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Synthesis of a core-shell silica nanoplatform for multi-modality imaging

Objectives: To synthesize and characterize a C-Dot silica-based nanoparticle containing “clickable” groups for the subsequent attachment of targeting moieties (e.g., peptides) and multiple contrast agents (e.g., radionuclides with high specific activity) [1,2]. These new constructs will be tested in suitable tumor models in vitro and in vivo to ensure maintenance of target-specificity and high specific activity. Methods: Cy5 dye molecules are cross-linked to a silica precursor which is reacted to form a dye-rich core particle. This core is then encapsulated in a layer of pure silica to create the coreshell C-Dot (Figure 1) [2]. A ‘click’ chemistry approach has been used to functionalize the silica shell with radionuclides conferring high contrast and specific activity (e.g. 64Cu and 89Zr) and peptides for tumor targeting (e.g. cRGD and octreotate) [3]. Based on the selective Diels-Alder reaction between tetrazine and norbornene, the reaction is bioorthogonal, highyielding, rapid, and water-compatible. This radiolabeling approach has already been employed successfully with both short peptides (e.g. octreotate) and antibodies (e.g. trastuzumab) as model systems for the ultimate labeling of the nanoparticles [1]. Results: PEGylated C-Dots with a Cy5 core and labeled with tetrazine have been synthesized (d = 55 nm, zeta potential = -3 mV) reliably and reproducibly and have been shown to be stable under physiological conditions for up to 1 month. Characterization of the nanoparticles revealed that the immobilized Cy5 dye within the C-Dots exhibited fluorescence intensities over twice that of the fluorophore alone. The nanoparticles were successfully radiolabeled with Cu-64. Efforts toward the conjugation of targeting peptides (e.g. cRGD) are underway. In vitro stability, specificity, and uptake studies as well as in vivo imaging and biodistribution investigations will be presented. Conclusions: C-Dot silica-based nanoparticles offer a robust, versatile, and multi-functional platform to enhance in vivo detection sensitivity and non-invasively assay receptor expression/status of tumor cellular targets, including those of low abundance, using nuclear-NIR fluorescence imaging approaches [2]. Improvements in molecular diagnostics, refined by the availability of nanotechnology platforms, will be a key determinant in driving early-stage disease detection and prevention, ultimately leading to decreases in mortality. Introduction and Background: The original application was in response to the FOA “DE-PS02-09ER09-18; Radiochemistry” and studied radiochemistry, multimodality imaging technology, and nanoparticles. To improve detection of low abundance systems, characterization, and treatment monitoring of diseases, we sought to construct highly-specific, molecular-targeted probes, along with high-resolution imaging strategies. Here, we discuss new techniques for the labeling of silica-based nanoparticles with contrast agents for SPECT, PET CT, MRI, and optical imaging. Hypothesis and Specific Aims: The central hypothesis of this application was that a robust and versatile silica-based nanoparticle platform could be functionalized to enhance in vivo detection sensitivity and noninvasively assay receptor expression/status of tumor cellular targets, including those of low abundance, using nuclear-NIR fluorescence imaging approaches. We addressed the following Specific Aims: SA1. Design and synthesis of silica-based nanoparticles containing “clickable” groups for the subsequent attachment of targeting moieties (e.g., peptides) and multiple contrast agents (e.g., radionuclides with high specific activity). SA2. Synthesis and physicochemical characterization of functionalized nanoparticles using model peptides and chelates. SA3. In vitro and in vivo testing of these new constructs in suitable tumor models to ensure maintenance of target-specificity and high specific activity, as compared with the corresponding native radiolabeled peptides.