Plasma Residence Time Research Articles

In vitro and in vivo studies of galactose-modified liver-targeting liposomes

Oridonin (ORI) is a bioactive diterpenoid compound extracted from the well known Chinese traditional medicine Rabdosia rubescens. The aim of this study was to prepare ORI loaded liposomes surface-modified with galactose (NOH-ORI-LP) and evaluate their characteristics compared with ORI loaded liposomes (ORI-LP) and ORI solution in vitro and in vivo. The NOH-ORI-LP was prepared by ethanol injection method. The NOH-ORI-LP was characterized by their morphology, particle size, zeta potential and encapsulation efficiency. The concentration of ORI in plasma and tissues at different sampling time points were determined. The liver concentration-time curves of NOH-ORI-LP in mice were determined, and the pharmacokinetic parameters were calculated and compared by statistical analysis. Our data revealed that NOH-ORI-LP has a particle size of about (173 ± 12) nm. The particles exhibit a negative electrical charge (−31.5 ± 1.6 mV), and possess high encapsulation efficiency (94.1 ± 1.2%). There were significantly different parameters of k10 and area under the plasma concentration-time curve (AUC0−t) between liposomes and solution. The mean residence time (MRT0−t) in plasma of NOH-ORI-LP was 5.56 times longer than that of solution. Compared with solution, NOH-ORI-LP delivered about 4.28 times higher ORI into liver. Thus, an optimum intravenous galactose-modified liposome formulation for ORI could be developed as an alternative to the commercial ORI preparations.

Electron temperature, ion density and energy influx measurements in a tubular plasma reactor for powder surface modification

The tubular plasma reactor was designed for the continuous surface modification of fine powders in non-equilibrium RF discharges. So far, little has been known about the plasma characteristics of this inductively coupled reactor system. Therefore, moderate pressure argon–oxygen discharges, commonly used for powder processing, are investigated with tailor-made probe techniques. The influence of plasma power, system pressure, gas composition and mean gas velocity on the axial profiles of plasma parameters was studied. Electron temperature and positive ion density profiles were measured with a Langmuir double probe and the energy influx due to the plasma was determined by a new type of calorimetric probe. The limits for the E–H-mode transition are provided and photographs of the discharge are presented to illustrate the relationship between process parameters and plasma characteristics. Both, ion density and energy influx increased with rising plasma power. The axial energy influx profiles were in addition strongly influenced by the mean gas velocity. Based on these profiles the maximum transient particle temperature was calculated as a function of the particle diameter. Particle temperatures in the order of 100 °C were estimated, whereas the thermal load of the substrates rises with increasing plasma power, residence time and pressure.

Preclinical pharmacokinetic analysis of felotaxel (SHR110008), a novel derivative of docetaxel, in rats and its protein binding ability in vitro

Felotaxel (SHR110008), currently under clinical investigation in phase I trial, is a new taxane with potent antitumor effects. The purpose of this research was to evaluate the pharmacokinetic profiles of felotaxel in rats and the protein binding in plasma. Data were collated from several preclinical investigations, where the plasma pharmacokinetics, tissue distribution and excretion of felotaxel were assessed after a single intravenous (i.v.) injection (5mg/kg) to rats. Samples felotaxel concentration was determined by a LC-MS/MS method. The plasma concentration versus time data was analyzed non-compartmental model. Plasma protein binding was assessed using ultrafiltration. Pharmacokinetic properties of felotaxel were similar to the previous data from the rats. Felotaxel was rapidly distributed to normal tissues, drug concentrations in the tissues tested except the brain were two to eight times higher than those in plasma, but half-lives and mean residence times were similar. The kidneys manifested as the dominant organs with high exposure that might be responsible for elimination of felotaxel. Approximately 0.21% and 0.72% of felotaxel was excreted via the urine and feces within 24h; 0.25% was excreted into the bile up to 12h after a single dose. The protein binding ability of felotaxel with concentration 100–5000ng/mL in the plasma was nearly linear. This study first provided the full absorption, distribution, and excretion characteristics of felotaxel, which would be helpful for its clinical regiment design.

Analysis on Initial Tritium Supply for Starting Up Fusion Power Reactor FDS-II

The initial tritium supply for starting up FDS-II was done by using the Tritium Analysis Software (TAS) developed by FDS Team. The results showed that the initial tritium supply for startup was strongly dependent on the tritium burn-up fraction in plasma and mean residence time of tritium in the plasma exhaust processing system. Considering the sensitive analysis and other advanced designs, the tritium burn-up fraction in plasma was selected to be 0.1 for FDS-II. The minimum initial tritium supply for startup was ˜4.2kg. Considering the potential malfunction in the fuel cycle system and assuming the reactor ran continuously before solving the malfunction, it was reasonable to keep the initial tritium supply for FDS-II as ˜8.9kg.

Investigation of polarization effects for nanosecond laser-induced breakdown spectroscopy

The spectral and temporal polarization dependencies of nanosecond laser-induced plasmas are explored for analysis of gaseous and solid samples using various experimental configurations. Plasma emission measurements were resolved into vertical and horizontal polarization components, and the ratio of the two polarization-resolved measurements was calculated for each sample and configuration. For the solid target, measurements were recorded with the sample oriented both normal to the incident laser beam as well as at oblique angles of incidence. The results for the breakdown of a pure, nitrogen gaseous sample revealed no degree of polarization in either the continuum or atomic emission, with the ratios of the horizontally-to-vertically resolved plasma emission showing values equal to unity when resolved both temporally and spectrally. The analysis of both copper and steel solid samples also showed no polarization dependency in the spectral and temporal data when the laser was incidentally normal to the sample surface. For oblique angles of incidence, some polarization (< 10%) was observed within the first tens of nanoseconds of plasma lifetime. The polarization was manifested as a slight reduction in the horizontal component of plasma emission, but significantly, the observed polarization was found to be spectrally flat, with no difference observed between continuum and atomic emission features. The small polarization effect was found to diminish with plasma residence time, effectively vanishing by about 1 μs following breakdown. The transient polarization is hypothesized to arise from reflection effects (i.e. Fresnel reflectivity) between the plasma light and the solid target surface present with oblique angles of incidence for reflected light, with temporal effects due to the dynamic nature of the plasma development and plasma–surface interactions. Overall, no evidence was found to support any inherent anisotropy or polarization specific to the plasma continuum or the atomic emission for the transitions studied.

Detection of Macrophages Via Paramagnetic Vesicles Incorporating Oxidatively Tailored Cholesterol Ester: An Approach for Atherosclerosis Imaging

Macrophages play a key role in the initiation, progression and complications of atherosclerosis. In this article we describe the synthesis of biocompatible, paramagnetic, fluorescent phosphatidylserine vesicles containing cholesterol ester with a free carboxylic acid function and its use for targeted imaging of macrophages. We synthesized anionic vesicles containing a combination of phosphatidylserine and a novel synthetic oxidized cholesterol ester derivative (cholesterol-9-carboxynonanoate [9-CCN]). In vitro studies to characterize particle size, MRI relaxation times and stability were performed. Vesicles containing 9-CCN demonstrated enhanced ability to bind human low-density lipoprotein and to be internalized by macrophages. Experiments in cultured macrophages with 9-CCN vesicles, alone and in the presence of low-density lipoprotein, indicated uptake of vesicles through scavenger receptor and integrin-dependent pathways. In vivo MRI using 9-CCN vesicles containing gadolinium in a rabbit model of atherosclerosis revealed protracted enhancement of 9-CCN vesicles and colocalization with arterial macrophages not seen with control vesicles. Pharmacokinetic experiments demonstrated prolonged plasma residence time of 9-CCN vesicles, perhaps due to its capacity to bind to low-density lipoprotein. Vesicles containing 9-CCN demonstrate prolonged plasma and plaque retention in experimental atherosclerosis. Such a strategy may represent a simple yet clinically relevant approach for macrophage imaging.

Delivering Drugs Into the Brain: Barriers and Possibilities

Delivering Drugs Into the Brain: Barriers and Possibilities

Characterization of Cationic Liposome Formulations Designed to Exhibit Extended Plasma Residence Times and Tumor Vasculature Targeting Properties

Cationic liposomes exhibit a propensity to selectively target tumor-associated blood vessels demonstrating potential value as anti-cancer drug delivery vehicles. Their utility however, is hampered by their biological instability and rapid elimination following i.v. administration. Efforts to circumvent rapid plasma elimination have, to date, focused on decreasing cationic lipid content and incorporating polyethylene glycol (PEG)-modified lipids. In this study we wanted to determine whether highly charged cationic liposomes with surface-associated PEG could be designed to exhibit extended circulation lifetimes, while retaining tumor vascular targeting properties in an HT29 colorectal cancer xenograft model. Cationic liposomes prepared of DSPC, cationic lipids (DODAC, DOTAP, or DC-CHOL), and DSPE-PEG(2000) were studied. Our results demonstrate that formulations prepared with 50 mol% DODAC or DC-CHOL, and 20 mol% DSPE-PEG(2000) exhibited circulation half-lives ranging from 6.5 to 12.5 h. Biodistribution studies demonstrated that DC-CHOL formulations prepared with DSPE-PEG(2000) accumulated threefold higher in s.c. HT29 tumors than its PEG-free counterpart. Fluorescence microscopy studies suggested that the presence of DSPE-PEG(2000) did not adversely affect liposomal tumor vasculature targeting. We show for the first time that it is achievable to design highly charged, highly pegylated (20 mol% DSPE-PEG(2000)) cationic liposomes which exhibit both extended circulation lifetimes and tumor vascular targeting properties.

Innate immune response triggered by triacyl lipid A is dependent on phospholipid transfer protein (PLTP) gene expression

Hexaacyl lipopolysaccharide (LPS) aggregates in aqueous media, but its partially deacylated lipid A moiety forms monomers with weaker toxicity. Because plasma phospholipid transfer protein (PLTP) transfers hexaacyl LPS, its impact on metabolism and biological activity of triacyl lipid A in mice was addressed. Triacyl lipid A bound readily to plasma high-density lipoproteins (HDLs) when active PLTP was expressed [HDL-associated lipid A after 4.5 h: 59.1+/-16.0% of total in wild-type (WT) vs. 32.5+/-10.3% in PLTP-deficient mice, P<0.05]. In the opposite to hexaacyl LPS, plasma residence time of lipid A was extended by PLTP, and proinflammatory cytokines were produced in higher amounts in WT than PLTP(-/-) mice (remaining lipid A after 8 h: 53+/-12 vs. 35+/-7%, and IL6 concentration after 4.5 h: 45.5+/-5.9 vs. 14.6+/-7.8 ng/ml, respectively; P<0.05 in all cases). After 1 wk, onset of B16-induced melanoma was observed in only 30% of lipid A-treated WT mice, whereas >80% of the untreated WT, untreated PLTP-deficient, or lipid A-treated PLTP-deficient animals bore tumors (P<0.05 in all cases). It is concluded that PLTP is essential in mediating the association of triacyl lipid A with lipoproteins, leading to extension of its residence time and to magnification of its proinflammatory and anticancer properties.

Plasma dispositions of ivermectin, doramectin and moxidectin following subcutaneous administration in rabbits

This study evaluated the comparative plasma dispositions of ivermectin (IVM), doramectin (DRM) and moxidectin (MXD) following subcutaneous administration in rabbits. Fifteen New Zealand white rabbits were allocated into three groups of five animals each. The animals in each group received IVM, DRM or MXD by subcutaneous injection at a single dose of 0.3 mg/kg. Blood samples were collected at various times between 1 h and 40 days after treatment and the plasma samples were analysed by high-performance liquid chromatography using fluorescence detection. Moxidectin was absorbed faster from the injection site and reached the peak plasma concentration (C(max)) significantly earlier than IVM and DRM. There was no significant difference in C(max) values among the three molecules, whereas the area under the concentration-time curves of DRM (258.40 ng.d/mL) and IVM (191.62 ng.d/mL) was significantly higher than that of MXD (83.17 ng.d/mL). The mean plasma residence time and terminal half-life (t(1/2lambdaz)) were longer for DRM (7.52 and 4.48 days, respectively) and MXD (8.97 and 8.16 days, respectively) compared with IVM (4.73 and 2.75 days, respectively). Considering the pharmacokinetic parameters for the parent molecules, the persistence of DRM and MXD are significantly longer than IVM and this may have a positive effect on their efficacy in rabbits following subcutaneous administration or utility relating to interdosing interval.

Abnormalities in lipoprotein kinetics in Type 2 diabetes

Lipoprotein kinetic abnormalities in patients with Type 2 diabetes, are the basis of diabetic dyslipidemia, which is likely to play an important role in the development of atherogenesis. In Type 2 diabetes, all lipoproteins (VLDL, IDL, LDL and HDL) demonstrate significant kinetic abnormalities. Hypertriglyceridemia is due mainly to increased production of VLDL (mostly large VLDL1 particles, potentially atherogenic) and, to a lesser extent, to reduced catabolism of VLDL and IDL. Low HDL-C is the result of increased catabolism of HDL. Although plasma LDL-C level is usually normal in patients with Type 2 diabetes, LDL turnover is significantly reduced and, as a consequence, LDL plasma residence time is increased, which is potentially harmful. The pathophysiology of lipid kinetic abnormalities in Type 2 diabetes has not yet been completely explained. However, insulin resistance and the ‘relative’ insulin deficiency observed in patients with Type 2 diabetes, are likely to play a key role in lipid kinetic abnor...

Uncertainty and sensitivity analysis of biokinetic models for radiopharmaceuticals used in nuclear medicine

Mathematical models for kinetics of radiopharmaceuticals in humans were developed and are used to estimate the radiation absorbed dose for patients in nuclear medicine by the International Commission on Radiological Protection and the Medical Internal Radiation Dose (MIRD) Committee. However, due to the fact that the residence times used were derived from different subjects, partially even with different ethnic backgrounds, a large variation in the model parameters propagates to a high uncertainty of the dose estimation. In this work, a method was developed for analysing the uncertainty and sensitivity of biokinetic models that are used to calculate the residence times. The biokinetic model of (18)F-FDG (FDG) developed by the MIRD Committee was analysed by this developed method. The sources of uncertainty of all model parameters were evaluated based on the experiments. The Latin hypercube sampling technique was used to sample the parameters for model input. Kinetic modelling of FDG in humans was performed. Sensitivity of model parameters was indicated by combining the model input and output, using regression and partial correlation analysis. The transfer rate parameter of plasma to other tissue fast is the parameter with the greatest influence on the residence time of plasma. Optimisation of biokinetic data acquisition in the clinical practice by exploitation of the sensitivity of model parameters obtained in this study is discussed.

Distribution of liposomal bifendate in liver following intravenous injection in mice

The purpose of this study was to develop and study the behaviors of bifendate (DDB) liposome in vivo. DDB liposome was prepared by the rotary evaporationextrusion method. The particle size, zeta-potential, encapsulation efficiency (EE), and in vitro drug release from liposome were determined and the in vivo studies were tested in mice and rats. The concentrations of DDB in plasma and liver at different sampling time points were determined by RP-HPLC. The liver concentration–time curves of DDB liposome and free drug solution in mice were determined, and the pharmacokinetic parameters in rats and mice were calculated and compared by statistical analysis. The average liposome diameter was 323 ± 29 nm (n = 3) and the EE was 91.52 ± 2.38%. There were significantly different parameters of k10 and area under the plasma concentrationtime curve (AUC0−T) between liposome and solution. The mean residence time (MRT0−T) in plasma of liposomal formulation was 3.72 times longer than that of solution. Compared with solution, DDB liposome delivered about 2.57 times higher DDB into liver. Thus, an optimum intravenous liposome formulation for DDB could be developed as an alternative to the commercial DDB preparations.

Study of analyte dissociation and diffusion in laser-induced plasmas: implications for laser-induced breakdown spectroscopy

Plasma–particle interactions are explored through the introduction of single microdroplets into laser-induced plasmas. Both spectroscopic analysis and direct imaging of analyte atomic emission are used to provide insight into the various fundamental processes, namely desolvation, atomization, and atomic diffusion. By doping the 50 µm droplets with Lu, Mg or Ca, the analyte excitation temperature and the ion-to-neutral emission ratio are explored as a function of plasma residence time following breakdown. The data suggest a change in the local plasma conditions about the analyte atoms around 15–20 µs following breakdown, which may be interpreted as an overall transition from localized (i.e. perturbed) plasma conditions to the global (i.e. bulk) plasma conditions. A direct assessment of the hydrogen atomic diffusion coefficient following analyte desolvation reveals a value of 1.7 m2 s−1 in the first 250–500 ns. This value is in good overall agreement with a theoretical analysis and with an analytical treatment of a surface source of hydrogen atoms. In contrast, calcium emission is only observed beyond about 1 µs, with a diffusion coefficient at least an order of magnitude below the hydrogen value. The temporal H and Ca emission data suggest that water vaporizes first, leaving an ever increasing Ca analyte concentration until finally, with nearly all water desorbed, the Ca fraction is vaporized. Overall, the data support the conclusion that finite time-scales of heat and mass transfer play an important role in localized plasma perturbations in the vicinity of the analyte, which has important implications for the LIBS analyte signal.

Strategies to prolong the plasma residence time of peptidedrugs

Well established as well as recently developed strategies to prevent the fast clearance of peptide drugs from the circulation are reviewed.

Scavenger receptors are associated with cellular interactions of S100A12 in vitro and in vivo

Increased plasma levels of S100 proteins and interaction of S100 proteins with receptor for advanced glycation end products (RAGE) have been associated with a number of disease states, including chronic inflammatory processes and atherosclerosis. However, data concerning the role of circulating S100 proteins in these pathologies in vivo are scarce and, furthermore, it is currently not known whether RAGE is the sole receptor for extracellular S100 proteins in vivo. We report a novel methodology using recombinant human S100 proteins radiolabelled with fluorine-18, particularly, (18)F-S100A12, in receptor binding studies and cellular association studies in vitro, and in dynamic small animal positron emission tomography (PET) studies in rats in vivo. Association to both human aortic endothelial cells and macrophages revealed specific binding of (18)F-S100A12 to RAGE, but, furthermore, provides evidence for interaction of (18)F-S100A12 to various scavenger receptors (SR). PET data showed temporary association of (18)F-S100A12 with tissues overexpressing RAGE (e.g., lung), and, moreover, accumulation of (18)F-S100A12 in tissues enriched in cells overexpressing SR (e.g., liver and spleen). Blockade of overall SR interaction by maleylated BSA (malBSA) clearly shows diminished in vivo association of (18)F-S100A12 to these tissues as well as a significant increment of the mean plasma residence time of (18)F-S100A12 (4.8+/-0.4 h vs. 2.3+/-0.3 h). The present approach first demonstrates that besides RAGE also scavenger receptors contribute to distribution, tissue association and elimination of circulating proinflammatory S100A12.

Lipid modification in type 2 diabetes: the role of LDL and HDL

Patients with type 2 diabetes feature important modification of both low density lipoprotein (LDL) and high density lipoprotein particles which are likely to play an important role in the development of atherosclerosis. Although plasma LDL cholesterol level is usually normal in type 2 diabetic patients, LDLs show a significant increase in their plasma residence time which may promote cholesterol deposition in the arterial wall. Moreover, important qualitative abnormalities of LDLs, potentially atherogenic, are observed in type 2 diabetic patients: small dense, triglyceride-rich, LDL particles (known as subclass B), oxidized LDL and glycated LDL. All these qualitative modification of LDLs amplify the atherosclerotic process. Plasma high density lipoprotein (HDL) cholesterol is decreased in type 2 diabetes related to increased catabolism of HDL particles. One of the mechanism responsible for increased catabolism of HDLs is hypertriglyceridemia, promoting through cholesteryl ester transfer protein (CETP) the transfer of triglycerides (TG) to HDL leading to the formation of TG-rich HDLs which are very good substrates for hepatic lipase, enzyme in charge of HDLs catabolism. The reduction in plasma adiponectin level, observed in type 2 diabetes may be another mechanism involved in the diminution of HDL cholesterol. Furthermore, qualitative abnormalities of HDLs are described in type 2 diabetes: enrichment in triglycerides and glycation, which may impair HDL-mediated cholesterol efflux and reverse cholesterol transport. In addition to their role in reverse cholesterol transport, HDLs usually show antioxidative, anti-inflammatory, anti-thrombotic and endothelium-dependent vasorelaxant effects. It has been shown that HDLs from patients with type 2 diabetes have a significant reduction in their antioxidative and endothelium-dependent vasorelaxant properties.

Pharmacokinetics and distribution of SN 28049, a novel DNA binding anticancer agent, in mice

N-[2-(Dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide (SN 28049) is a potent DNA binding topoisomerase II poison that shows excellent antitumour activity in a colon-38 murine tumour model in comparison to standard topoisomerase II poisons. We report here the preclinical pharmacokinetics of SN 28049. C57 Bl/6 mice (n = 3 per time point) were treated with a single i.v., i.p. or p.o. administration (8.9 mg/kg). Plasma and tissue samples were analysed using a validated LC/MS method utilizing a homologue as an internal standard. The assay range was 0.062-2.5 microM with a quantitation limit of 0.062 microM and a detection limit of 0.025 microM. Acceptable intra- and inter-assay accuracy (95-105%) and precision (<6.5% RSD) were achieved. Following i.v. administration, SN 28049 demonstrated 2-compartment model kinetics with a volume of distribution of 42.3 +/- 4.1 l/kg, a plasma clearance of 12.1 +/- 0.5 l/h per kg and distribution and elimination half-lives of 0.15 +/- 0.02 and 2.8 +/- 0.2 h (mean +/- SE), respectively. For all administration routes, SN 28049 concentrations in normal tissues (brain, heart, liver, lung, and kidney) were 12- to 120-fold higher than those in plasma, but half-lives and mean residence times were similar. The i.p. and p.o. bioavailabilities were 83.1 +/- 1.5 and 54.5 +/- 1.1%, respectively. In the tumour tissue, elimination half-life (9.1 +/- 0.7 h) and the mean residence time (18.2 +/- 0.7 h) were significantly (P < 0.001) longer than those of plasma and normal tissues. The tumour area under the concentration-time curve (AUC) (1,316 +/- 66 microM h) was also 693-fold greater than the plasma AUC, and considerably higher (approximately 5-fold) than any other tissue examined, indicating selective uptake and retention of SN 28049 in the tumour. We conclude that SN 28049's high tumour exposure and long tumour retention time is likely to contribute to its high antitumour activity in vivo.

Long-lasting inhibitors of the gastric H,K-ATPase

Proton pump inhibitors (PPIs) are acid-activated prodrugs that covalently bind to the gastric H,K-ATPase on its luminal surface. Only active pumps can be inhibited. The short plasma residence time of current PPIs prevents inhibition of pumps synthesized or activated after the PPI has disappeared, limiting the degree of acid inhibition even with twice-daily administration. PPIs with a longer residence time should improve acid control. Various K+ competitive inhibitors of the pump are being developed (acid pump antagonists or potassium-competitive acid blockers), with the advantage of complete inhibition of acid secretion independent of pump activity. Early data on these suggest that twice daily administration would improve acid control compared with PPIs.

Preparation and evaluation of alpha-phenyl-n-tert-butyl nitrone (PBN)-encapsulated chitosan and PEGylated chitosan nanoparticles

Alpha-phenyl-n-tert-butyl nitrone (PBN) shows its major effect by scavenging free radicals formed in the ischemia and it has the ability to penetrate through the blood brain barrier easily. The in vivo stability of PBN is very low and when administered systemically, it has a mean plasma half life of about three hours. Therefore, formulations which are able to prolong the plasma residence time of PBN are of major interest, because oxygen radicals are usually continuously formed under pathological conditions. In this study, PBN, a nitrone compound having neuroprotective properties, was encapsulated in chitosan (CS) and chitosan-poly(ethylene glycol) (CS-PEG) nanoparticles for treatment of diseases such as stroke, in which sustained free radical production is reported. The nanoparticles were characterized through particle size determination, zeta potential, encapsulation efficiency, surface morphology determinations and in vitro release studies. The surface morphologies were evaluated by transmission electron microscopy (TEM) and nanoparticles having spherical shapes were characterized. The particle size distribution was between approximately 97 nm and approximately 322 nm; and the zeta potentials varied between approximately 9 mV and approximately 33 mV. Size of the nanoparticle formulations was important for the release of PBN from nanoparticles. The quantitative determination of PBN has been evaluated by a validated analytical HPLC method. The presented chitosan-based nanotechnology opens new perspectives for testing antioxidant activity in vivo.