ABSTRACT
The residual tumor after surgery is the most significant prognostic factor of patients with epithelial ovarian cancer. Near-infrared (NIR) fluorescence-guided surgery is actively utilized for tumor localization and complete resection during surgery. However, currently available contrast-enhancing agents display low on-target binding, unfavorable pharmacokinetics, and toxicity, thus not ideal for clinical use. Here we report ultrabright and stable squaraine fluorophores with optimal pharmacokinetics by introducing an asymmetric molecular conformation and surface charges for rapid transporter-mediated cellular uptake. Among the tested, OCTL14 shows low serum binding and rapid distribution into cancer tissue via organic cation transporters (OCTs). Additionally, the charged squaraine fluorophores are retained in lysosomes, providing durable intraoperative imaging in a preclinical murine model of ovarian cancer up to 24â h post-injection. OCTL14 represents a significant departure from the current bioconjugation approach of using a non-targeted fluorophore and would provide surgeons with an indispensable tool to achieve optimal resection.
Subject(s)
Cyclobutanes , Ovarian Neoplasms , Animals , Carcinoma, Ovarian Epithelial/diagnostic imaging , Contrast Media , Cyclobutanes/chemistry , Fluorescent Dyes/chemistry , Humans , Ionophores , Mice , Optical Imaging/methods , Ovarian Neoplasms/diagnostic imaging , Ovarian Neoplasms/pathology , Ovarian Neoplasms/surgery , PhenolsABSTRACT
Near-infrared (NIR) fluorescence imaging has advanced medical imaging and image-guided interventions during the past three decades. Despite tremendous advances in imaging devices, surprisingly only a few dyes are currently available in the clinic. Previous fluorophores, ZW800-1A and ZW800-1C, significantly improved the poor performance of the FDA-approved indocyanine green. However, ZW800-1A is not stable in serum and ZW800-1C induces severe stacking in aqueous media. To solve such dilemmas, ZW800-PEG was designed by introducing a flexible yet stable thiol PEG linker. ZW800-PEG shows high solubility in both aqueous and organic solvents, thus improving renal clearance with minimal binding to serum proteins during systemic circulation. The sulfide group on the meso position of the heptamethine core improves serum stability and physicochemical properties including the maximum emission wavelength shift to 800â nm, enabling the use of ZW800-PEG for image-guided interventions and augmenting photothermal therapy.
Subject(s)
Fluorescent Dyes/chemistry , Polyethylene Glycols/chemistry , Humans , Optical Imaging , Photothermal Therapy , Spectroscopy, Near-InfraredABSTRACT
Elastin is a key elastomeric protein responsible for the elasticity of many organs, including heart, skin, and blood vessels. Due to its intrinsic long life and low turnover rate, damage in elastin induced by pathophysiological conditions, such as hypercalcemia and hyperglycemia, accumulates during biological aging and in aging-associated diseases, such as diabetes mellitus and atherosclerosis. Prior studies have shown that calcification induced by hypercalcemia deteriorates the function of aortic tissues. Glycation of elastin is triggered by hyperglycemia and associated with elastic tissue damage and loss of mechanical functions via the accumulation of advanced glycation end products. To evaluate the effects on elastin's structural conformations and elasticity by hypercalcemia and hyperglycemia at the molecular scale, we perform classical atomistic and steered molecular dynamics simulations on tropoelastin, the soluble precursor of elastin, under different conditions. We characterize the interaction sites of glucose and calcium and associated structural conformational changes. Additionally, we find that elevated levels of calcium ions and glucose hinder the extensibility of tropoelastin by rearranging structural domains and altering hydrogen bonding patterns, respectively. Overall, our investigation helps to reveal the behavior of tropoelastin and the biomechanics of elastin biomaterials in these physiological environments. STATEMENT OF SIGNIFICANCE: Elastin is a key component of elastic fibers which endow many important tissues and organs, from arteries and veins, to skin and heart, with strength and elasticity. During aging and aging-associated diseases, such as diabetes mellitus and atherosclerosis, physicochemical stressors, including hypercalcemia and hyperglycemia, induce accumulated irreversible damage in elastin, and consequently alter mechanical function. Yet, molecular mechanisms associated with these processes are still poorly understood. Here, we present the first study on how these changes in elastin structure and extensibility are induced by hypercalcemia and hyperglycemia at the molecular scale, revealing the essential roles that calcium and glucose play in triggering structural alterations and mechanical stiffness. Our findings yield critical insights into the first steps of hypercalcemia- and hyperglycemia-mediated aging.
Subject(s)
Atherosclerosis , Hypercalcemia , Hyperglycemia , Humans , Elastin/chemistry , Tropoelastin/chemistry , Calcium , GlucoseABSTRACT
Near-infrared (NIR) cyanine dyes showed enhanced properties for biomedical imaging. A systematic modification within the cyanine skeleton has been made through a facile design and synthetic route for optimal bioimaging. Herein, we report the synthesis of 11 NIR cyanine fluorophores and an investigation of their physicochemical properties, optical characteristics, photostability, and in vivo performance. All synthesized fluorophores absorb and emit within 610-817 nm in various solvents. These dyes also showed high molar extinction coefficients ranging from 27,000 to 270,000 cm-1 M-1, quantum yields 0.01 to 0.33, and molecular brightness 208-79,664 cm-1 M-1 in the tested solvents. Photostability data demonstrate that all tested fluorophores 28, 18, 20, 19, 25, and 24 are more photostable than the FDA-approved indocyanine green. In the biodistribution study, most compounds showed tissue-specific targeting to selectively accumulate in the adrenal glands, lymph nodes, or gallbladder while excreted to the hepatobiliary clearance route. Among the tested, compound 23 showed the best targetability to the bone marrow and lymph nodes. Since the safety of cyanine fluorophores is well established, rationally designed cyanine fluorophores established in the current study will expand an inventory of contrast agents for NIR imaging of not only normal tissues but also cancerous regions originating from these organs/tissues.
ABSTRACT
Elastic fibers are an important component of the extracellular matrix, providing stretch, resilience, and cell interactivity to a broad range of elastic tissues. Elastin makes up the majority of elastic fibers and is formed by the hierarchical assembly of its monomer, tropoelastin. Our understanding of key aspects of the assembly process have been unclear due to the intrinsic properties of elastin and tropoelastin that render them difficult to study. This review focuses on recent developments that have shaped our current knowledge of elastin assembly through understanding the relationship between tropoelastin's structure and function.
ABSTRACT
Successful imaging of atherosclerosis, one of the leading global causes of death, is crucial for diagnosis and intervention. Near-infrared fluorescence (NIRF) imaging has been widely adopted along with multimodal/hybrid imaging systems for plaque detection. We evaluate two macrophage-targeting fluorescent tracers for NIRF imaging (TLR4-ZW800-1C and Feraheme-Alexa Fluor 750) in an atherosclerotic murine cohort, where the left carotid artery (LCA) is ligated to cause stenosis, and the right carotid artery (RCA) is used as a control. Imaging performed on dissected tissues revealed that both tracers had high uptake in the diseased vessel compared to the control, which was readily visible even at short exposure times. In addition, ZW800-1C's renal clearance ability and Feraheme's FDA approval puts these two tracers in line with other NIRF tracers such as ICG. Continued investigation with these tracers using intravascular NIRF imaging and larger animal models is warranted for clinical translation.
Subject(s)
Carotid Artery Diseases/diagnostic imaging , Plaque, Atherosclerotic/diagnostic imaging , Quaternary Ammonium Compounds/administration & dosage , Succinimides/administration & dosage , Sulfonic Acids/administration & dosage , Animals , Carotid Artery Diseases/chemically induced , Carotid Artery Diseases/metabolism , Diet, High-Fat/adverse effects , Disease Models, Animal , Ferrosoferric Oxide/chemistry , Humans , Macrophages/metabolism , Male , Mice , Molecular Imaging , Optical Imaging , Plaque, Atherosclerotic/chemically induced , Plaque, Atherosclerotic/metabolism , Quaternary Ammonium Compounds/chemistry , Quaternary Ammonium Compounds/pharmacokinetics , Succinimides/chemistry , Succinimides/pharmacokinetics , Sulfonic Acids/chemistry , Sulfonic Acids/pharmacokinetics , Toll-Like Receptor 4/metabolismABSTRACT
Background: Advances in tissue engineering and regenerative medicine over the last three decades have made great progress in the development of diagnostic and therapeutic methodologies for damaged tissues. However, regenerative medicine is still not the first line of treatment for patients due to limited understanding of the tissue regeneration process. Therefore, it is prerequisite to develop molecular imaging strategies combined with appropriate contrast agents to validate the therapeutic progress of damaged tissues. Methods: The goal of this review is to discuss the progress in the development of near-infrared (NIR) contrast agents and their biomedical applications for labeling cells and scaffolds, as well as monitoring the treatment progress of native tissue in living organisms. We also discuss the design consideration of NIR contrast agents for tissue engineering and regenerative medicine in terms of their physicochemical and optical properties. Results: The use of NIR imaging system and targeted contrast agents can provide high-resolution and high sensitivity imaging to track/monitor the in vivo fate of administered cells, the degradation rate of implanted scaffolds, and the tissue growth and integration of surrounding cells during the therapeutic period. Conclusion: NIR fluorescence imaging techniques combined with targeted contrast agents can play a significant role in regenerative medicine by monitoring the therapeutic efficacy of implanted cells and scaffolds which would enhance the development of cell therapies and promote their successful clinical translations.