Abstract
Gold nanoparticles (GNPs) have tremendous potential as cancer-targeted contrast agents for diagnostic imaging. The ability to modify the particle surface with both disease-targeting molecules (such as the cancer-specific aptamer AS1411) and contrast agents (such as the gadolinium chelate Gd(III)-DO3A-SH) enables tailoring the particles for specific cancer-imaging and diagnosis. While the amount of image contrast generated by nanoparticle contrast agents is often low, it can be augmented with the assistance of computer image analysis algorithms. In this work, the ability of cancer-targeted gold nanoparticle–oligonucleotide conjugates to distinguish between malignant (MDA-MB-231) and healthy cells (MCF-10A) is tested using a T1-weighted image analysis algorithm based on three-dimensional, deformable model-based segmentation to extract the Volume of Interest (VOI). The gold nanoparticle/algorithm tandem was tested using contrast agent GNP-Gd(III)-DO3A-SH-AS1411) and nontargeted c-rich oligonucleotide (CRO) analogs and control (CTR) counterparts (GNP-Gd(III)-DO3A-SH-CRO/CTR) via in vitro studies. Remarkably, the cancer cells were notably distinguished from the nonmalignant cells, especially at nanomolar contrast agent concentrations. The T1-weighted image analysis algorithm provided similar results to the industry standard Varian software interface (VNMRJ) analysis of T1 maps at micromolar contrast agent concentrations, in which the VNMRJ produced a 19.5% better MRI contrast enhancement. However, our algorithm provided more sensitive and consistent results at nanomolar contrast agent concentrations, where our algorithm produced ~500% better MRI contrast enhancement.
Highlights
Nanoparticle systems are becoming increasingly popular for development as contrast agents for biomedical imaging due to the potential to combine multimodal imaging contrast, disease targeting, longer circulation times, and engineered clearance pathways into a single entity
We have developed a new algorithm that has the ability to automatically extract the Volume of Interest (VOI) and apply 3D nonrigid registration to provide voxel-on-voxel matching that will aid in visualizing the T1 relaxation locally using a color map, as well as calculating global contrast agent-induced changes in relaxation
Oligonucleotides having a regular DNA backbone, a 5’-Thiol C6 S-S modification (Thio-MC6-D), 5’-6T spacer and high-performance liquid chromatography (HPLC) purification were supplied by Integrated DNA Technologies (IDT) [Coralville, IA]
Summary
Nanoparticle systems are becoming increasingly popular for development as contrast agents for biomedical imaging due to the potential to combine multimodal imaging contrast, disease targeting, longer circulation times (compared to conventional small molecule agents), and engineered clearance pathways into a single entity. DNA functionalization on GNPs has been shown to have efficient penetration into cancerous cells that further engenders contrast enhancement via their intracellular accumulation and decreased magnitude of longitudinal or transverse relaxation time [5,7]. The AS1411 (ACT-GRO-777) forms a G-quadruplex structure that selectively binds nucleolin proteins present on the cell surface and in the cytoplasm of most types of cancer [10]. Nucleolin is produced, but localized in the nucleus These non-nuclear nucleolin proteins found in cancer cells facilitate the survival of cancer cells via increasing the concentration of antiapoptotic mRNA and miRNA in the cytoplasm [11,12]. The AS1411 functionalized spherical GNPs have higher cellular internalization and increased cytotoxicity in comparison to AS1411 alone, making them excellent candidates as a core structure for a cancer-targeted contrast agent [8,9]
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