Lung-to-finger circulation time can be measured stably with high reproducibility by simple breath holding method in cardiac patients.

Lung to finger circulation time (LFCT) has been used to estimate cardiac function. We developed a new LFCT measurement device using a laser sensor at fingertip. We measured LFCT by measuring time from re-breathing after 20 s of breath hold to the nadir of the difference of transmitted red light and infrared light, which corresponds to percutaneous oxygen saturation. Fifty patients with heart failure were enrolled. The intrasubject stability of the measurement was assessed by the intraclass correlation coefficient (ICC). The ICC calculated from 44 cases was 0.85 (95% confidence interval: 0.77-0.91), which means to have "Excellent reliability." By measuring twice, at least one clear LFCT value was obtained in 89.1% of patients and the overall measurability was 95.7%. We conducted all LFCT measurements safely. High ICCs were obtained even after dividing patients according to age, cardiac index (CI); 0.85 and 0.84 (≥ 75 or < 75 years group, respectively), 0.81 and 0.84 (N = 26, ≥ or < 2.2 L/min/M2). These results show that our new method to measure LFCT is highly stable and feasible for any type of heart failure patients.

Contrast-Enhanced Ultrasonography-Based Hepatic Perfusion for Early Prediction of Prognosis in Acute Liver Failure.

BACKGROUND AND AIMS: Acute liver failure (ALF) is a rare but dramatic clinical syndrome characterized by massive hepatic necrosis leading to multiorgan failure. It is difficult to predict the outcomes in patients with ALF using existing prognostic models. We aimed to analyze hepatic perfusion using contrast-enhanced ultrasound and Doppler ultrasound in patients with ALF and investigate its utility as a prognostic biomarker. APPROACH AND RESULTS: In this prospective observational study, 208 patients with acute liver injury/ALF were enrolled from 2015 to 2019. We evaluated 50 consecutive patients with ALF with Doppler ultrasound and contrast-enhanced ultrasound performed on admission. The cases were divided into the following two groups: survivors (recovered without surgical intervention) and nonsurvivors (died of ALF or underwent liver transplantation). The time to peak and peak intensity of hepatic artery, portal vein, hepatic vein, and liver parenchyma were calculated using the time-intensity curve analysis. The hepatic artery (HA) resistive index was calculated using the fast Fourier transform analysis of Doppler ultrasound. The time interval (TI) between the time to peak of HA and liver parenchyma (LP) was significantly shorter in the nonsurvivors than in the survivors (P < 0.0001). The area under the receiver operating curve values for TI (HA, LP), Japanese scoring system, HE prediction model, Model for End-Stage Liver Disease score, and King's College Hospital criteria for the prediction of poor prognosis were 0.953, 0.914, 0.861, 0.816, and 0.731, respectively. The most appropriate cutoff value of TI (HA, LP) was 6.897 seconds; the sensitivity, specificity, positive and negative predictive values were 94.4%, 90.6%, 85.0%, and 96.7%, respectively. CONCLUSIONS: TI (HA, LP) accurately predicts the outcome in patients with ALF and may be useful in clinical decision making.

Difference in Cerebral Circulation Time between Subtypes of Moyamoya Disease and Moyamoya Syndrome.

In this study, we evaluated the differences in hemodynamics between hemorrhagic and non-hemorrhagic moyamoya disease (MMD) and moyamoya syndrome (MMS) by measuring cerebral circulation time (CCT). This case-control study included 136 patients with MMD or MMS diagnosed between April 2015 and July 2016 at Beijing Tian Tan Hospital. Each hemisphere was analyzed separately. The difference in clinical, radiological characteristics and CCT between subtypes of MMD and MMS were analyzed statistically. The results showed that total CCT between hemorrhagic and non-hemorrhagic sides was not statistically different (16.55 s vs. 16.06 s, P = 0.562). The cerebral filling circulation time (CFCT) of hemorrhagic sides was significantly shorter than that of non-hemorrhagic sides (4.52 s vs. 5.41 s, P < 0.001), and the cerebral venous circulation time (CVCT) of hemorrhagic sides was significantly longer than that of non-hemorrhagic sides (12.02 s, vs. 10.64 s, P < 0.001). The ratio of CFCT to CVCT (F-V ratio) was inversely correlated with the possibility of hemorrhagic stroke. Therefore, we conclude that the rapid filling and poor venous drainage of cerebral circulation are likely risk factors of hemorrhagic stroke secondary to MMD or MMS. The F-V ratio can be used to identify individuals at high risk of hemorrhagic stroke.

Improved Accuracy of Automated Estimation of Cardiac Output Using Circulation Time in Patients with Heart Failure.

BACKGROUND: Lung-to-finger circulation time of oxygenated blood during nocturnal periodic breathing in heart failure patients measured using polysomnography correlates negatively with cardiac function but possesses limited accuracy for cardiac output (CO) estimation. METHODS AND RESULTS: CO was recalculated from lung-to-finger circulation time using a multivariable linear model with information on age and average overnight heart rate in 25 patients who underwent evaluation of heart failure. The multivariable model decreased the percentage error to 22.3% relative to invasive CO measured during cardiac catheterization. CONCLUSIONS: This improved automated noninvasive CO estimation using multiple variables meets a recently proposed performance criterion for clinical acceptability of noninvasive CO estimation, and compares very favorably with other available methods.

A Novel Method for Assessing Cardiac Output With the Use of Oxygen Circulation Time.

BACKGROUND: We investigated whether a simple breath hold would yield dynamic oxygen (O2) saturation change and whether the derived circulation time would be useful in assessing cardiac function. METHODS AND RESULTS: Patients undergoing right heart catheterization for clinical indications (n = 48), including heart failure (HF; n = 24), were prospectively recruited. Each subject was instructed to hold their breath for 20-40 seconds. Lung to finger circulation time (LFCT), defined as the time from the point of rebreathing to nadir O2 desaturation, was correlated with cardiac output. Among 48 subjects recruited, 37 manifested ≥3% O2 desaturation allowing for an LFCT measurement. Mean LFCT was 38.5 ± 17.5 seconds (range 18.9-94.7 s). LFCT in patients with a clinical diagnosis of HF was significantly longer than those without (45.9 ± 19.9 s vs 31.5 ± 11.5 s; P = .01). Overall, the LFCT was inversely correlated with cardiac output (Fick: r = -0.56; P < .001 [n = 37]; thermodilution: r = -0.6; P = .001 [n = 27]). CONCLUSIONS: LFCT is prolonged in low cardiac output. LFCT is a novel method that may be useful to noninvasively assess cardiac function in HF.

Determination of blood circulation times of superparamagnetic iron oxide nanoparticles by T2* relaxometry using ultrashort echo time (UTE) MRI.

Blood circulation is an important determinant of the biodistribution of superparamagnetic iron oxide nanoparticles. Here we present a magnetic resonance imaging (MRI) technique based on the use of ultrafast echo times (UTE) for the noninvasive determination of blood half-lives at high particle concentrations, when conventional pulse sequences fail to produce a useful MR signal. Four differently coated iron oxide nanoparticles were administered intravenously at a dose of 500 µmol Fe/kg bodyweight and UTE images of C57BL/6 mice were acquired on a 1-T ICON scanner (Bruker). T2* relaxometry was done by acquiring UTE images with echo times of 0.1, 0.8 and 1.6 ms. Blood circulation time was then determined by fitting an exponential curve to the time course of the measured relaxation rates. Circulation time was shortest for particles coated with malic acid (t1/2=23 min) and longest for particles coated with tartaric acid (t1/2=63 min). UTE-based T2* relaxometry allows noninvasive determination of blood circulation time and is especially useful when high particle concentrations are present.

A nanoparticle-encapsulated non-nucleoside reverse-transcriptase inhibitor with enhanced anti-HIV-1 activity and prolonged circulation time in plasma.

Non-nucleoside reverse-transcriptase inhibitors (NNRTIs), major components of highly active antiretroviral therapy (HAART), are effective in suppressing viral replication and preventing the progress of HIV-1 infection to AIDS. However, rapid blood clearance in vivo could significantly impair the efficiency of the anti-HIV-1 activity and result in multiple daily doses which might lead to poor patient compliance. Here we attempted to employ biodegradable organic nanoparticles (NPs) to encapsulate DAAN15h, a derivative of 4-substituted 1, 5-diarylaniline with potent anti-HIV activities. Nanoparticles encapsulating DAAN15h (NP-DAAN15h) displayed a spherical shape with a size of 97.01 ± 3.64 nm and zeta potential of -19.1 ± 3.78 mV, and they exhibited a sustained controlled release behavior in vitro. The cellular uptake of NPs on TZM-b1 cells, MT-2 cells and M7 cells, possibly through lipid raft-mediated and energydependent active transport processes, was significantly enhanced. NP-DAAN15h, which possessed no significant in vitro cytotoxicity, showed improved antiviral activity against laboratory-adapted and primary HIV-1 isolates with different subtypes and tropisms, including RT-resistant variants. NP-DAAN15h exhibited a significantly prolonged blood circulation time, decreased plasma elimination rate, and enhanced AUC(0-t). NP-DAAN15h, a nanoparticle-encapsulated NNRTI, exhibits enhanced cellular uptake, improved anti-HIV-1 efficacy and prolonged in vivo circulation time, suggesting good potential for further development as a new NNRTI formulation for clinical use.

Relationship between angiographic vasospasm, cerebral blood flow, and cerebral infarction after subarachnoid hemorrhage.

Delayed cerebral ischemia (DCI) and cerebral infarction are major contributors to poor functional recovery after subarachnoid hemorrhage (SAH). Cerebral vasospasm, the narrowing of proximal intracranial arteries after SAH, has long been assumed to be the primary cause of DCI, and has therefore been the primary therapeutic target in attempts to diminish disability after SAH. However, emerging evidence has questioned the strength and causality of the relationship between vasospasm and DCI. To address this fundamental question, we performed two parallel studies assessing the relationship between the presence of vasospasm in a vascular territory and both regional reductions in cerebral blood flow (CBF) and development of cerebral infarction.In a cohort of SAH patients at high-risk for DCI, we identified regions of hypoperfusion using positron emission tomography (PET) and compared their distribution with territories exhibiting vasospasm on concurrent angiography. We found that regional hypoperfusion was common in the absence of proximal vasospasm and that some patients without any significant vasospasm still could have hypoperfused brain regions. Similarly, our parallel study demonstrated that both patients and brain territories without vasospasm could develop delayed cerebral infarction, and that such vasospasm-independent infarcts account for more than a quarter of the infarct burden from DCI. These findings suggest that other processes, perhaps at a microvascular level, contribute at least part of the burden of DCI and future interventions should also address these other pathophysiologic processes.

Detection of delayed cerebral ischemia (DCI) in subarachnoid haemorrhage applying near-infrared spectroscopy: elimination of the extracerebral signal by transcutaneous and intraparenchymatous measurements in parallel.

BACKGROUND: Detection of delayed cerebral ischemia (DCI) in high-grade subarachnoid haemorrhage (SAH) is an unsolved issue. Conventional near-infrared spectroscopy (NIRS) with optodes applied over the skin is controversial because the NIRS signal is contaminated by extracerebral tissue. The objective is to quantify and subtract the contribution from extracerebral tissue from the signal by using measurements in parallel with a NIRS brain tissue probe and conventional NIRS. METHODS: In a patient with high-grade SAH, two approaches for NIRS were applied. First, a conventional brain tissue probe for intracranial pressure (ICP) monitoring, supplied by optical fibres, was placed into the brain tissue 2 cm deep from the dura. Second, for conventional NIRS, a plaster-based patch carrying optodes (one emitter, two detectors) was attached to the skin. Central venous injections of 0.3 mg/kg body weight (bw) indocyanine green (ICG) were performed. ICG dye dilution curves obtained with the probe and patch were collected simultaneously and analysed for blood flow values. RESULTS: Twelve measurements in parallel with the probe and patch were performed. Mean cerebral blood flow (CBF) for the probe was higher (24.8 ± 9.1 ml/100 g/min) compared with the values obtained with the patch (for detector 1, extra-cerebral blood flow [ECBF] mean 5.1 ± 1.8 ml/100 g/min; p = 0.002; for detector 2, 6.6 ± 2.1 ml/100 g/min; p = 0.002). CBF values obtained with the probe correlated with blood flow values obtained with the patch (for CBF vs. ECBF detector 1, r = 0.72 [p = 0.008]; ECBF detector 2, r = 0.79 [p = 0.002]). CONCLUSIONS: Blood flow values obtained with conventional NIRS correlated significantly with absolute CBF values obtained directly within the brain tissue. Simultaneous measurements with the NeMo Probe and NeMo Patch allow quantification and subtraction of the contribution from extracerebral tissues from the signal obtained with conventional NIRS.

Arterial spin labelling reveals prolonged arterial arrival time in idiopathic Parkinson's disease.

Idiopathic Parkinson's disease (IPD) is the second most common neurodegenerative disease, yet effective disease modifying treatments are still lacking. Neurodegeneration involves multiple interacting pathological pathways. The extent to which neurovascular mechanisms are involved is not well defined in IPD. We aimed to determine whether novel magnetic resonance imaging (MRI) techniques, including arterial spin labelling (ASL) quantification of cerebral perfusion, can reveal altered neurovascular status (NVS) in IPD. Fourteen participants with IPD (mean ± SD age 65.1 ± 5.9 years) and 14 age and cardiovascular risk factor matched control participants (mean ± SD age 64.6 ± 4.2 years) underwent a 3T MRI scan protocol. ASL images were collected before, during and after a 6 minute hypercapnic challenge. FLAIR images were used to determine white matter lesion score. Quantitative images of cerebral blood flow (CBF) and arterial arrival time (AAT) were calculated from the ASL data both at rest and during hypercapnia. Cerebrovascular reactivity (CVR) images were calculated, depicting the change in CBF and AAT relative to the change in end-tidal CO2. A significant (p = 0.005) increase in whole brain averaged baseline AAT was observed in IPD participants (mean ± SD age 1532 ± 138 ms) compared to controls (mean ± SD age 1335 ± 165 ms). Voxel-wise analysis revealed this to be widespread across the brain. However, there were no statistically significant differences in white matter lesion score, CBF, or CVR between patients and controls. Regional CBF, but not AAT, in the IPD group was found to correlate positively with Montreal cognitive assessment (MoCA) scores. These findings provide further evidence of alterations in NVS in IPD.

Circulation time measurement from sleep studies in patients with obstructive sleep apnea.

INTRODUCTION: Lung to finger circulation time (LFCT) can be estimated from polysomnography (PSG) in the presence of an apneic event by using oxygen as an indicator and a finger as the site of detection. The purpose of this study was to refine the methodology of LFCT measurement and to compare LFCT in patients with obstructive sleep apnea (OSA) with and without heart failure (HF). METHODS: In a retrospective manner, 10 LFCT measurements per patient were made from the PSG in 171 consecutive patients with a diagnosis of OSA who were divided into two groups: (a) those with a clinical history of underlying HF (N = 42) and (b) those without HF (N = 129). Mean values were compared between the two groups. We also examined associations of LFCT with various factors in each group and the combined group separately using multiple regression analysis. RESULTS: Gender and age were significantly associated with LFCT in patients with OSA alone. Use of ß-blockers was associated with LFCT in the group with OSA with HF. Among the entire cohort, HF, ß-blocker, gender, and age were found to be significantly associated with LFCT. The presence of HF was the strongest predictor of a prolonged LFCT (adjusted mean LFCT: OSA only = 18.5 [95% CI: 17.2-19.7 sec] vs. OSA with HF = 26.1 [95% CI: 24.3-28.0 sec], p < 0.0001). CONCLUSION: LFCT can be reliably measured and is prolonged in patients with OSA and underlying HF. LFCT based on PSG may be a useful marker for detection of coexisting HF in patients with OSA.

Computed tomography-guided screening of surfactant effect on blood circulation time of emulsions: application to the design of an emulsion formulation for paclitaxel.

PURPOSE: In an effort to apply the imaging techniques currently used in disease diagnosis for monitoring the pharmacokinetics and biodisposition of particulate drug carriers, we sought to use computed tomography (CT) scanning methodology to investigate the impact of surfactant on the blood residence time of emulsions. METHODS: We prepared the iodinated oil Lipiodol emulsions with different compositions of surfactants and investigated the impact of surfactant on the blood residence time of emulsions by CT scanning. RESULTS: The blood circulation time of emulsions was prolonged by including Tween 80 or DSPE-PEG (polyethylene glycol 2000) in emulsions. Tween 80 was less effective than DSPE-PEG in terms of prolongation effect, but the blood circulating time of emulsions was prolonged in a Tween 80 content-dependent manner. As a proof-of-concept demonstration of the usefulness of CT-guided screening in the process of formulating drugs that need to be loaded in emulsions, paclitaxel was loaded in emulsions prepared with 87 or 65% Tween 80-containing surfactant mixtures. A pharmacokinetics study showed that paclitaxel loaded in 87% Tween 80 emulsions circulated longer in the bloodstream compared to those in 65% Tween 80 emulsions, as predicted by CT imaging. CONCLUSIONS: CT-visible, Lipiodol emulsions enabled the simple evaluation of surfactant composition effects on the biodisposition of emulsions.

Physiologically based structure of mean residence time.

A mean residence time (MRT) is an important pharmacokinetic parameter. To the author's knowledge, however, a physiologically based structure of MRT (thereafter MRT structure) has not been published so far. Primarily this is because MRT structures cannot be identified by traditional pharmacokinetic methods used for the determination of MRT. Therefore, tools from the theory of linear dynamic systems were used for the structural identification of MRT in this study. The MRT structure identified is physiologically meaningful. Accordingly, it seems that the MRT structure identified may contribute to already established knowledge about MRT.

Design of multifunctional non-viral gene vectors to overcome physiological barriers: dilemmas and strategies.

Gene-based therapeutics hold great promise for medical advancement and have been used to treat various human diseases with mixed success. However, their therapeutic application in vivo is limited due largely to several physiological barriers. The design of non-viral gene vectors with the ability to overcome delivery obstacles is currently under extensive investigation. These efforts have placed an emphasis on the development of multifunctional vectors able to execute multiple tasks to simultaneously overcome both extracellular and intracellular obstacles. However, the assembly of these different functionalities into a single system to create multifunctional gene vectors faces many conflicts that largely limit the safe and efficient application of lipoplexes and polyplexes in a systemic delivery. In the review, we have described the dilemmas inherent in the design of a viable, non-viral gene vector equipped with multiple functionalities. The strategies directed towards individual delivery barriers are first summarized, followed by a focus on the design of so-called smart multifunctional vectors with the capability to overcome the delivery difficulties of gene medicines, including the so-called the "polycation dilemma", the "PEG dilemma" and the "package and release dilemma".

Spatial frequency-based analysis of mean red blood cell speed in single microvessels: investigation of microvascular perfusion in rat cerebral cortex.

BACKGROUND: Our previous study has shown that prenatal exposure to X-ray irradiation causes cerebral hypo-perfusion during the postnatal development of central nervous system (CNS). However, the source of the hypo-perfusion and its impact on the CNS development remains unclear. The present study developed an automatic analysis method to determine the mean red blood cell (RBC) speed through single microvessels imaged with two-photon microscopy in the cerebral cortex of rats prenatally exposed to X-ray irradiation (1.5 Gy). METHODOLOGY/PRINCIPAL FINDINGS: We obtained a mean RBC speed (0.9±0.6 mm/sec) that ranged from 0.2 to 4.4 mm/sec from 121 vessels in the radiation-exposed rats, which was about 40% lower than that of normal rats that were not exposed. These results were then compared with the conventional method for monitoring microvascular perfusion using the arteriovenous transit time (AVTT) determined by tracking fluorescent markers. A significant increase in the AVTT was observed in the exposed rats (1.9±0.6 sec) as compared to the age-matched non-exposed rats (1.2±0.3 sec). The results indicate that parenchyma capillary blood velocity in the exposed rats was approximately 37% lower than in non-exposed rats. CONCLUSIONS/SIGNIFICANCE: The algorithm presented is simple and robust relative to monitoring individual RBC speeds, which is superior in terms of noise tolerance and computation time. The demonstrative results show that the method developed in this study for determining the mean RBC speed in the spatial frequency domain was consistent with the conventional transit time method.

Cerebral blood flow by arterial spin labeling in poststroke dementia.

OBJECTIVE: To investigate the relationship between cerebral blood flow and dementia in older stroke survivors and subjects with Alzheimer disease (AD). METHODS: This cohort study used arterial spin labeling MRI at 3 T to examine cerebral blood flow (CBF). We scanned 39 patients 6 years after stroke. They were older than 75 years at the time of stroke and free of dementia 3 months poststroke, with 8 subsequently developing dementia. We also scanned 17 subjects with AD and 29 healthy control subjects. We determined the perfusion in regions of interest (ROIs). Hippocampal volume was also measured using a previously validated automated procedure. RESULTS: The gray matter/white matter CBF ratio was reduced globally in the poststroke dementia (PSD) group (1.55 SD = 0.12) relative to control subjects (1.78 SD = 0.18; p = 0.03). The CBF ratio in a parietal ROI was reduced in the AD (1.34 SD = 0.31; p = 0.003), PSD (1.32 SD = 0.22; p = 0.041), and poststroke no-dementia (PSND) (1.44 SD = 0.34; p = 0.014) groups relative to that of control subjects (1.70 SD = 0.32). In subjects without stroke, the best predictor of dementia was hippocampus volume, whereas in the stroke group, it was the global CBF gray matter/white matter ratio. Hippocampus volume was not significantly different between the AD and PSD groups, and both had reduced hippocampi relative to those of control subjects and the PSND group. CONCLUSIONS: We found evidence for both vascular and AD pathology in PSD, suggesting that both the direct impact of the stroke and subsequent development of AD-type changes play a role in the etiology of PSD.

Methamphetamine causes sustained depression in cerebral blood flow.

The use prevalence of the highly addictive psychostimulant methamphetamine (MA) has been steadily increasing over the past decade. MA abuse has been associated with both transient and permanent alterations in cerebral blood flow (CBF), hemorrhage, cerebrovascular accidents and death. To understand MA-induced changes in CBF, we exposed C56BL/6 mice to an acute bolus of MA (5mg/kg MA, delivered IP). This elicited a biphasic CBF response, characterized by an initial transient increase (~ 5 minutes) followed by a prolonged decrease (~ 30 minutes) of approximately 25% relative to baseline CBF--as measured by laser Doppler flowmetry over the somatosensory cortex. To assess if this was due to catecholamine derived vasoconstriction, phentolamine, an α-adrenergic antagonist was administered prior to MA treatment. This reduced the initial increase in CBF but failed to prevent the subsequent, sustained decrease in CBF. Consistent with prior reports, MA caused a transient increase in mean arterial blood pressure, body temperature and respiratory rate. Elevated respiratory rate resulted in hypocapnia. When respiratory rate was controlled by artificially ventilating mice, blood PaCO(2) levels after MA exposure remained unchanged from physiologic levels, and the MA-induced decrease in CBF was abolished. In vivo two-photon imaging of cerebral blood vessels revealed sustained MA-induced vasoconstriction of pial arterioles, consistent with laser Doppler flowmetry data. These findings show that even a single, acute exposure to MA can result in profound changes in CBF, with potentially deleterious consequences for brain function.

Investigating the effect of polymeric approaches on circulation time and physical properties of nanobubbles.

PURPOSE: A challenge in the field of nanobubbles, including lipobubbles and polymeric nanobubbles, is identification of formulation approaches to enhance circulation time or "bubble life" in the specific organ to allow for organ visualization. The aim of this study was to investigate the potential of two specific preparation approaches, polymeric surface modification to lipobubbles and a one-step approach for the preparation of ionotropically originated polymeric hydrogel nanobubbles for the production of biocompatible, biodegradable, and sufficiently echogenic ('flexible') bubbles, preferably within the nanometer range, that possess an enhanced in vivo lifetime compared to an unmodified lipobubble to allow visualization of the lymph node vasculature. METHODS: In the first approach, formed liposomes (basic and polymerically enhanced) were sequentially layered with appropriate cationic and anionic polyelectrolytes followed by transformation into polymer-coated nanobubbles. In addition, a one-step approach was employed for the fabrication of ionotropically originated polymeric hydrogel bubbles. RESULTS: Bubble lifetime was marginally enhanced by self-deposition of polyelectrolytes onto the normal lipobubble, however, not significantly (P = 0.0634). In general, formulations possessing a higher ratio of anionic:cationic coats and highly anionic overall surface charge (-20.62 mV to -17.54 mV) possessed an enhanced lifetime. The improvement in bubble lifetime was significant when a purely polymeric polyionic hydrogel bubble shell was instituted compared to a normal unmodified lipobubble (P = 0.004). There was enhanced persistence of these systems compared to lipobubbles, attributed to the highly flexible, interconnected hydrogel shell which minimized gas leakage. The prolonged contrast signal may also be attributed to a degree of polymeric deposition/endothelial attachment. CONCLUSIONS: This study identified the relevance of polymeric modifications to nanobubbles for an improved circulating lifetime, which would be essential for application of these systems in passive drug or gene targeting via the enhanced permeability and retention effect.