Metallo-fluorocarbon nanoemulsion for PET detection of cancer inflammation

In cancer, macrophages play a multifaceted role in disease progression and response to therapies. Tumor-
associated macrophages (TAMs) serve several pro-tumoral functions including the expression of factors
promoting growth, immune suppression and angiogenesis. A high TAM burden in the tumor microenvironment
is often associated with poor prognosis and therapeutic resistance to certain immunotherapies. Moreover, TAMs
are emerging as a target for anti-cancer therapeutics. Overall, an imaging probe that can non-invasively detect
TAM burden could help stratify patients and personalize treatments to improve response rates. Recently, our
laboratory has developed novel molecular probes enabling sensitive and precise imaging of inflammatory foci in
vivo. We synthesized functionalized fluorocarbon nanoemulsions incorporating a fluorous-encapsulated
radiometal chelate (FERM). Pre-formed FERM nanoemulsion rapidly captures zirconium-89 into the fluorous
phase. The highly hydrophobic nature of fluorocarbons helps exclude competition from water, cations, lipids and
proteins that contribute to the dissociation of 89Zr from the carrier. By encapsulating the radiometal inside the
volume of nanoemulsion droplet one can achieve a high payload and cell detection sensitivity, with low
background. Following an intravenous injection of FERM, nanoemulsion droplets are scavenged by phagocytic
macrophages. The labeled cells accumulate at inflammatory sites resulting in sensitive and quantifiable positron
emission tomography (PET) signals reflecting predominantly macrophage burden. Preliminary PET results from
our lab demonstrate excellent sensitivity and versatility of the FERM probe in a diversity of inflammation rodent
models, including solid tumor, acute infection and autoimmune disease. Building on these results, our project
has three Aims: Aim 1. 89Zr FERM formulation. We will perform FERM nanoemulsion formulation optimization
and scale-up. We will also develop optimal radiopharmacy methods to maximize labeling efficiency of FERM
and product yield. Aim 2. Biological characterizations. Cell-based assays will be performed to evaluate
potential toxicity of 89Zr FERM. Moreover, we will characterize the in vivo blood half-life, probe stability, and
preliminary dosimetry. Aim 3. In vivo immuno-oncology studies. We will characterize the effectiveness of
FERM for TAM detection and quantification, responsiveness to treatments that deplete TAM burden, and the
probe’s potential for predicting response to immunotherapeutic interventions in multiple murine solid tumor
models. Parallel phenotypic profiling of FERM-labeled cells in the tumor will be performed. The proposed studies
will generate essential data needed to drive potential clinical translation of the FERM imaging biomarker for use
in future immuno-oncology clinical trials.

Grant Number: 5R01CA279271-03
NIH Institute/Center: NIH
Principal Investigator: ERIC AHRENS