Optical and MRI-Guided Theranostic Application of Ultrasmall Superparamagnetic Iron Oxide Nanodrug Conjugate for PSMA-Positive Prostate Cancer Therapy

High Resolution Image Download MS PowerPoint Slide Active targeting is more effective than conventional passive targeted drug delivery systems in increasing therapeutic efficacy and minimizing systemic toxicities. Importantly, the nanoparticle-based targeted drug delivery systems combine active and passive targeting properties and significantly enhance therapeutic efficacy. In this study, we utilized ultrasmall superparamagnetic iron oxide (uSPIO) nanoparticles conjugated with anti-prostate-specific membrane antigen (PSMA) 5D3 monoclonal antibody, mertansine (DM1) antitubulin agent, and fluorophore to develop a targeted uSPIO-5D3-DM1-AF488/CF750 nanotheranostic for PSMA(+) prostate cancer (PC) therapy. This agent enables multimodality in vivo imaging using near-infrared (NIR) fluorescence and magnetic resonance imaging (MRI). uSPIO-5D3-DM1-AF488 is selectively internalized into PSMA-positive cells by receptor-mediated endocytosis, and uSPIO-5D3-DM1-CF750 exhibited 1.62 and 166.2 ng/mL IC 50 values in PSMA(+) and PSMA(−) cells, respectively. The image-guided therapeutic study was conducted in vivo in human PC xenograft mouse models bearing bilateral PSMA(±) tumors ( n = 10, two 10 mg/kg doses on days 1 and 14). The therapeutic results exhibited a significant control of the growth of PSMA(+) tumors starting at day 5 ( p = 0.05) and significantly improved efficacy after day 9 ( p = 0.0005) during the treatment period ( t = 21 days). We observed the PSMA-specific uptake of uSPIO-5D3-DM1-CF750 in tumors in NIR IVIS Xenogen images and T 1 - and T 2 -weighted MRI with 20.6% and 42% reduction of overall T 1 and T 2, respectively. Approximately 70% of mice with PSMA(+) tumors treated with uSPIO-5D3-DM1-CF750 survived or did not exceed the threshold level of the tumor size during the treatment. Ex vivo biodistribution study proved 50% and 45% higher uptake of uSPIO-5D3-DM1-CF750 by PSMA(+) tumors compared to untargeted uSPIO-DM1-CF750 by PSMA(+) tumors and uSPIO-5D3-DM1-CF750 by PSMA(−) tumors, respectively. ICP-MS analysis demonstrated a 73% increase in uSPIO-5D3-DM1-CF750 uptake by PSMA(+) tumors compared to PSMA(+) tumors treated with pure uSPIO. The toxicological results reveal the safe profile in systemic toxicities without life-threatening changes in the complete blood count and clinical chemistry profile of toxicology.