Tumor-Targeted Perfluorinated Micelles as Efficient Theranostic Agents Combining Positron Emission Tomography and Radiosensitization.

We report the synthesis of biocompatible perfluorinated micelles designed to improve radiotherapeutic efficacy in a radioresistant tumor environment. In vitro and in vivo behaviors of perfluorinated micelles were assessed at both cellular and tissular levels. The micellar platform offers key advantages as theranostic tool: (i) small size, allowing deep tissue penetration; (ii) oxygen transport to hypoxic tissues; (iii) negligible toxicity in the absence of ionizing radiation; (iv) internalization into cancer cells; (v) potent radiosensitizing effect; and (vi) excellent tumor-targeting properties, as monitored by positron emission tomography. We have demonstrated strong in vitro radiosensitizing effects of the micelle and in vivo tumor targeting, making this nanometric carrier a promising tool for the potentiation of focused radiotherapy.

Sonoporation-assisted micelle delivery in subcutaneous glioma-bearing mice evaluated by PET/fluorescent bi-modal imaging.

Tumor-specific drug delivery is a major challenge for the pharmaceutical industry. Nanocarrier systems have been widely investigated to increase and control drug delivery to the heterogeneous tumor microenvironment. Classically, the uptake of nanocarriers by solid tumor tissues is mainly mediated by the enhanced permeability and retention effect (EPR). This EPR effect depends on the tumor type, its location, the physicochemical properties of the carriers, and the blood perfusion of the tumoral lesions. The main goal of this study was to evaluate in vivo tumor uptake of micelle carriers, assisted by microbubble/ultrasound sonoporation. Micelles were tracked using bi-modal imaging techniques to precisely localize both the nanocarrier and its payload. Micelles were loaded with a near infrared fluorophore and radiolabeled with zirconium-89. Their pharmacokinetics, biodistribution and passive tumor targeting properties were evaluated in a subcutaneous glioblastoma (U-87 MG) mouse model using optical and PET imaging. Finally, accumulation and diffusion into the tumor micro-environment was investigated under microbubble-assisted sonoporation, which helped homogenize the delivery of the micelles. The in vivo experiments showed a good correlation between optical and PET images and demonstrated the stability of the micelles in biological media, their high and long-term retention in the tumors and their clearance through the hepato-biliary pathway. This study demonstrates that bi-modal imaging techniques are powerful tools for the development of new nanocarriers and that sonoporation is a promising method to homogenize nanomedicine delivery to tumors.

ImmunoPET imaging-based pharmacokinetic profiles of an antibody and its Fab targeting endothelin A receptors on glioblastoma stem cells in a preclinical orthotopic model.

BACKGROUND: The resistance of glioblastoma stem cells (GSCs) to treatment is one of the causes of glioblastoma (GBM) recurrence. Endothelin A receptor (ETA) overexpression in GSCs constitutes an attractive biomarker for targeting this cell subpopulation, as illustrated by several clinical trials evaluating the therapeutic efficacy of endothelin receptor antagonists against GBM. In this context, we have designed an immunoPET radioligand combining the chimeric antibody targeting ETA, chimeric-Rendomab A63 (xiRA63), with 89Zr isotope and evaluated the abilities of xiRA63 and its Fab (ThioFab-xiRA63) to detect ETA+ tumors in a mouse model xenografted orthotopically with patient-derived Gli7 GSCs. RESULTS: Radioligands were intravenously injected and imaged over time by µPET-CT imaging. Tissue biodistribution and pharmacokinetic parameters were analyzed, highlighting the ability of [89Zr]Zr-xiRA63 to pass across the brain tumor barrier and achieve better tumor uptake than [89Zr]Zr-ThioFab-xiRA63. CONCLUSIONS: This study shows the high potential of [89Zr]Zr-xiRA63 in specifically targeting ETA+ tumors, thus raising the possibility of detecting and treating ETA+ GSCs, which could improve the management of GBM patients.

Pharmacokinetics derived from PET imaging of inspiring radio-enhancer platinum nanoparticles.

Personalized medicine approach in radiotherapy requires the delivery of precise dose to the tumor. The concept is to increase the effectiveness of radiotherapy while sparing the surrounding heathy tissue. This can be achieved by the use of high-Z metal-based nanoparticles (NPs) as radio-enhancers and PET imaging for mapping NPs distribution to guide the irradiation. In the present study, radio-enhancing platinum NPs were radiolabeled and imaged to assess their pharmacokinetics over time. PET imaging of these NPs revealed high enhanced permeation and retention effect. The maximal tumor accumulation (4.8 ± 0.8 %ID/cc) was observed at 24 h post-injection along with persistent accumulation of the NPs, especially at the tumor ring, even after several days. These properties positively suggest the potential clinical use of these NPs.

Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells.

Checkpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8+ T cell effector functions in mice and humans. Monalizumab, a humanized anti-NKG2A antibody, enhanced NK cell activity against various tumor cells and rescued CD8+ T cell function in combination with PD-x axis blockade. Monalizumab also stimulated NK cell activity against antibody-coated target cells. Interim results of a phase II trial of monalizumab plus cetuximab in previously treated squamous cell carcinoma of the head and neck showed a 31% objective response rate. Most common adverse events were fatigue (17%), pyrexia (13%), and headache (10%). NKG2A targeting with monalizumab is thus a novel checkpoint inhibitory mechanism promoting anti-tumor immunity by enhancing the activity of both T and NK cells, which may complement first-generation immunotherapies against cancer.

In vivo imaging of DNA lipid nanocapsules after systemic administration in a melanoma mouse model.

The biodistribution of intravenously injected DNA lipid nanocapsules (DNA LNCs), encapsulating pHSV-tk, was analysed by in vivo imaging on an orthotopic melanoma mouse model and by a subsequent treatment with ganciclovir (GCV), using the gene-directed enzyme prodrug therapy (GDEPT) approach. Luminescent melanoma cells, implanted subcutaneously in the right flank of the mice, allowed us to follow tumour growth and tumour localisation with in vivo bioluminescence imaging (BLI). In parallel, DNA LNCs or PEG DNA LNCs (DNA LNCs recovered with PEG(2000)) encapsulating a fluorescent probe, DiD, allowed us to follow their biodistribution with in vivo biofluorescence imaging (BFI). The BF-images confirmed a prolonged circulation-time for PEG DNA LNCs as was previously observed on an ectotopic model of glioma; comparison with BL-images evidenced the colocalisation of PEG DNA LNCs and melanoma cells. After these promising results, treatment with PEG DNA LNCs and GCV on a few animals was performed and the treatment efficacy measured by BLI. The first results showed tumour growth reduction tendency and, once optimised, this therapy strategy could become a new option for melanoma treatment.