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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.