Purpose: To evaluate the effect of androgen receptor (AR) inhibition on Prostate Specific Membrane Antigen (PSMA) uptake imaged using ⁶⁸Ga-PSMA-11 Positron Emission Tomography (PET) in a mouse xenograft model and in a patient with castration sensitive prostate cancer. Procedures: We imaged three groups of four mice bearing LNCaP-AR xenografts before and seven days after treatment with ARN-509, orchiectomy and control vehicle. Additionally, we imaged one patient with castration sensitive prostate cancer before and four weeks after treatment with androgen deprivation therapy (ADT). Uptake on pre- and post-treatment imaging was measured and compared. Results: PSMA uptake increased 1.5 to 2.0 fold in the xenograft mouse model after treatment with both orchiectomy and ARN-509, but not with vehicle. Patient imaging demonstrated a seven-fold increase in PSMA uptake after the initiation of ADT. 13 of 22 lesions in the imaged patient were only visualized on PSMA PET after treatment with ADT. Conclusion: Inhibition of the AR can increase PSMA expression in prostate cancer metastases and increase the number of lesions visualized using PSMA PET. The effects seen in cell and animal models can be recapitulated in humans. Further work needs to be done to better understand temporal changes of PSMA expression in order to leverage this effect for both improved diagnosis and therapy.

We previously reported the synthesis of gadolinium-based nanoparticles (NPs) denoted AGuIX (activation and guiding of irradiation by X-ray) NPs and demonstrated their potential as an MRI contrast agent and their efficacy as radiosensitizing particles during X-ray cancer treatment. Here we focus on the elimination kinetics of AGuIX NPs from the subcellular to whole-organ scale using original and complementary methods such as laser-induced breakdown spectroscopy (LIBS), intravital two-photon microscopy, inductively coupled plasma optical emission spectrometry (ICP-OES), transmission electron microscopy (TEM), and electrospray ionization mass spectrometry (ESI-MS). This combination of techniques allows the exact mechanism of AGuIX NPs elimination to be elucidated, including their retention in proximal tubules and their excretion as degraded or native NPs. Finally, we demonstrated that systemic AGuIX NP administration induced moderate and transient effects on renal function. These results provide useful and promising preclinical information concerning the safety of theranostic AGuIX NPs.

The PERK-eIF2α pathway is activated in aggressive prostate cancer and associated with patient outcome, providing a therapeutic target for the disease.

AGuIX® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human.