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Nano Letters Jan 2024Senescence of activated hepatic stellate cells (HSCs) is crucial for the regression of liver fibrosis. However, impaired immune clearance can result in the accumulation...
Senescence of activated hepatic stellate cells (HSCs) is crucial for the regression of liver fibrosis. However, impaired immune clearance can result in the accumulation of senescent HSCs, exacerbating liver fibrosis. The activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is essential for both senescence and the innate immune response. Additionally, the specific delivery to activated HSCs is hindered by their inaccessible anatomical location, capillarization of liver sinusoidal endothelial cells (LSECs), and loss of substance exchange. Herein, we propose an antifibrotic strategy that combines prosenescence with enhanced immune clearance through targeted delivery of manganese (a cGAS-STING stimulator) via albumin-mediated transcytosis, specifically aimed at inducing senescence and eliminating activated HSCs in liver fibrosis. Our findings demonstrate that only albumin efficiently transfers manganese to activated HSCs from LSECs via transcytosis compared to liposomes, resulting in significant antifibrotic effects in vivo while exhibiting negligible toxicity.
Topics: Humans; Hepatic Stellate Cells; Liver; Manganese; Endothelial Cells; Liver Cirrhosis; Albumins; Nucleotidyltransferases
PubMed: 38164915
DOI: 10.1021/acs.nanolett.3c03689 -
Journal of Controlled Release :... Feb 2022Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein overexpressed by several cancers. Because SPARC shows high binding affinity to...
Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein overexpressed by several cancers. Because SPARC shows high binding affinity to albumin, we reasoned that pediatric sarcoma xenografts expressing SPARC would show enhanced uptake and accumulation of nanoparticle albumin-bound (nab)-paclitaxel, a potent anticancer drug formulation. We first evaluated the expression of SPARC in patient-derived xenografts (PDXs) of Ewing sarcoma, rhabdomyosarcoma and osteosarcoma, finding variable SPARC gene expression that correlated well with SPARC protein measured by immunoblotting. We revealed that the activity of the fusion gene chimera EWSR1-FLI1, the genetic driver of Ewing sarcoma, leads to lower expression of the gene SPARC in these tumors, likely due to enriched acetylation marks of the histone H3 lysine 27 at regions including the SPARC promoter and potential enhancers. Then, we used SPARC-edited Ewing sarcoma cells (A673 line) to demonstrate that SPARC knocked down (KD) cells accumulated significantly less amount of nab-paclitaxel in vitro than SPARC wild type (WT) cells. In vivo, SPARC KD and SPARC WT subcutaneous xenografts in mice achieved similar maximum intratumoral concentrations of nab-paclitaxel, though drug clearance from SPARC WT tumors was significantly slower. We confirmed such SPARC-mediated long-term intratumoral accumulation of nab-paclitaxel in Ewing sarcoma PDX with high expression of SPARC, which accumulated significantly more nab-paclitaxel than SPARC-low PDX. SPARC-high PDX responded better to nab-paclitaxel than SPARC-low tumors, although these results should be taken cautiously, given that the PDXs were established from different patients that could have specific determinants predisposing response to paclitaxel. In addition, SPARC KD Ewing sarcoma xenografts responded better to soluble docetaxel and paclitaxel than to nab-paclitaxel, while SPARC WT ones showed similar response to soluble and albumin-carried drugs. Overall, our results show that pediatric sarcomas expressing SPARC accumulate nab-paclitaxel for longer periods of time, which could have clinical implications for chemotherapy efficacy.
Topics: Albumins; Animals; Bone Neoplasms; Humans; Mice; Osteonectin; Osteosarcoma; Paclitaxel
PubMed: 34974029
DOI: 10.1016/j.jconrel.2021.12.035 -
Frontiers in Oncology 2022Over the last 20 years, granulocyte colony-stimulating factors (G-CSFs) have become the major therapeutic option for the treatment of patients with neutropenia. Most of... (Review)
Review
Over the last 20 years, granulocyte colony-stimulating factors (G-CSFs) have become the major therapeutic option for the treatment of patients with neutropenia. Most of the current G-CSFs require daily injections, which are inconvenient and expensive for patients. Increased understanding of G-CSFs' structure, expression, and mechanism of clearance has been very instrumental in the development of new generations of long-acting G-CSFs with improved efficacy. Several approaches to reducing G-CSF clearance conjugation techniques have been investigated. PEGylation, glycosylation, polysialylation, or conjugation with immunoglobulins or albumins have successfully increased G-CSFs' half-lives. Pegfilgrastim (Neulasta) has been successfully approved and marketed for the treatment of patients with neutropenia. The rapidly expanding market for G-CSFs has increased demand for G-CSF biosimilars. Therefore, the importance of this review is to highlight the principle, elimination's route, half-life, clearance, safety, benefits, and limitations of different strategies and techniques used to increase the half-life of biotherapeutic G-CSFs. Understanding these strategies will allow for a new treatment with more competitive manufacturing and lower unit costs compared with that of Neulasta.
PubMed: 36686781
DOI: 10.3389/fonc.2022.1026377 -
Pharmaceuticals (Basel, Switzerland) Jan 2023Zaltoprofen is a drug used for various pain and inflammatory diseases. Scientific and quantitative dosage regimen studies regarding its clinical application are scarce....
Zaltoprofen is a drug used for various pain and inflammatory diseases. Scientific and quantitative dosage regimen studies regarding its clinical application are scarce. This study aimed to discover effective covariates related to interindividual pharmacokinetic variability through population pharmacokinetic modeling for zaltoprofen and to explore dosage regimens. The bioequivalence results of healthy Korean males, biochemical analysis, and CYP2C9 genotyping information were utilized in modeling. The established model has been sufficiently verified through a bootstrap, goodness-of-fit, visual predictive check, and normalized prediction distribution error. External data sets derived from the literature were used for further model validation. The final model could be used to verify the dosage regimen through multiple exposure simulations according to the numerical change of the selected covariates. Zaltoprofen pharmacokinetics could be explained by a two-compartment with a first-order absorption model. Creatinine clearance (CrCL) and albumin were identified as effective covariates related to interindividual zaltoprofen pharmacokinetic variability, and they had positive and negative correlations with clearance (CL/F), respectively. The differences in pharmacokinetics between individuals according to CYP2C9 genetic polymorphisms (*1/*1 and *1/*3) were not significant or valid covariates. The model simulation confirmed that zaltoprofen pharmacokinetics could significantly differ as the CrCL and albumin levels changed within the normal range. Steady-state plasma exposure to zaltoprofen was significantly reduced in the group with CrCL and albumin levels of 130 mL/min and 3.5 g/dL, respectively, suggesting that dose adjustment may be necessary. This study is useful to guide precision medicine of zaltoprofen and provides scientific quantitative judgment data for its clinical applications.
PubMed: 37259312
DOI: 10.3390/ph16020161 -
Drug Metabolism and Disposition: the... Nov 2023Prediction of hepatic clearance of drugs (via uptake or metabolism) from in vitro systems continues to be problematic, particularly when plasma protein binding is high....
Exploring the Boundaries for In Vitro-In Vivo Extrapolation: Use of Isolated Rat Hepatocytes in Co-culture and Impact of Albumin Binding Properties in the Prediction of Clearance of Various Drug Types.
Prediction of hepatic clearance of drugs (via uptake or metabolism) from in vitro systems continues to be problematic, particularly when plasma protein binding is high. The following work explores simultaneous assessment of both clearance processes, focusing on a commercial hepatocyte-fibroblast co-culture system (HREL) over a 24-hour period using six probe drugs (ranging in metabolic and transporter clearance and low-to-high plasma protein binding). A rat hepatocyte co-culture assay was established using drug depletion (measuring both medium and total concentrations) and cell uptake kinetic analysis, both in the presence and absence of plasma protein (1% bovine serum albumin). Secretion of endogenous albumin was monitored as a marker of viability, and this reached 0.004% in incubations (at a rate similar to in vivo synthesis). Binding to stromal cells was substantial and required appropriate correction factors. Drug concentration-time courses were analyzed both by conventional methods and a mechanistic cell model prior to in vivo extrapolation. Clearance assayed by drug depletion in conventional suspended rat hepatocytes provided a benchmark to evaluate co-culture value. Addition of albumin appeared to improve predictions for some compounds (where fraction unbound in the medium is less than 0.1); however, for high-binding drugs, albumin significantly limited quantification and thus predictions. Overall, these results highlight ongoing challenges concerning in vitro hepatocyte system complexity and limitations of practical expediency. Considering this, more reliable measurement of hepatically cleared compounds seems possible through judicious use of available hepatocyte systems, including co-culture systems, as described herein; this would include those compounds with low metabolic turnover but high active uptake clearance. SIGNIFICANCE STATEMENT: Co-culture systems offer a more advanced tool than standard hepatocytes, with the ability to be cultured for longer periods of time, yet their potential as an in vitro tool has not been extensively assessed. We evaluate the strengths and limitations of the HREL system using six drugs representing various metabolic and transporter-mediated clearance pathways with various degrees of albumin binding. Studies in the presence/absence of albumin allow in vitro-in vivo extrapolation and a framework to maximize their utility.
PubMed: 37580106
DOI: 10.1124/dmd.123.001309 -
Scientific Reports Aug 2023Age-related cognitive decline is associated with dysfunctional lymphatic drainage of cerebrospinal fluid (CSF) through meningeal lymphatic vessels. In this study,...
Age-related cognitive decline is associated with dysfunctional lymphatic drainage of cerebrospinal fluid (CSF) through meningeal lymphatic vessels. In this study, intrathecal [Cu]Cu-albumin positron emission tomography (PET) was applied in mice to evaluate lymphatic drainage of CSF and its variation with age. [Cu]Cu-albumin PET was performed at multiple time points after intrathecal injection of [Cu]Cu-albumin at an infusion rate of 700 nl/min in adult and aged mice (15-25 months old). CSF clearance and paravertebral lymph nodes were quantified after injection and during the stationary phase. Stationary phase of the next day followed the initial perturbed state by injection of 6 ul (1/7 of total CSF volume) and CSF clearance half-time from the subarachnoid space was 93.4 ± 19.7 and 123.3 ± 15.6 min in adult and aged mice (p = 0.01), respectively. While the % injected dose of CSF space were higher, the activity of the paravertebral lymph nodes were lower in the aged mice on the next day. [Cu]Cu-albumin PET enabled us to quantify CSF-lymphatic drainage across all levels of brain spinal cords and to visualize and quantify lymph node activity due to CSF drainage. [Cu]Cu-albumin PET revealed the age-related decrease of the lymphatic drainage of CSF due to this decreased drainage from the subarachnoid space, especially during the stationary phase, in aged mice.
Topics: Mice; Animals; Lymphatic System; Lymphatic Vessels; Lymph Nodes; Glymphatic System; Positron-Emission Tomography; Cerebrospinal Fluid
PubMed: 37558700
DOI: 10.1038/s41598-023-39903-y -
International Journal of Molecular... Jan 2023Cadmium (Cd) is a toxic metal that accumulates in kidneys, especially in the proximal tubular epithelial cells, where virtually all proteins in the glomerular...
Cadmium (Cd) is a toxic metal that accumulates in kidneys, especially in the proximal tubular epithelial cells, where virtually all proteins in the glomerular ultrafiltrate are reabsorbed. Here, we analyzed archived data on the estimated glomerular filtration rate (eGFR) and excretion rates of Cd (E), total protein (E), albumin (E), β-microglobulin (E), and α1-microglobulin (E), which were recorded for residents of a Cd contamination area and a low-exposure control area of Thailand. Excretion of Cd and all proteins were normalized to creatinine clearance (C) as E/C and E/C to correct for differences among subjects in the number of surviving nephrons. Low eGFR was defined as eGFR ≤ 60 mL/min/1.73 m, while proteinuria was indicted by E/C ≥ 20 mg/L of filtrate. E/C varied directly with E/C (β = 0.263, < 0.001) and age (β = 0.252, < 0.001). In contrast, eGFR values were inversely associated with E/C (β = -0.266, < 0.001) and age (β = -0.558, < 0.001). At E/C > 8.28 ng/L of filtrate, the prevalence odds ratios for proteinuria and low eGFR were increased 4.6- and 5.1-fold, respectively ( < 0.001 for both parameters). Thus, the eGFR and tubular protein retrieval were both simultaneously diminished by Cd exposure. Of interest, E/C was more closely correlated with E/C ( = 0.507), E ( = 0.430), and E/C ( = 0.364) than with E/C ( = 0.152). These data suggest that Cd may differentially reduce the ability of tubular epithelial cells to reclaim proteins, resulting in preferential reabsorption of albumin.
Topics: Humans; Cadmium; Proteinuria; Kidney; Kidney Glomerulus; Glomerular Filtration Rate; beta 2-Microglobulin; Albumins; Creatinine
PubMed: 36768208
DOI: 10.3390/ijms24031893 -
Peptides Nov 2020Tumor cells overexpress a variety of receptors that are emerging targets in cancer chemotherapy. Radiolabeled peptides with high affinity and selectivity for these... (Review)
Review
Tumor cells overexpress a variety of receptors that are emerging targets in cancer chemotherapy. Radiolabeled peptides with high affinity and selectivity for these overexpressed receptors have been designed for both imaging and therapy purposes. Such peptides display advantages such as high selectivity for tumor cells, rapid tumor tissue penetration, and rapid clearance from non-target tissues and the circulation. However, the very short in vivo half-life of radiolabeled peptides, arising from enzymatic degradation and/or efficient clearance by the kidney, limits their accumulation in tumors. This review presents various strategies that have been applied to extend the half-life extension and improve the pharmacokinetic characteristics of radiolabeled peptides. These include amino acid substitution, modification of the peptide termini, dimerization and multimerization of the peptide, cyclization, conjugation with polymers, sugars and albumin and use of peptidase inhibitors.
Topics: Amino Acid Substitution; Animals; Cyclization; Diagnostic Imaging; Drug Stability; Half-Life; Humans; Isotope Labeling; Peptides; Protein Multimerization; Radiopharmaceuticals
PubMed: 32822772
DOI: 10.1016/j.peptides.2020.170385 -
The International Journal of Artificial... Sep 2023Besides standard medical therapy and critical care monitoring, extracorporeal liver support may provide a therapeutic option in patients with liver failure. However,...
BACKGROUND
Besides standard medical therapy and critical care monitoring, extracorporeal liver support may provide a therapeutic option in patients with liver failure. However, little is known about detoxification capabilities, efficacy, and efficiency among different devices.
METHODS
Retrospective single-center analysis of patients treated with extracorporeal albumin dialysis. Generalized Estimating Equations with robust variance estimator were used to account for repeated measurements of several cycles and devices per patient.
RESULTS
Between 2015 and 2021 = 341 cycles in = 96 patients were eligible for evaluation, thereof = 54 (15.8%) treatments with Molecular Adsorbent Recirculating System, = 64 (18.7%) with OpenAlbumin, = 167 (48.8%) Advanced Organ Support treatments, and = 56 (16.4%) using Single Pass Albumin Dialysis. Albumin dialysis resulted in significant bilirubin reduction without differences between the devices. However, ammonia levels only declined significantly in ADVOS and OPAL. First ECAD cycle was associated with highest percentage reduction in serum bilirubin. With the exception of SPAD all devices were able to remove the water-soluble substances creatinine and urea and stabilized metabolic dysfunction by increasing pH and negative base excess values. Platelets and fibrinogen levels frequently declined during treatment. Periprocedural bleeding and transfusion of red blood cells were common findings in these patients.
CONCLUSIONS
From this clinical perspective ADVOS and OPAL may provide higher reduction capabilities of liver solutes (i.e. bilirubin and ammonia) in comparison to MARS and SPAD. However, further prospective studies comparing the effectiveness of the devices to support liver impairment (i.e. bile acid clearance or albumin binding capacity) as well as markers of renal recovery are warranted.
Topics: Humans; Ammonia; Critical Illness; Prospective Studies; Retrospective Studies; Renal Dialysis; Liver Failure; Albumins; Bilirubin
PubMed: 37609875
DOI: 10.1177/03913988231191952 -
ACS Applied Bio Materials Jan 2021Nanoparticles find increasing applications in life science and biomedicine. The fate of nanoparticles in a biological system is determined by their protein corona, as...
Nanoparticles find increasing applications in life science and biomedicine. The fate of nanoparticles in a biological system is determined by their protein corona, as remodeling of their surface properties through protein adsorption triggers specific recognition such as cell uptake and immune system clearance and nonspecific processes such as aggregation and precipitation. The corona is a result of nanoparticle-protein and protein-protein interactions and is influenced by particle design. The state-of-the-art design of biomedical nanoparticles is the core-shell structure exemplified by superparamagnetic iron oxide nanoparticles (SPIONs) grafted with dense, well-hydrated polymer shells used for biomedical magnetic imaging and therapy. Densely grafted polymer chains form a polymer brush, yielding a highly repulsive barrier to the formation of a protein corona nonspecific particle-protein interactions. However, recent studies showed that the abundant blood serum protein albumin interacts with dense polymer brush-grafted SPIONs. Herein, we use isothermal titration calorimetry to characterize the nonspecific interactions between human serum albumin, human serum immunoglobulin G, human transferrin, and hen egg lysozyme with monodisperse poly(2-alkyl-2-oxazoline)-grafted SPIONs with different grafting densities and core sizes. These particles show similar protein interactions despite their different "stealth" capabilities in cell culture. The SPIONs resist attractive interactions with lysozymes and transferrins, but they both show a significant exothermic enthalpic and low exothermic entropic interaction with low stoichiometry for albumin and immunoglobulin G. Our results highlight that protein size, flexibility, and charge are important to predict protein corona formation on polymer brush-stabilized nanoparticles.
Topics: Adsorption; Ferric Compounds; Humans; Immunoglobulin G; Magnetite Nanoparticles; Opsonin Proteins; Polyamines; Polymers; Protein Corona; Serum Albumin; Thermodynamics
PubMed: 33490885
DOI: 10.1021/acsabm.0c01355