Abstract:Transgenic mice with Tie2- green fluorescent protein (GFP) are used as a model to study the kinetic distribution of the Cy5-siRNA delivered by lipid nanoparticles (LNP) into the liver. After the mouse is injected with the LNP, it undergoes a procedure of intra-vital multi-photon microscopy imaging over a period of two hours, during which the process for the nanoparticle to diffuse into the hepatocytes from the vasculature system is monitored. Since the images are obtained in-vivo, the quantification of Cy5 kin… Show more
“…[261] These studies highlighted a strategy to manipulate cellular biodistribution of NPs via altering surface coating and charge of the nanomaterials. Single-cell hepatic distributions of PMMA NPs, [262] liposomes, [263] and silicone NPs [264] were studied by IVM. In particular, van der Vos et al have used data obtained from IVM to construct computational models of NP biodistribution in an effort to minimize the hepatic uptake and maximize the tumor accumulation.…”
Section: Imaging Pk and Biodistribution Of Materials In Clearance Organsmentioning
Engineered materials are ubiquitous in biomedical applications ranging from systemic drug delivery systems to orthopedic implants, and their actions unfold across multiple time‐ and length‐scales. The efficacy and safety of biologics, nanomaterials, and macroscopic implants are all dictated by the same general principles of pharmacology as applied to small molecule drugs, comprising how the body affects materials (pharmacokinetics, PK) and conversely how materials affect the body (pharmacodynamics, PD). Imaging technologies play an increasingly insightful role in monitoring both of these processes, often simultaneously: translational macroscopic imaging modalities such as magnetic resonance imaging and positron emission tomography/computed tomography offer whole‐body quantitation of biodistribution and structural or molecular response, while ex vivo approaches and optical imaging via in vivo (intravital) microscopy reveal behaviors at subcellular resolution. In this review, the authors survey developments in imaging the in situ behavior of systemically and locally administered materials, with a particular focus on using microscopy to understand transport, target engagement, and downstream host responses at a single‐cell level. The themes of microenvironmental influence, controlled drug release, on‐target molecular action, and immune response, especially as mediated by macrophages and other myeloid cells, are examined. Finally, the future directions of how new imaging technologies may propel efficient clinical translation of next‐generation therapeutics and medical devices are proposed.
“…[261] These studies highlighted a strategy to manipulate cellular biodistribution of NPs via altering surface coating and charge of the nanomaterials. Single-cell hepatic distributions of PMMA NPs, [262] liposomes, [263] and silicone NPs [264] were studied by IVM. In particular, van der Vos et al have used data obtained from IVM to construct computational models of NP biodistribution in an effort to minimize the hepatic uptake and maximize the tumor accumulation.…”
Section: Imaging Pk and Biodistribution Of Materials In Clearance Organsmentioning
Engineered materials are ubiquitous in biomedical applications ranging from systemic drug delivery systems to orthopedic implants, and their actions unfold across multiple time‐ and length‐scales. The efficacy and safety of biologics, nanomaterials, and macroscopic implants are all dictated by the same general principles of pharmacology as applied to small molecule drugs, comprising how the body affects materials (pharmacokinetics, PK) and conversely how materials affect the body (pharmacodynamics, PD). Imaging technologies play an increasingly insightful role in monitoring both of these processes, often simultaneously: translational macroscopic imaging modalities such as magnetic resonance imaging and positron emission tomography/computed tomography offer whole‐body quantitation of biodistribution and structural or molecular response, while ex vivo approaches and optical imaging via in vivo (intravital) microscopy reveal behaviors at subcellular resolution. In this review, the authors survey developments in imaging the in situ behavior of systemically and locally administered materials, with a particular focus on using microscopy to understand transport, target engagement, and downstream host responses at a single‐cell level. The themes of microenvironmental influence, controlled drug release, on‐target molecular action, and immune response, especially as mediated by macrophages and other myeloid cells, are examined. Finally, the future directions of how new imaging technologies may propel efficient clinical translation of next‐generation therapeutics and medical devices are proposed.
“…Although many studies have reported the organ‐level distribution of NPs, very few have addressed their disposition in organs at the cellular level . The uptake, distribution and excretion of fluorescent or fluorescent labelled NPs can be investigated using TPEF imaging at the single cell resolution . Polymeric NPs with high bond repetition rate are highly suitable for CARS imaging because the CARS signal scales quadratically with the bond concentration .…”
Section: Pharmacokinetic Imaging In the Livermentioning
Multiphoton microscopy (MPM) has become increasingly popular and widely used in both basic and clinical liver studies over the past few years. This technology provides insights into deep live tissues with less photobleaching and phototoxicity, which helps us to better understand the cellular morphology, microenvironment, immune responses and spatiotemporal dynamics of drugs and therapeutic cells in the healthy and diseased liver. This review summarizes the principles, opportunities, applications and limitations of MPM in hepatology. A key emphasis is on the use of fluorescence lifetime imaging (FLIM) to add additional quantification and specificity to the detection of endogenous fluorescent species in the liver as well as exogenous molecules and nanoparticles that are applied to the liver in vivo. We anticipate that in the near future MPM‐FLIM will advance our understanding of the cellular and molecular mechanisms of liver diseases, and will be evaluated from bench to bedside, leading to real‐time histology of human liver diseases.
“…The analysis of the diffusion of Cy5-siRNA into the hepatocytes was done by computation of the percentage signal strength in the region of interest over time. 78 Another study reported a significant uptake of positively charged, but not negatively charged moieties. Negatively charged nanoparticles were found to be taken up by Kupffer cells as shown by intravital imaging.…”
Multiphoton microscopy is the preferred method when in vivo deep-tissue imaging is required. This review presents the application of multiphoton microscopy in defining liver function. In particular, multiphoton microscopy is useful in imaging intracellular events, such as mitochondrial depolarization and cellular metabolism in terms of NAD(P)H changes with fluorescence lifetime imaging microscopy. The morphology of hepatocytes can be visualized without exogenously administered fluorescent dyes by utilizing their autofluorescence and second harmonic generation signal of collagen, which is useful in diagnosing liver disease. More specific imaging, such as studying drug transport in normal and diseased livers are achievable, but require exogenously administered fluorescent dyes. If these techniques can be translated into clinical use to assess liver function, it would greatly improve early diagnosis of organ viability, fibrosis, and cancer.
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