The following is a summary of projects currently under way in the Bradbury Lab.
First-in-Human Trial in Metastatic Melanoma Patients Using an FDA IND-Approved (IND#110375) Multimodal 124I-Labeled cRGDY Silica Nanomolecular Particle Tracer
Schematic of the 124I-cRGDY-PEGylated core-shell silica nanoparticle with surface-bearing radiolabels and peptides and core-containing reactive-dye molecules (insets).
We are evaluating a novel, tumor-selective silica nanoparticle tracer (124I-cyclic Arg-Gly-Asp-Tyr (cRGDY)-PEG-dots or 124I-cRGDY-PEG-dots) to determine whether this probe has desirable in vivo characteristics as a PET radiotracer, including efficient renal clearance, low background signal, stability, and biosafety, in humans. It is the first inorganic particle of its class to be approved as a “drug” for clinical use.
Multicenter Trial Investigating Sodium Magnetic Resonance Imaging (MRI) for Monitoring Brain Tumor Response to Radiation
As part of a multicenter clinical trial with the University of Illinois at Chicago, we are using sodium MRI in high-grade glioma patients to serially monitor tissue viability, in the form of tissue sodium concentrations, during radiation therapy. A goal of the study is to evaluate whether sodium MRI is sensitive to tumor response on a time scale that could inform decision making about radiation therapy during treatment.
Image-Guided Stereotactic Biopsy of High-Grade Gliomas
We are investigating potential links between MRI-PET imaging findings at sites of regional heterogeneity within high-grade gliomas and correlative tissue markers and/or expression profiles derived from tissue biopsy specimens.
Preclinical Translational Initiatives
We are combining new, translatable multimodal platforms for cancer diagnostics with state-of-the-art imaging tools (PET, optical) for image-guided surgery/interventions, as well as non-surgical applications.
We are exploring a range of potential applications of nanotechnology within the context of cancer diagnosis and staging.
Novel Particle Probe Development
Imaging of Metastatic Disease in a Spontaneous Melanoma Miniswine Model. (A) Whole-body 18F-FDG PET-CT sagittal and axial views demonstrate primary tumor (green arrow) and single SLN (white arrow) posteriorly within the right neck after IV injection. (B) High-resolution dynamic PET-CT scan one hour after subdermal, peritumoral injection of 124I-RGD-PEG-dots (SLN, arrow; left-sided node, arrowhead). (C) Whole-body Cy5 optical image of the excised SLN. (D) Gross image of the cut surface of the black-pigmented SLN (arrow), which measured 1.3 x 1.0 x 1.5 cm3, and annotated gamma counted activity. E Low-power view of H&E stained SLN demonstrating scattered melanomatous clusters.
We are developing, characterizing, and optimizing the use of multimodal silica particle platforms for the detection and localization of primary tumors and metastatic disease spread in small and large animal models. These particles are cancer selective, with ligands (i.e., peptides, antibodies) attached to their surface that specifically target cancer cells. For surgical applications, we are implementing these platforms in tandem with state-of-the-art hand-held optical and PET detection devices (see below). We are also exploring correlative cancer biology at the cellular and molecular levels in clinically relevant tumor models.
- Sentinel Lymph Node (SLN) Mapping
We are performing mapping studies in spontaneous metastatic melanoma miniswine models to enhance detection of nodal metastases, stage tumors, and sensitively assess relative disease burden.
- Tumor Cell Binding and Uptake
We are conducting studies to investigate the influence of particle size and surface composition on internalization, modulation of signaling pathways, and biological processes such as cell migration and proliferation.
New Hand-Held Device Co-developments
We are using a fluorescence camera system designed by ArteMIS Molecular Imaging BV to perform real-time optical imaging during both open and minimally invasive surgical procedures. We are testing the device in large animal models of melanoma to detect metastatic disease following administration of near-infrared dye-containing probes.
We are also developing an approach that combines fluorescence imaging and reflectance confocal microscopy in conjunction with new optical probes for imaging skin lesions and other superficial lesions along mucosal surfaces.
By combining tracer amounts of radiolabeled particle therapeutics with dynamic microPET imaging methods, we can sensitively monitor the drug-delivery process and extract key properties relating to the kinetics of cumulative particle tracer uptake. Tumor-specific readouts may be used to estimate therapeutic dosing in the setting of personalized care.
Therapeutic C Dots
Attaching radiolabeled tyrosine kinase inhibitors (TKIs) and chemotherapeutics to C dots enhances treatment efficacy in selective tumor models, while limiting non-specific uptake in the body.
Mesoporous Silica Nanomaterials (MSNs)
To improve efficacy and drug-toxicity profiles, we are using multimodal (PET-optical) MSNs as controlled release platforms for increasing intratumoral localization and retention of therapeutic agents in select tumor models. Novel porous particles, ranging in size from <10 nm to about 150 nm and exhibiting a range of surface charge and pore characteristics, are available to accommodate a variety of therapeutics and to evaluate controlled-release profiles and efficacy.
By evaluating several small targeting ligands and optimizing the C dot surface chemistry, we are working toward the development of a robust particle radiotherapeutic that can both target and treat certain types of radiosensitive tumors.