Radiolabeling and PET–MRI microdosing of the experimental cancer therapeutic, MN-anti-miR10b, demonstrates delivery to metastatic lesions in a murine model of metastatic breast cancer

Abstract

Background In our earlier work, we identified microRNA-10b (miR10b) as a master regulator of the viability of metastatic tumor cells. This knowledge allowed us to design a miR10b-targeted therapeutic consisting of an anti-miR10b antagomir conjugated to ultrasmall iron oxide nanoparticles (MN), termed MN-anti-miR10b. In mouse models of breast cancer, we demonstrated that MN-anti-miR10b caused durable regressions of established metastases with no evidence of systemic toxicity. As a first step towards translating MN-anti-miR10b for the treatment of metastatic breast cancer, we needed to determine if MN-anti-miR10b, which is so effective in mice, will also accumulate in human metastases. Results In this study, we devised a method to efficiently radiolabel MN-anti-miR10b with Cu-64 (64Cu) and evaluated the pharmacokinetics and biodistribution of the radiolabeled product at two different doses: a therapeutic dose, referred to as macrodose, corresponding to 64Cu-MN-anti-miR10b co-injected with non-labeled MN-anti-miR10b, and a tracer-level dose of 64Cu-MN-anti-miR10b, referred to as microdose. In addition, we evaluated the uptake of 64Cu-MN-anti-miR10b by metastatic lesions using both in vivo and ex vivo positron emission tomography–magnetic resonance imaging (PET–MRI). A comparable distribution of the therapeutic was observed after administration of a microdose or macrodose. Uptake of the therapeutic by metastatic lymph nodes, lungs, and bone was also demonstrated by PET–MRI with a significantly higher PET signal than in the same organs devoid of metastatic lesions. Conclusion Our results demonstrate that PET–MRI following a microdose injection of the agent will accurately reflect the innate biodistribution of the therapeutic. The tools developed in the present study lay the groundwork for the clinical testing of MN-anti-miR10b and other similar therapeutics in patients with cancer.

Enhancing RNA Payload and Temperature Stability and Activity with Cationic Peptide-Coated Zinc Oxide Nanoparticles

“…12−14 The majority of clinical work thus far has focused on iron oxide nanoparticles, 15 none of which has yet been extended to RNA with one noteworthy preclinical example for miRNA. 16 Yet, to the best of our knowledge none of this work has yet made the transition from preclinical to clinical for mRNA. 1,2 Indeed, despite the widespread acceptance of LNPs, in addition to inefficient RNA loading and poor RNA temperature stability, there are some recent safety concerns for these systems.…”

“…That work involved gold particles that are nonphysiologically based, and, unfortunately, nanoscale gold must be chemically derivatized to load siRNA and for which relatively little mRNA work has thus far been reported . Although there have been some physiologically based inorganic and surface-coated nanoparticles, thus far, the few reports of their RNA surface absorption, RNA temperature stabilization, and RNA delivery are relatively modest. − The majority of clinical work thus far has focused on iron oxide nanoparticles, none of which has yet been extended to RNA with one noteworthy preclinical example for miRNA . Yet, to the best of our knowledge none of this work has yet made the transition from preclinical to clinical for mRNA. , …”