Impact of PSMA Targeted Gold Nanoparticles on Prostate Cancer Radiation Bystander Effect

Abstract

nanoparticles (IONPs) were then incorporated into the cores of liposomes to enable particle tracking with MRI. Results: Intravenous administration of RNA-NPs composed of DOTAP and RNA induced robust activation of innate immune cells resulting in prolonged survival in murine models of subcutaneous and intracranial melanoma. Inclusion of cholesterol in the lipid backbone enabled delivery of nucleic acids across the blood brain barrier and into tumor-associated myeloid cells in intracranial GL261 and KR158b tumors. These cholesterolbearing liposomes not only activated innate immune cells in the tumor microenvironment (i.e., increased expression of CD80 and MHCII), but also enabled further manipulation of this compartment. Use of RNA-NPs to deliver siRNA targeting PD-L1 resulted in significant reduction in PD-L1 expression among tumor associated myeloid cells, leading to 37% long term survivorship in combination with systemic checkpoint blockade in an otherwise fatal model of GL261. IONPs were also incorporated into the cores of these particles to enable non-invasive tracking of particle localization with MRI. Preliminary experiments utilizing dendritic cells treated with iron-oxide-loaded RNA-NPs ex vivo demonstrate that a single dose of this therapy produces immunologic rejection of a murine melanoma model in which a dendritic cell vaccine currently in clinical trials yields no benefit. Furthermore, quantification of particle accumulation in lymph nodes with MRI correlates strongly with survival outcome (R =, indicating that tracking particle localization may be used to reliably differentiate responders from non-responders just two days after treatment. Conclusion: RNA-NPs are a versatile platform for RNA delivery to immune cells. These particles are currently under investigation in canine trials with human clinical trials of our first-generation therapy beginning this year.