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

Implantable SDF-1α-loaded silk fibroin hyaluronic acid aerogel sponges as an instructive component of the glioblastoma ecosystem: between chemoattraction and tumor shaping into resection cavities

In view of inevitable recurrences despite resection, glioblastoma (GB) is still an unmet clinical need. Dealing with the stromal-cell derived factor 1-alpha (SDF-1α)/CXCR4 axis as a hallmark of infiltrative GB tumors and with the resection cavity situation, the present study described the effects and relevance of a new engineered micro-nanostructured SF-HA-Hep aerogel sponges, made of silk fibroin (SF), hyaluronic acid (HA) and heparin (Hep) and loaded with SDF-1α, to interfere with the GB ecosystem and residual GB cells, attracting and confining them in a controlled area before elimination. 70 µm-pore sponges were designed as an implantable scaffold to trap GB cells. They presented shape memory and fit brain cavities. Histological results after implantation in brain immunocompetent Fischer rats revealed that SF-HA-Hep sponges are well tolerated for more than 3 months while moderately and reversibly colonized by immuno-inflammatory cells. The use of human U87MG GB cells overexpressing the CXCR4 receptor (U87MG-CXCR4+) and responding to SDF-1α allowed demonstrating directional GB cell attraction and colonization of the device in vitro and in vivo in orthotopic resection cavities in Nude rats. Not modifying global survival, aerogel sponge implantation strongly shaped U87MG-CXCR4+ tumors in cavities in contrast to random infiltrative growth in controls. Overall, those results support the interest of SF-HAHep sponges as modifiers of the GB ecosystem dynamics acting as “cell meeting rooms” and biocompatible niches whose properties deserve to be considered toward the development of new clinical procedures

Lipid Nanocapsules Loaded with Rhenium-188 Reduce Tumor Progression in a Rat Hepatocellular Carcinoma Model

International audienceBACKGROUND: Due to their nanometric scale (50 nm) along with their biomimetic properties, lipid nanocapsules loaded with Rhenium-188 (LNC(188)Re-SSS) constitute a promising radiopharmaceutical carrier for hepatocellular carcinoma treatment as its size may improve tumor penetration in comparison with microspheres devices. This study was conducted to confirm the feasibility and to assess the efficacy of internal radiation with LNC(188)Re-SSS in a chemically induced hepatocellular carcinoma rat model. METHODOLOGY/PRINCIPAL FINDINGS: Animals were treated with an injection of LNC(188)Re-SSS (80 MBq or 120 MBq). The treated animals (80 MBq, n = 12; 120 MBq, n = 11) were compared with sham (n = 12), blank LNC (n = 7) and (188)Re-perrhenate (n = 4) animals. The evaluation criteria included rat survival, tumor volume assessment, and vascular endothelial growth factor quantification. Following treatment with LNC(188)Re-SSS (80 MBq) therapeutic efficiency was demonstrated by an increase in the median survival from 54 to 107% compared with control groups with up to 7 long-term survivors in the LNC(188)Re-SSS group. Decreased vascular endothelial growth factor expression in the treated rats could indicate alterations in the angiogenesis process. CONCLUSIONS/SIGNIFICANCE: Overall, these results demonstrate that internal radiation with LNC(188)Re-SSS is a promising new strategy for hepatocellular carcinoma treatment

Nanomedicine to overcome radioresistance in glioblastoma stem-like cells and surviving clones

International audienceRadiotherapy is one of the standard treatments for glioblastoma, but its effectiveness often encounters the phenomenon of radioresistance. This resistance was recently attributed to distinct cell contingents known as glioblastoma stem-like cells (GSCs) and dominant clones. It is characterized in particular by the activation of signaling pathways and DNA repair mechanisms. Recent advances in the field of nanomedicine offer new possibilities for radiosensitizing these cell populations. Several strategies have been developed in this direction, the first consisting of encapsulating a contrast agent or synthesizing metal-based nanocarriers to concentrate the dose gradient at the level of the target tissue. In the second strategy the physicochemical properties of the vectors are used to encapsulate a wide range of pharmacological agents which act in synergy with the ionizing radiation to destroy the cancerous cells. This review reports on the various molecular anomalies present in GSCs and the predominant role of nanomedicines in the development of radiosensitization strategies

Tumour targeting of lipid nanocapsules grafted with cRGD peptides.

International audienceCombining targeting to therapy remains a major challenge in cancer treatment. To address this subject, the surface of lipid nanocapsules (LNC) was modified by grafting cRGD peptides, which are known to be recognised by αvβ3 integrins expressed by tumour endothelium and cancer cells. Applicability of this LNC-cRGD in tumour targeting was first assessed in vitro by the use of U87MG glioma cells. Biodistribution and tumour accumulation of radiolabelled LNC-cRGD in vivo were then evaluated in mice bearing the same subcutaneous xenograft. Flow cytometry and confocal microscopy results revealed that the cRGD grafting improved binding and internalisation compared to negative control LNC-cRAD and blank LNC. The peptide-grafted LNC remained in the blood circulation up to 3h with reduced capture by the RES organs. Tumour accumulation of LNC-cRGD with respect to LNC-cRAD was significantly higher at 1-3h. These results show that cRGD grafted to LNC has created a promising tumour-targetable nanocarrier that could be used in cancer treatment

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

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Développement d’un procédé de génération de particules de carbonate de calcium en milieu CO2 supercritique pour applications biomédicales

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Brain targeting using novel lipid nanovectors.

International audienceThe present study shows the potential of novel nanovectors for the delivery of lipophilic radionuclides and therapeutic molecules to the brain. Lipid nanocapsules (LNC) inhibiting the P-gp pump efflux, were conjugated to OX26 monoclonal antibodies (OX26 MAb) and Fab' fragments. The OX26 MAb is directed against the transferrin receptor (TfR) highly expressed on the cerebral endothelium. The specific association of immunonanocapsules to rat brain capillary endothelial cells was demonstrated. Biodistribution of immunonanocapsules, labeled with a (188)Re lipophilic complex, was determined in healthy rats. At 24 h post-injection, the brain concentrations of Fab'-immunonanocapsules and OX26-immunonanocapsules were, respectively, 1.5 and 2-fold higher than non-targeted nanocapsules. In addition, Fab' fragments helped prolong the vascular residence time of the nanovectors but their affinity to TfR was lower than whole antibodies. The ability of immunonanocapsules to specifically target cerebral tissues in addition to the promising features of LNC is of importance to the field of nanomedicine

Effective Targeting Of Endometrial Tissue By 16α-[18f]Fluoro-17β-Œstradiol ([18f]-Fes): Preliminary Results In The Diagnosis Of Endometriosis

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