the correct determination of the DS of CS-g-PEG by depolymerization by nitrous acidThis work was financially supported by the Spanish Government (CTQ2009-10963, CTQ2012-34790, CTQ2009-14146-C02-02, and CTQ2012-33436) and the Xunta de Galicia (10CSA209021PR and CN2011/037)S

Stepwise Filtering of the Internal Layers of Dendrimers by Transverse-Relaxation-Edited NMR

The characteristic distribution of transverse relaxation times (T2) within dendrimers (shorter values at the core than the periphery) can be exploited in T2-edited 1D and 2D NMR experiments for the stepwise filtering of internal nuclei according to their topology within the dendritic structure. The resulting filtered spectra, which can be conceived as corresponding to virtual hollow dendrimers, benefit from reduced signal overlap, thus facilitating signal assignment and characterization. The generality of the method as a powerful tool in structural and end-group analysis has been confirmed with various dendritic families and nuclei (1H, 13C, 31P)This work was financially supported by the Spanish Government (CTQ2009-10963, CTQ2012-34790, CTQ2009-14146-C02-02, CTQ2012-33436) and the Xunta de Galicia (10CSA209021PR and CN2011/037). L.F.P. thanks the Portuguese Foundation for Science and Technology (FCT MCTES) for a Ph.D. grant (SFRH/BD/37341/2007)S

Real-Time Evaluation of Binding Mechanisms in Multivalent Interactions: A Surface Plasmon Resonance Kinetic Approach

Multivalency is a key, ubiquitous phenomenon in nature characterized by a complex combination of binding mechanisms, with special relevance in carbohydrate–lectin recognition. Herein we introduce an original surface plasmon resonance kinetic approach to analyze multivalent interactions that has been validated with dendrimers as monodisperse multivalent analytes binding to lectin clusters. The method, based on the analysis of early association and late dissociation phases of the sensorgrams provides robust information of the glycoconjugate binding efficiency and real-time structural data of the binding events under the complex scenario of the glyco-cluster effect. Notably, it reveals the dynamic nature of the interaction and offers experimental evidence on the contribution of binding mechanismsThis work was financially supported by the Spanish Government (CTQ2009-10963, CTQ2012-34790, CTQ2009-14146-C02-02) and the Xunta de Galicia (10CSA209021PR and CN2011/037). E.M.M. thanks the Xunta de Galicia for a “Parga Pondal” research contractS

Predicting PSR Filters by Transverse Relaxation Enhancements

The paramagnetic spin relaxation (PSR) filter allows the suppression of the NMR resonances of individual components in mixtures according to their Gd3+-complexing ability. The difficulty in predicting this property hampers, however, the widespread application of this filter. Herein we describe that the PSR filter is dominated by the transverse relaxation enhancement (R2p) experienced by nuclei in the presence of Gd3+, so that R2p represents a reliable predictive tool of suppression in the 1D and 2D PSR filter of complex mixtures. The robustness of R2p as a predictive tool in PSR filters has been demonstrated at different magnetic fields and for the 1H, 13C, COSY, and HMQC filtering of commercial multicomponent compositions, including beverages and drugsThis work was financially supported by the Spanish Government (CTQ2012-34790, CTQ2012-33436) and the Xunta de Galicia (CN2011/037). L.F.P. thanks the Portuguese Foundation for Science and Technology (FCT MCTES) for a Ph.D. grant (SFRH/BD/37341/2007)S

In situ nanofabrication of hybrid PEG-dendritic–inorganic nanoparticles and preliminary evaluation of their biocompatibility

An in situ template fabrication of inorganic nanoparticles using carboxylated PEG-dendritic block copolymers of the GATG family is described as a function of the dendritic block generation, the metal (Au, CdSe) and metal molar ratio. The biocompatibility of the generated nanoparticles analysed in terms of their aggregation in physiological media, cytotoxicity and uptake by macrophages relates to the PEG density of the surface of the hybridsC.S.E. and A.G.-F. thank to the European Commission BIOCAPS (316265, FP7/REGPOT-2012-2013.1) and Xunta de Galicia (Agrupamento INBIOMED and Grupo con potencial crecimiento). A.S.-H. and E.F.-M. thank the Spanish Government (CTQ2012-34790) and the Xunta de Galicia (CN2011/037)S

GATG Dendrimers and PEGylated Block Copolymers: from Synthesis to Bioapplications

This is a post-peer-review, pre-copyedit version of an article published in The AAPS Journal. The final authenticated version is available online at: https://doi.org/10.1208/s12248-014-9642-3Dendrimers are synthetic macromolecules composed of repetitive layers of branching units that emerge from a central core. They are characterized by a tunable size and precise number of peripheral groups which determine their physicochemical properties and function. Their high multivalency, functional surface, and globular architecture with diameters in the nanometer scale makes them ideal candidates for a wide range of applications. Gallic acid-triethylene glycol (GATG) dendrimers have attracted our attention as a promising platform in the biomedical field because of their high tunability and versatility. The presence of terminal azides in GATG dendrimers and poly(ethylene glycol) (PEG)-dendritic block copolymers allows their efficient functionalization with a variety of ligands of biomedical relevance including anionic and cationic groups, carbohydrates, peptides, or imaging agents. The resulting functionalized dendrimers have found application in drug and gene delivery, as antiviral agents and for the treatment of neurodegenerative diseases, in diagnosis and as tools to study multivalent carbohydrate recognition and dendrimer dynamics. Herein, we present an account on the preparation and recent applications of GATG dendrimers in these fieldsThe authors wish to acknowledge past and present lab members who have contributed to the development of dendrimers in our group. This work was financially supported by the Spanish Government (CTQ2009-10963, CTQ2012-34790, CTQ2009-14146-C02-02, CTQ2012-33436) and the Xunta de Galicia (10CSA209021PR and CN2011/037)S