Novel Radiation-Guided Nanoparticle Drug Delivery System for Prostate Cancer

Article Outline

• Purpose/Objective(s)
• Materials/Methods
• Results
• Conclusions
• Copyright

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Purpose/Objective(s) 

To characterize a novel radiation-guided drug delivery system in mouse models of prostate cancer. Peptides that bind to radiation-inducible receptors in prostate cancer were used for nanoparticle drug delivery.

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Materials/Methods 

Phage-displayed peptide libraries were utilized to identify peptides that bind within irradiated prostate cancer. We identified the HVGGSSV peptide as the predominant ligand. This peptide was then conjugated to nanoparticles to study its pharmacokinetics and biodistribution in mouse models. Several mouse models of prostate cancer were used including: heterotopic xenograft with PC3 cells in a hind-limb model, an orthotopic xenograft with PC3 cells (tumor development in 2 wks), and prostate-specific conditional PTEN transgenic mice which developed tumors over 5 mos. HVGGSSV peptide was conjugated at the aminoterminus to nanoparticles labeled with near infrared imaging (NIR), fluorochrome and with radionuclides. Biodistribution and pharmacokinetics were studied utilizing the Xenogen in vivo imaging system and gamma camera imaging. Prostate tumors were treated with 3 Gy to activate ligand binding to receptors. Peptide-conjugated nanoparticles were injected by jugular vein.

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Results 

Microscopic imaging of nanoparticle binding within prostate tumor microvasculature revealed binding within 4 hrs of radiation with persistent binding for 9 days. In contrast, tumors that were not treated with radiation demonstrated no binding. The nanoparticles labeled with NIR fluourochromes were imaged by Xenogen IVIS demonstrating specific binding of nanoparticles to irradiated tranagenic, orthotopic (Fig. A) and heterotopic prostate tumors. A 90-fold increase in nanoparticle binding to prostate tumors over that of background normal organ binding was observed (p = 0.001). Radiolabeled nanoparticle cleared from circulation within 24 hrs and persistent binding within the irradiated prostate tumors was observed for over 9 days. To verify binding within prostate tumors, the prostate was resected (Fig. B) and imaged by NIR or gamma camera imaging. This showed specific binding within prostate tumors with no activity within bladder, intestine or other organs (Fig C). Radiolabeled nanoparticles achieved therapeutic irradiation of prostate tumors. Tumor growth delay was significantly increased in prostate tumors treated with radiolabeled nanoparticles as compared to nanoparticles conjugated to scrambled control peptide and other controls (p < 0.05).

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Conclusions 

The HVGGSSV peptide targets radiolabeled nanoparticles to irradiated prostate cancers. This radiation-guided drug delivery system is planned for pharmacokinetic clinical trials.

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