Visualization Of Drug Distribution Research Articles

Tumor microenvironment-based smart beacon drug delivery system for in situ visualization of tumor therapy

Real-time monitoring of the effectiveness of tumor-targeted drugs is crucial for assessing their impact. To address this need, we developed a beacon drug delivery system, MDB, which incorporates tumor targeting, anti-tumor effects, and near-infrared fluorescence emission for on-site visualization of tumor therapy. In non-cancerous cells, MDB remains inactive as a prodrug but is selectively activated within tumor cells when the borate ester group reacts with H2O2 in the tumor microenvironment (TME), releasing the beacon drug MDBRe. MDBRe can down-regulate the expression of the protein heme oxygenase 1 (HO-1), ultimately disrupting the mitochondrial energy supply system and leading to tumor cell death. It also emits near-infrared fluorescence for drug tracking under structured illumination microscopy (SIM). Both in vitro and in vivo experiments confirm the effective delivery of MDBRe by MDB to H2O2-enriched tumor tissues, resulting in a potent anti-tumor effect, visualization of drug distribution in tumors, and monitoring of therapy progress. In conclusion, our approach presents a novel method for targeted drug delivery to tumors and enables real-time visual monitoring of the treatment process.

A facile fluorescence-coupling approach to visualizing leonurine uptake and distribution in living cells and Caenorhabditis elegans

BackgroundCaenorhabditis elegans (C. elegans) has been recognized for being a useful model organism in small-molecule drug screens and drug efficacy investigation. However, there remain bottlenecks in evaluating such processes as drug uptake and distribution due to a lack of appropriate chemical tools. PurposeThis study aims to prepare fluorescence-labeled leonurine as an example to monitor drug uptake and distribution of small molecule in C. elegans and living cells. MethodsFITC-conjugated leonurine (leonurine-P) was synthesized and characterized by LC/MS, NMR, UV absorption and fluorescence intensity. Leonurine-P was used to stain C. elegans and various mammalian cell lines. Different concentrations of leonurine were tested in conjunction with a competing parent molecule to determine whether leonurine-P and leonurine shared the same biological targets. Drug distribution was analyzed by imaging. Fluorometry in microplates and flow cytometry were performed for quantitative measurements of drug uptake. ResultsThe UV absorption peak of leonurine-P was 490∼495 nm and emission peak was 520 nm. Leonurine-P specifically bound to endogenous protein targets in C. elegans and mammalian cells, which was competitively blocked by leonurine. The highest enrichment levels of leonurine-P were observed around 72 h following exposure in C. elegans. Leonurine-P can be used in a variety of cells to observe drug distribution dynamics. Flow cytometry of stained cells can be facilely carried out to quantitatively detect probe signals. ConclusionsThe strategy of fluorescein-labeled drugs reported herein allows quantification of drug enrichment and visualization of drug distribution, thus illustrates a convenient approach to study phytodrugs in pharmacological contexts.

Activation imaging: New concept of visualizing drug distribution with wide-band X-ray and gamma-ray imager

The visualization of drug distribution in the body plays an essential role in cancer therapy. Although various imaging methods have been proposed, a versatile method for visualizing multiple types of drugs is yet to be established. Therefore, we propose “activation imaging” as a new method for visualizing various drugs. Activation imaging activates drugs with protons or neutrons, enabling the visualization of drugs using gamma rays and/or X-rays emitted from the activated drugs. This method does not require labeling drugs with specific tracers because the constituent elements of the drugs become radiotracers through proton/neutron irradiation. Therefore, activation imaging can be used to visualize various types of existing drugs, including anticancer drugs, drug carriers, and contrast agents. In this study, we activated drugs using low-energy neutrons and performed gamma-ray spectroscopy and imaging. We used several types of drugs, such as cisplatin, a platinum-based anticancer drug; gold and platinum nanoparticles, which are promising drug carriers; and gadoteridol, a gadolinium-based contrast agent. Imaging was performed using a hybrid Compton camera, which can visualize X-rays and gamma rays ranging from a few tens of keV to nearly 1 MeV. With this wide-band X-ray and gamma-ray imager, various X-rays and gamma rays emitted from drugs can be visualized. Moreover, high-performance liquid chromatography (HPLC) was performed for cisplatin and gadoteridol to investigate whether the molecules of the drugs were degraded by neutron irradiation. Consequently, gamma rays from the activated drugs were observed in the spectra, and all drugs were successfully visualized. Furthermore, the HPLC results showed that most gadoteridol and cisplatin molecules retained their structure through activation.

Development of an Integrated Tissue Pretreatment Protocol for Enhanced MALDI MS Imaging of Drug Distribution in the Brain.

The matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) technique has attracted intense interest in the visualization of drug distribution in tissues. Its capability to spatially resolve individual molecules makes it a unique tool in drug development and research. However, low drug content and severe ion suppression in tissues hinder its broader application to resolve drug tissue distribution, especially small molecule drugs with a molecular weight below 500 Da. In this work, an integrated tissue pretreatment protocol was developed to enhance the detection of central nervous system drugs in the mouse brain using MALDI MSI. To evaluate the protocol, brain sections from mice dosed intraperitoneally with donepezil, tacrine, clozapine, haloperidol, and aripiprazole were used. The tissue sections were pretreated serially by washing with ammonium acetate solution, incubation with trifluoroacetic acid vapor, and n-hexane washing before MALDI MSI. Compared with the untreated sample, the signal intensities for the test drugs increased by 4.7- to 31.5-fold after pretreatment. Besides the enhancement of signal intensity, fine optimization of pretreatment time and washing solvents preserved the spatial distribution of target drug molecules. The utility of the developed protocol also provided tissue-specific distribution for five drugs which were well resolved when imaged by MALDI MS.

A radiolabeled drug tracing method to study neurotrophin-3 retention and distribution in the cochlea after nano-based local delivery

Hearing loss is the most common sensory deficit worldwide with no approved therapeutics for treatment. Local neurotrophin delivery into the cochlea has shown great potential in protecting and repairing the sensory cells important for hearing. However, delivery of these factors into the inner ear at therapeutic levels over a sustained period of time has remained a challenge restricting clinical translation. We have developed a method to test the pharmacokinetics of neurotrophin released from porous silica particles called ‘supraparticles’ that can provide sustained release of neurotrophins to the inner ear.•This report describes a radiolabeling method to examine neurotrophin retention and distribution in the cochlea. The neurotrophin was labeled with a radioactive tracer (iodine 125: 125I) and delivered into the cochlea via the supraparticle system.•Gamma counts reveal drug levels and clearance in the intact cochlea, as well as accumulation in off-target organs (safety test). Autoradiography analyses using film and emulsion permit quantification and visualization of drug distribution at the cellular level. The method has a detection limit of 0.8 pg of radiolabeled neurotrophin-3 in cochlear sections exposed to film.•The tracer 125I with a half-life of 59.4 days can be used to label other drugs/substances with a tyrosine residue and therefore be broadly applicable for long-term pharmacokinetic studies in other systems.

イメージング質量顕微鏡による薬物分布の可視化

イメージング質量顕微鏡による薬物分布の可視化

Imaging mass spectrometry: challenges in visualization of drug distribution in solid tumors

Mass spectrometry imaging (MSI) is an emerging technique that allows molecular visualization of the distribution of drugs and metabolites in a two-dimensional space directly in biological tissues. Imaging drug distribution inside a tumor is an important tool to support strategies to improve penetration of anticancer drugs and consequently the outcome of chemotherapy. MSI has some advantages in comparison to other imaging techniques, that is, whole body autoradiography, positron emission tomography or microscopy imaging. It is a label-free technique with better specificity and provides the possibility to combine histological data with MS ones and to visualize simultaneously the distribution of biomarkers in relation to tumor heterogeneity. We overview here publications on MSI applied to studies of the distribution of anticancer agents in tumor tissue. In addition, we focused our attention on technical limitations and future perspectives pertaining to this technique.

Determination ofIn VivoBehavior of Mitomycin C-Loaded O/W Soybean Oil Microemulsion and Mitomycin C Solution Via Gamma Camera Imaging

In this study, a microemulsion system was evaluated for delivery of mitomycin C (MMC). To track the distribution of the formulated drug after intravenous administration, radiochemical labeling and gamma scintigraphy imaging were used. The aim was to evaluate a microemulsion system for intravenous delivery of MMC and to compare its in vivo behavior with that of the MMC solution. For microemulsion formulation, soybean oil was used as the oil phase. Lecithin and Tween 80 were surfactants and ethanol was the cosurfactant. To understand the whole body localization of MMC-loaded microemulsion, MMC was labeled with radioactive technetium and gamma scintigraphy was applied for visualization of drug distribution. Radioactivity in the bladder 30 minutes after injection of the MMC solution was observed, according to static gamma camera images. This shows that urinary excretion of the latter starts very soon. On the other hand, no radioactivity appeared in the urinary bladder during the 90 minutes following the administration of MMC-loaded microemulsion. The unabated radioactivity in the liver during the experiment shows that the localization of microemulsion formulation in the liver is stable. In the light of the foregoing, it is suggested that this microemulsion formulation may be an appropriate carrier system for anticancer agents by intravenous delivery in hepatic cancer chemotherapy.

Nanotheranostics: combining non-invasive imaging with tumor-targeted drug delivery to individualize (chemo-) therapeutic interventions

Nanomedicine formulations aim to improve the biodistribution and the target site accumulation of systemically administered (chemo-) therapeutic agents. Various different passively and actively targeted nanomedicines have been evaluated over the years, based e.g. on liposomes, polymers, micelles and antibodies, and a significant amount of (pre-) clinical evidence has been obtained showing that these 5–200 nm-sized carrier materials are able to improve the therapeutic index of low-molecular-weight drugs. Besides for therapeutic purposes, however, nanomedicine formulations have also been more and more used for imaging applications, as well as, in recent years, for theranostic approaches, i.e. for systems and strategies in which disease diagnosis and therapy are combined. Potential applications of theranostic nanomedicine formulations range from the noninvasive assessment of the biodistribution and the target site accumulation of low-molecular-weight drugs, and the visualization of drug distribution and drug release at the target site, to the optimization of strategies relying on triggered drug release, and the prediction and real-time monitoring of therapeutic responses. Nanotheranostic systems are consequently considered to be highly suitable systems for (pre-) clinical implementation, not only because they might assist in better understanding various important aspects of the drug delivery process, and in developing better drug delivery systems, but also because they might contribute to realizing the potential of “personalized medicine”, and to establishing more effective and less toxic treatment regimens for individual patients.

Nanotheranostics and Image-Guided Drug Delivery: Current Concepts and Future Directions

Nanomedicine formulations aim to improve the biodistribution and the target site accumulation of systemically applied (chemo-) therapeutics. Various different passively and actively targeted nanomedicines have been evaluated over the years, based e.g. on liposomes, polymers, micelles and antibodies, and a significant amount of (pre-) clinical evidence has been obtained showing that these 5-200 nm sized carrier materials are able to improve the therapeutic index of low-molecular-weight drugs. Besides for therapeutic purposes, however, nanomedicine formulations have also been more and more used for imaging applications, as well as, in recent years, for theranostic approaches, i.e. for systems and strategies in which disease diagnosis and therapy are combined. Potential applications of theranostic nanomedicine formulations range from the noninvasive assessment of the biodistribution and the target site accumulation of low-molecular-weight drugs, and the visualization of drug distribution and drug release at the target site, to the optimization of strategies relying on triggered drug release, and the prediction and real-time monitoring of therapeutic responses. Nanotheranostic systems are consequently considered to be highly suitable systems for (pre-) clinical implementation, not only because they might assist in better understanding various important aspects of the drug delivery process, and in developing better drug delivery systems, but also because they might contribute to realizing the potential of "personalized medicine", and to developing more effective and less toxic treatment regimens for individual patients.