A Multimeric Near IR-MR Contrast Agent for Multimodal In Vivo Imaging (original) (raw)
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Bioresponsive, Cell-Penetrating, and Multimeric MR Contrast Agents
Accounts of Chemical Research, 2009
Magnetic resonance imaging (MRI) has become increasingly popular in molecular imaging and clinical radiology because it is non-invasive and capable of producing three-dimensional representations of opaque organisms with high spatial and temporal resolution. While approximately 35% of all clinical MR scans utilize contrast media, a primary limitation of MR imaging is the low sensitivity to detect contrast agents requiring high concentrations of agent for enhanced signal intensity (0.1-0.6 mM). 1 A number of strategies have been employed to amplify the observed in vivo signal of MR contrast agents. Approaches include attachment of Gd(III) chelates to polymers, proteins and particles, encapsulation into micelles and caged structures, and targeting to receptors. While each of these approaches has yielded significant increases in the relaxivity of MR contrast agents (and therefore sensitivity), all of these classes of complexes possess intrinsic background signal and function solely as anatomical reporters due to their constitutive activity. In order to reduce the background signal and simultaneously create probes that are modulated by biochemical events, caged complexes were designed to coordinatively saturate the paramagnetic ion. Coupled with amplification strategies, these agents represent a means to selectively modulate the observed MR signal and function as in vivo biochemical reporters. For example, to create an in vivo MR assay of enzymatic activities and secondary messengers, agents have been designed and synthesized with removable protection groups that largely prevent access of water to a paramagnetic center. By limiting the access of bulk water (q-modulation) the unprocessed agent is designed to be an ineffective contrast agent, and hence serves as a reliable marker for regions of enzyme activity or secondary messengers. In this Account we describe our results toward designing new classes of MR agents that are i. responsive to in vivo physiological or biochemical events ii. cell-permeable to increase local concentration, and iii. attached to large molecules or are synthesized with multiply labeled conjugates for signal amplification.
Cell Labeling via Membrane-Anchored Lipophilic MR Contrast Agents
Bioconjugate Chemistry, 2014
Cell tracking in vivo with MR imaging requires the development of contrast agents with increased sensitivity that effectively label and are retained by cells. Most clinically approved Gd(III)-based contrast agents require high incubation concentrations and prolonged incubation times for cellular internalization. Strategies to increase contrast agent permeability have included conjugating Gd(III) complexes to cell penetrating peptides, nanoparticles, and small molecules which have greatly improved cell labeling but have not resulted in improved cellular retention. To overcome these challenges, we have synthesized a series of lipophilic Gd(III)-based MR contrast agents that label cell membranes in vitro. Two of the agents were synthesized with a multiplexing strategy to contain three Gd(III) chelates (1 and 2) while the third contains a single Gd(III) chelate (3). These new agents exhibit significantly enhanced labeling and retention in HeLa and MDA-MB-231-mcherry cells compared to agents that are internalized by cells (4 and Prohance).
Correlating Molecular Character of NIR Imaging Agents with Tissue-Specific Uptake
Journal of medicinal chemistry, 2015
Near-infrared (NIR) fluorescent contrast agents are emerging in optical imaging as sensitive, cost-effective, and nonharmful alternatives to current agents that emit harmful ionizing radiation. Developing spectrally distinct NIR fluorophores to visualize sensitive vital tissues to selectively avoid them during surgical resection of diseased tissue is of great significance. Herein, we report the synthetic variation of pentamethine cyanine fluorophores with modifications of physicochemical properties toward prompting tissue-specific uptake into sensitive tissues (i.e., endocrine glands). Tissue-specific targeting and biodistribution studies revealed localization of contrast agents in the adrenal and pituitary glands, pancreas, and lymph nodes with dependence on molecular characteristics. Incorporation of hydrophobic heterocyclic rings, alkyl groups, and halogens allowed a fine-tuning capability to the hydrophobic character and dipole moment for observing perturbation in biological act...
A review of NIR dyes in cancer targeting and imaging
The development of multifunctional agents for simultaneous tumor targeting and near infrared (NIR) fluorescence imaging is expected to have significant impact on future personalized oncology owing to the very low tissue autofluorescence and high tissue penetration depth in the NIR spectrum window. Cancer NIR molecular imaging relies greatly on the development of stable, highly specific and sensitive molecular probes. Organic dyes have shown promising clinical implications as non-targeting agents for optical imaging in which indocyanine green has long been implemented in clinical use. Recently, significant progress has been made on the development of unique NIR dyes with tumor targeting properties. Current ongoing design strategies have overcome some of the limitations of conventional NIR organic dyes, such as poor hydrophilicity and photostability, low quantum yield, insufficient stability in biological system, low detection sensitivity, etc. This potential is further realized with the use of these NIR dyes or NIR dye-encapsulated nanoparticles by conjugation with tumor specific ligands (such as small molecules, peptides, proteins and antibodies) for tumor targeted imaging. Very recently, natively multifunctional NIR dyes that can preferentially accumulate in tumor cells without the need of chemical conjugation to tumor targeting ligands have been developed and these dyes have shown unique optical and pharmaceutical properties for biomedical imaging with superior signal-to-background contrast index. The main focus of this article is to provide a concise overview of newly developed NIR dyes and their potential applications in cancer targeting and imaging. The development of future multifunctional agents by combining targeting, imaging and even therapeutic routes will also be discussed. We believe these newly developed multifunctional NIR dyes will broaden current concept of tumor targeted imaging and hold promise to make an important contribution to the diagnosis and therapeutics for the treatment of cancer.
Journal of Nuclear Medicine, 2013
Multimodal nanoparticles have been extensively studied for target-specific imaging and therapy of various diseases, including cancer. In this study, radiolabeled arginine-glycine-aspartic acid (RGD)-functionalized Er 31 /Yb 31 co-doped NaGdF 4 upconversion nanophosphors (UCNPs) were synthesized and evaluated as a multimodal PET/MR/optical probe with tumor angiogenesisspecific targeting properties. Methods: A dimeric cyclic RGDyk ((cRGDyk) 2) peptide was conjugated to polyacrylic acid-coated NaGdF 4 :Yb 31 /Er 31 UCNPs along with polyethylene glycol molecules and was consecutively radiolabeled with 124 I. In vitro cytotoxicity testing was performed for 3 d. Upconversion luminescence imaging of (cRGDyk) 2-UCNP was performed on U87MG cells with a laboratory-made confocal microscope. In vivo small-animal PET and clinical 3-T T1-weighted MR imaging of 124 I-labeled RGD-functionalized UCNPs was acquired with or without blocking of cyclic RGD peptide in a U87MG tumor model. Inductively coupled plasma mass spectrometry and biologic transmission electron microscopy were done to evaluate gadolinium concentration and UCNP localization, respectively. Results: Polymer-coated UCNPs and dimeric RGD-conjugated UCNPs were monodispersely synthesized, and those of hydrodynamic size were 30 6 8 nm and 32 6 9 nm, respectively. (cRGDyk) 2-UCNPs have a low cytotoxic effect on cells. Upconversion luminescence signals of (cRGDyk) 2-UCNP were specifically localized on the surface of U87MG cells. 124 I-c(RGDyk) 2-UCNPs specifically accumulated in U87MG tumors (2.8 6 0.8 vs. 1.3 6 0.4 percentage injected dose per gram in the blocking experiment), and T1-weighted MR images showed significant positive contrast enhancement in U87MG tumors. Tumor localization of 124 I-c(RGDyk) 2-UCNPs was confirmed by inductively coupled plasma mass spectrometry and biologic transmission electron microscopy analysis. Conclusion: These results suggest that 124 Ilabeled RGD-functionalized UCNPs have high specificity for a v b 3 integrin-expressing U87MG tumor cells and xenografted tumor models. Multimodal UCNPs can be used as a platform nanoparticle with multimodal imaging for cancer-specific diagnoses.
Theranostics, 2021
Rationale: Most contemporary cancer therapeutic paradigms involve initial imaging as a treatment roadmap, followed by the active engagement of surgical operations. Current approved intraoperative contrast agents exemplified by indocyanine green (ICG) have a few drawbacks including the inability of pre-surgical localization. Alternative near-infrared (NIR) dyes including IRDye800cw are being explored in advanced clinical trials but often encounter low chemical yields and complex purifications owing to the asymmetric synthesis. A single contrast agent with ease of synthesis that works in multiple cancer types and simultaneously allows presurgical imaging, intraoperative deep-tissue three-dimensional visualization, and high-speed microscopic visualization of tumor margins via spatiotemporally complementary modalities would be beneficial. Methods: Due to the lack of commercial availability and the absence of detailed synthesis and characterization, we proposed a facile and scalable synthesis pathway for the symmetric NIR water-soluble heptamethine sulfoindocyanine IRDye78. The synthesis can be accomplished in four steps from commercially-available building blocks. Its symmetric resonant structure avoided asymmetric synthesis problems while still preserving the benefits of analogous IRDye800cw with commensurable optical properties. Next, we introduced a low-molecular-weight protein alpha-lactalbumin (α-LA) as the carrier that effectively modulates the hepatic clearance of IRDye78 into the preferred renal excretion pathway. We further implemented 89 Zr radiolabeling onto the protein scaffold for positron emission tomography (PET). The multimodal imaging capability of the fluorophore-protein complex was validated in breast cancer and glioblastoma. Results: The scalable synthesis resulted in high chemical yields, typically 95% yield in the final step of the chloro dye. Chemical structures of intermediates and the final fluorophore were confirmed. Asymmetric IRDye78 exhibited comparable optical features as symmetric IRDye800cw. Its well-balanced quantum yield affords concurrent dual fluorescence and optoacoustic contrast without self-quenching nor concentration-dependent absorption. The NHS ester functionality modulates efficient covalent coupling to reactive side-chain amines to the protein carrier, along with desferrioxamine (DFO) for stable radiolabeling of 89 Zr. The fluorophore-protein complex advantageously shifted the biodistribution and can be effectively cleared through the urinary pathway. The agent accumulates in tumors and enables triple-modal visualization in mouse xenograft models of both breast and brain cancers.
Cell-Permeable MR Contrast Agents with Increased Intracellular Retention
Bioconjugate Chemistry, 2008
Magnetic resonance imaging (MRI) is a technique used in both clinical and experimental settings to produce high resolution images of opaque organisms without ionizing radiation. Currently, MR imaging is augmented by contrast agents and the vast majority these small molecule Gd(III) chelates are confined to the extracellular regions. As a result, contrast agents are confined to vascular regions reducing their ability to provide information about cell physiology or molecular pathology. We have shown that polypeptides of arginine have the capacity to transport Gd(III) contrast agents across cell membranes. However, this transport is not unidirectional and once inside the cell the argininemodified contrast agents efflux rapidly, decreasing the intracellular Gd(III) concentration and corresponding MR image intensity. By exploiting the inherent disulfide reducing environment of cells, thiol compounds, Gd(III)-DOTA-SS-Arg 8 and Gd(III)-DTPA-SS-Arg 8 , are cleaved from their cell penetrating peptide transduction domains upon cell internalization. This reaction prolongs the cell-associated lifetime of the chelated Gd(III) by cleaving it from the cell transduction domain.