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Use of targeted nanoparticles for imaging and therapy of prostate cancer Pamela J Russell*,1, Brian W.C. Tse2, Amanda K. Pearce3, Adrian V. Fuchs3, Mei- Chun Yeh1, Steve S. Huang4, Warren D. Heston5, Elizabeth D. Williams1, Andrew K. Whittaker3 and Kristofer J. Thurecht3 Australian Prostate Cancer Research Centre − Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology at Translational Research Institute, Brisbane 4102, Australia 2 Translational Research Institute, Brisbane, 4102, Australia 3 ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and †Australian Institute of Bioengineering and Nanotechnology and Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia 4 Department of Nuclear Medicine, Cleveland Clinic, Cleveland, Ohio 44195, United States 5 Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio 44195, United States 1 Pamela Russell email: [email protected] Nearly one million men globally will be diagnosed with prostate cancer each year, and 260,000 men will ultimately succumb to this disease. Despite the development of new drugs for treating metastatic late stage (castrate resistant) prostate cancer, there is still an unmet need for new therapeutics that target and directly treat advanced prostate cancer. Our early studies used ferric oxide nanoparticles bound to J591, an antibody that recognizes prostate specific membrane antigen (PSMA) to improve MRI of prostate cancer. We have used the biomarker, PSMA, for targeting as it is highly expressed on the membrane in aggressive prostate cancer and its metastases and is internalised after binding. Moreover the recent use of PSMA-PET in the clinic has been a game changer for monitoring prostate cancer and its metastases. In further studies, we have used hyperbranched polymers (HBPs), an emerging class of promising biocompatible agents for cancer imaging and therapy. Their structure allows for conjugation with several specific functionalities. We aimed to assess imaging and therapeutic potential of HBP targeted to prostate cancer and loaded with a chemotherapeutic agent. We synthesised polyethylene glycol HBP, conjugated with Cy5 fluorophore and targeting ligand (peptide1,2 or glutamate urea3) that bind to PSMA. Chemotherapeutics were then attached through hydrazone formation allowing their controlled release under endosomal conditions. In vitro, PSMA-HBP-drug conjugates were internalised into PSMA+ but not PSMA- cells in a dose- and time-dependent manner. Confocal microscopy indicated that the drug travelled with the polymer into cells by receptor mediated internalisation with subsequent release following hydrazone degradation, providing comparable cytoxicity to free drug. In vivo studies were performed in BALB/c nude mice bearing subcutaneous or orthotopic PSMA+ or PSMA- xenografts. After injection of HBP- peptide, Cy5 accumulated in PSMA+ xenografts. Long term tumour regression studies showed that PSMA-HBP-drug conjugates significantly reduced PCa xenograft volume compared with free drug or polymer control, with no adverse toxicity to the mice. This work demonstrates the potential of an HBP system for use in prostate cancer theranostics.