Neutrophil-inspired photothermo-responsive drug delivery system for targeted treatment of bacterial infection and endotoxins neutralization
Chengnan LiYingying GanZongshao LiMengjing FuYuzhen LiXinran PengYongqiang YangGuo‐Bao TianYi Yan YangPeiyan YuanXin Ding
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P. aeruginosa, a highly virulent Gram-negative bacterium, can cause severe nosocomial infections, and it has developed resistance against most antibiotics. New therapeutic strategies are urgently needed to treat such bacterial infection and reduce its toxicity caused by endotoxin (lipopolysaccharide, LPS). Neutrophils have been proven to be able to target inflammation site and neutrophil membrane receptors such as Toll-like receptor-4 (TLR4) and CD14, and exhibit specific affinity to LPS. However, antibacterial delivery system based on the unique properties of neutrophils has not been reported.A neutrophil-inspired antibacterial delivery system for targeted photothermal treatment, stimuli-responsive antibiotic release and endotoxin neutralization is reported in this study. Specifically, the photothermal reagent indocyanine green (ICG) and antibiotic rifampicin (RIF) are co-loaded into poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP-ICG/RIF), followed by coating with neutrophil membrane to obtain antibacterial delivery system (NM-NP-ICG/RIF). The inflammation targeting properties, synergistic antibacterial activity of photothermal therapy and antibiotic treatment, and endotoxin neutralization have been studied in vitro. A P. aeruginosa-induced murine skin abscess infection model has been used to evaluate the therapeutic efficacy of the NM-NP-ICG/RIF.Once irradiated by near-infrared lasers, the heat generated by NP-ICG/RIF triggers the release of RIF and ICG, resulting in a synergistic chemo-photothermal antibacterial effect against P. aeruginosa (~ 99.99% killing efficiency in 5 min). After coating with neutrophil-like cell membrane vesicles (NMVs), the nanoparticles (NM-NP-ICG/RIF) specifically bind to inflammatory vascular endothelial cells in infectious site, endowing the nanoparticles with an infection microenvironment targeting function to enhance retention time. Importantly, it is discovered for the first time that NMVs-coated nanoparticles are able to neutralize endotoxins. The P. aeruginosa murine skin abscess infection model further demonstrates the in vivo therapeutic efficacy of NM-NP-ICG/RIF.The neutrophil-inspired antibacterial delivery system (NM-NP-ICG/RIF) is capable of targeting infection microenvironment, neutralizing endotoxin, and eradicating bacteria through a synergistic effect of photothermal therapy and antibiotic treatment. This drug delivery system made from FDA-approved compounds provides a promising approach to fighting against hard-to-treat bacterial infections.Keywords:
Indocyanine Green
PLGA
Abstract Indocyanine green is a tricarbocyanine dye, that is stable in human blood plasma and can be completely eliminated by liver in several days. Due to its properties it can be used to assess the metabolic liver function. We present optical densitometry device and theory for taking measurements of concentration of indocyanine green in patient’s blood in vivo.
Indocyanine Green
Densitometry
Liver function
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The authors describe the intraoperative use of indocyanine green dye elimination to detect critical reductions in donor liver function.
Indocyanine Green
Liver function
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A simple yet effective strategy to enhance the thermal stability, anti-photobleaching and photothermal efficiency of indocyanine green via carbonization has been developed, which is likely to have broad applications in other systems.
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1. The validity of a two-compartment pharmacokinetic model for the estimation of the hepatic extraction ratio of Indocyanine Green was tested in six patients with cirrhosis of the liver. 2. No agreement was found between the value of the hepatic extraction ratio measured directly and that calculated using the two-compartment model. 3. To investigate the reasons for the failure of the model, an extended sampling period was used to define the time course of Indocyanine Green in plasma in six healthy subjects and in six patients with cirrhosis of the liver after a bolus injection of the dye. 4. Indocyanine Green was measurable in the plasma for up to 10 h after injection in healthy subjects, and up to 48 h after injection in the patients. The plasma elimination curve in both groups was best described by a triexponential function. 5. The clearance of Indocyanine Green calculated using data collected in the first 20 min after injection overestimated that calculated using data collected for as long as Indocyanine Green was measurable in the plasma. In the patients with cirrhosis the mean overestimate was 87%. 6. Thus, a two-compartment pharmacokinetic model was inappropriate for the description of the disposition of Indocyanine Green and estimates of the hepatic extraction ratio obtained using this model in patients with cirrhosis were inaccurate.
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• To evaluate hepatic function, the kinetics of indocyanine green clearance were studied in seven injured patients with hepatic venous catheters. Indocyanine green clearance after a bolus injection of 20 mg was relatively monoexponential on the first day after injury. Following this, a second slower compartment of indocyanine green clearance was uniformly evident, becoming most prominent around the fourth day after injury. Indocyanine green clearance again became more uniform as recovery continued. Fractional indocyanine green extraction ten minutes after injection decreased from 0.9 on the first day after injury to 0.2 three days later, and then returned to 0.7 on the seventh day after injury. These decreases in indocyanine green clearance preceded an increase in total serum bilirubin concentration to a mean value of 1.9 mg/dL. Indocyanine green clearance was thus found to be an early and sensitive indicator of impaired hepatic function. (Arch Surg1984;119:264-268)
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Because the disappearance rate of indocyanine green depends not only on hepatocyte function but also hepatic blood flow, the disappearance rate of indocyanine green is considered to be affected by the systemic circulation. Although the disappearance rate of indocyanine green is slower in cirrhotic patients, a hyperdynamic state is reported to be present. Purpose of this study was to evaluate hepatic function and systemic circulation simultaneously with reference to the hyperdynamic state of cirrhotic liver.Forty-six patients were selected randomly for this study. Simultaneous measurement of effective hepatic blood flow and systemic circulation using an indocyanine green clearance meter was performed. We calculated the effective hepatic blood flow using the early disappearance rate of indocyanine green movement, cardiac output, and circulating time simultaneously with indocyanine green clearance meter.Hepatic function and hyperdynamic circulation could be evaluated quantitatively. The indocyanine green disappearance rate was dependent on cardiac index in normal subjects, whereas the indocyanine green disappearance rate was lower in cirrhotic patients, although the cardiac index was relatively high.Hepatic function and systemic circulation could be evaluated simultaneously with this indocyanine green clearance meter. Hyperdynamic circulation was suggested to compensate the impaired hepatic function of cirrhotic liver. Simultaneous measurement of hepatic function and systemic circulation may be essential to studying liver function.
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1. The hepatic extraction ratio of Indocyanine Green was measured directly by trans-hepatic catheterization in 14 outbred swine (eight well-fed, six malnourished). A specific two-compartment pharmacokinetic model was fitted to the arterial Indocyanine Green concentration-time data and used to estimate the hepatic extraction ratio of Indocyanine Green. 2. The specific two-compartment pharmacokinetic model was modified to represent more accurately the physiological process of Indocyanine Green removal. Simulations were performed using this new model to estimate the hepatic extraction ratio of Indocyanine Green in the swine. 3. Similarly to previous findings, our data showed that the original model consistently overestimated the hepatic extraction ratio of Indocyanine Green (i.e. the model estimate was compared with the true, directly measured value). 4. The comparison of the modified model and the original model clearly indicates the reason for the overprediction of the hepatic extraction ratio of Indocyanine Green by the latter. The simulations using the new model indicate that the percentage of binding of Indocyanine Green to its transport protein (glutathione S-transferase) for removal in the bile will affect the estimation of the hepatic extraction ratio of Indocyanine Green. Thus, the amount of Indocyanine Green available for removal is less than that assumed by the original model.
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Bile acids are increasingly used as test substances for the estimation of liver function and it has been postulated that radioactive labeled bile acids have advantages over indocyanine green (ICG) for measurement of hepatic blood flow. Therefore, the hepatic extractions of 14C-taurocholate and ICG were compared in 23 patients with liver disease and correlated with various parameters of hepatic function. The hepatic extractions of 14C-taurocholate (mean: 42 +/- SD 17%) and ICG (mean: 35 +/- SD 18%) were similar. The correlations with galactose elimination capacity and BSP plasma disappearance were closer for ICG than for 14C-taurocholate extraction. Hepatic blood flow measured with 14C-taurocholate (mean: 1.45 +/- SD 0.51 l/min) correlated well (r = 0.81) with the respective values obtained with ICG (mean: 1.17 +/- SD 0.49 l/min), but was about 22% larger. This study does not provide evidence that 14C-taurocholate is superior to ICG as an intravenous test substance for measurement of hepatic function or blood flow.
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Aims: In patients suffering from acute liver failure (ALF) prediction of prognosis is of major importance to decide whether liver transplantation is needed. The King´s College criteria (KCC) are widely used to determine prognosis. However, the specificity of the KCC to predict the need for transplantation is low. Indocyanine green (ICG) is a dye that is biliary cleared from the blood and its plasma concentration can be determined non-invasively by the rate of absorption of infrared light. The clearance of ICG depends on hepatic blood flow and hepatocyte function.
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The clearance and extraction by the liver of the dye, indocyanine green, was studied in dogs anesthetized with sodium pentobarbital (30 mg/kg). A simultaneous comparison ‘ in vivo’ indicated that within experimental error indocyanine space equals Evans blue space. Additional in vitro experiments suggest that indocyanine space is a reasonably satisfactory measure of plasma volume. Adequate mixing of the injected dye occurs within 2–3 minutes after injection. From 2 to 20 minutes after injection, the peripheral arterial and hepatic venous decay slopes are logarithmic and easily analyzable. Right hepatic vein concentrations of indocyanine were consistently higher (3.3%) than those of the left. Most of the assumptions made in the clearance-extraction principle of measuring hepatic flow are valid. At least two factors, the obtaining of representative hepatic venous samples and determination of true extraction ratio (because of hepatic circulatory time) represent ill-defined sources of error. The soundness of the clearance-extraction principle and unique characteristics of indocyanine make the single injection method a potentially useful tool for study of hepatic blood flow.
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Extraction ratio
Liver circulation
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