-
Molecules (Basel, Switzerland) Feb 2022The PD-1/PD-L1 pathway blockade can generate a good clinical response by reducing immunosuppression and provoking durable antitumor immunity. In addition to antibodies,...
The PD-1/PD-L1 pathway blockade can generate a good clinical response by reducing immunosuppression and provoking durable antitumor immunity. In addition to antibodies, aptamers can also block the interaction between PD-1 and PD-L1. For the in vivo application, however, free aptamers are usually too small in size and quickly removed from blood via glomerular filtration. To avoid renal clearance of aptamer, we conjugated the PD-L1 aptamer to albumin to form a larger complex (BSA-Apt) and evaluated whether BSA-Apt would enhance the in vivo antitumor efficacy. The PD-L1 aptamer was thiol-modified and conjugated to the amino group of BSA via a SMCC linker. The average size of BSA-Apt was 11.65 nm, which was above the threshold for renal clearance. Functionally, BSA-Apt retained the capability of the PD-L1 aptamer to bind with PDL1-expressing tumor cells. Moreover, both the free aptamer and BSA-Apt augmented the PBMC-induced antitumor cytotoxicity in vitro. Furthermore, BSA-Apt generated a significantly stronger antitumor efficacy than the free PD-L1 aptamer in vivo without raising systemic toxicity. The results indicate that conjugating the PD-L1 aptamer to albumin may serve as a promising strategy to improve the in vivo functionality of the aptamer and that BSA-Apt may have application potential in cancer immunotherapy.
Topics: B7-H1 Antigen
PubMed: 35268583
DOI: 10.3390/molecules27051482 -
Pharmaceuticals (Basel, Switzerland) Feb 2022Integrin αβ promotes migration and invasion of cancer cells, and its overexpression often correlates with poor survival. Therefore, targeting αβ with radioactive...
Integrin αβ promotes migration and invasion of cancer cells, and its overexpression often correlates with poor survival. Therefore, targeting αβ with radioactive peptides would be beneficial for cancer imaging and therapy. Previous studies have successfully developed radiotracers based on the peptide A20FMDV2 that showed good binding specificity for αβ. However, one concern of these αβ integrin-targeting probes is that their rapid blood clearance and low tumor uptake would preclude them from being used for therapeutic purposes. In this study, albumin binders were used to increase tumor uptake for therapeutic applications while the non-albumin peptide was evaluated as a potential positron emission tomography (PET) imaging agent. All peptides used the DOTA chelator for radiolabeling with either Ga for imaging or Lu for therapy. PET imaging with [Ga]Ga-DOTA-(PEG28)-A20FMDV2 revealed specific tumor uptake in αβ-positive tumors. Albumin-binding peptides EB-DOTA-(PEG28)-A20FMDV2 and IBA-DOTA-(PEG28)-A20FMDV2 were radiolabeled with Lu. Biodistribution studies in normal mice showed longer blood circulation times for the albumin binding peptides compared to the non-albumin peptide. Therapy studies in mice demonstrated that both Lu-labeled albumin binding peptides resulted in significant tumor growth inhibition. We believe these are the first studies to demonstrate the therapeutic efficacy of a radiolabeled peptide targeting an αβ-positive tumor.
PubMed: 35215341
DOI: 10.3390/ph15020229 -
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 -
Frontiers in Physiology 2020Chronic kidney disease (CKD) can have an insidious onset because there is a gradual decline in nephron number throughout life. There may be no overt symptoms of renal... (Review)
Review
Chronic kidney disease (CKD) can have an insidious onset because there is a gradual decline in nephron number throughout life. There may be no overt symptoms of renal dysfunction until about two thirds or more of the nephrons have been destroyed and glomerular filtration rate (GFR) falls to below 25% of normal (often in mid-late life) (Martinez-Maldonaldo et al., 1992). Once End Stage Renal Disease (ESRD) has been reached, survival depends on renal replacement therapy (RRT). CKD causes hypertension and cardiovascular disease; and hypertension causes CKD. Albuminuria is also a risk factor for cardiovascular disease. The age of onset of CKD is partly determined during fetal life. This review describes the mechanisms underlying the development of CKD in adult life that results from abnormal renal development caused by an adverse intrauterine environment. The basis of this form of CKD is thought to be mainly due to a reduction in the number of nephrons formed which impacts on the age dependent decline in glomerular function. Factors that affect the risk of reduced nephron formation during intrauterine life are discussed and include maternal nutrition (malnutrition and obesity, micronutrients), smoking and alcohol, use of drugs that block the maternal renin-angiotensin system, glucocorticoid excess and maternal renal dysfunction and prematurity. Since CKD, hypertension and cardiovascular disease add to the disease burden in the community we recommend that kidney size at birth should be recorded using ultrasound and those individuals who are born premature or who have small kidneys at this time should be monitored regularly by determining GFR and albumin:creatinine clearance ratio. Furthermore, public health measures aimed at limiting the prevalence of obesity and diabetes mellitus as well as providing advice on limiting the amount of protein ingested during a single meal, because they are all associated with increased glomerular hyperfiltration and subsequent glomerulosclerosis would be beneficial.
PubMed: 32765290
DOI: 10.3389/fphys.2020.00757 -
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 -
Balkan Medical Journal Oct 2023Identifying mortality risk in critically ill children is central to diagnostic and treatment practices. For this purpose, scoring systems, such as the Pediatric Index of...
BACKGROUND
Identifying mortality risk in critically ill children is central to diagnostic and treatment practices. For this purpose, scoring systems, such as the Pediatric Index of Mortality 3 (PIM 3), have been proposed; however, the role of biochemical markers, such as albumin-corrected anion gap (cAG) and lactate clearance (LC), in predicting mortality in pediatric intensive care unit (PICU) patients is yet to be explored.
AIMS
To evaluate the predictive value of the cAG and LC for mortality in pediatric patients admitted to a PICU.
STUDY DESIGN
Retrospective single-center cohort study.
METHODS
Clinical and laboratory data from the time of PICU admission were collected, and patients were classified into based on their 0- and 6-hour of admission lactate levels into an LC(+) group (patients with normal or decreasing lactate levels) or an LC(−) group (increasing lactate levels). LC and cAG levels were compared using the Mann-Whitney U test and Student’s t-test, respectively. Additionally, multiple logistic regression analysis was performed to evaluate the effect of LC and cAG on mortality.
RESULTS
We included 825 patients in the study; the mortality rate was 8.6%. The absence of LC [adjusted odds ratio (AOR) =4.735; 95% confidence interval (CI): 2.163-10.367; < 0.001], cAG (AOR =1.064; 95% CI: 1.010-1.122; = 0.019) and PIM 3 (AOR = 1.871; 95% CI: 1.553-2.254; < 0.001) were independent risk factors for mortality. Using the receiver operating characteristic curve analysis of PIM 3 as a predictor of mortality, area under the curve values of 0.832 (95% CI: 0.805-0.857; < 0.001) for the original score and 0.858 for a revised PIM 3 score (based on the β coefficients obtained for cAG and LC; 95% CI 0.832-0.881; < 0.001) were obtained, which was significantly different ( = 0.027).
CONCLUSION
A cAG value > 18 at the time of PICU admission high lactate levels which do not decrease within 6 hours of hospitalization are associated with an increased risk of mortality. The revised PIM 3 score, which includes cAG and LC, is a better predictor of mortality than the classical PIM 3 score.
Topics: Child; Humans; Acid-Base Equilibrium; Lactic Acid; Cohort Studies; Retrospective Studies; Hospital Mortality; Albumins; Critical Care
PubMed: 37815408
DOI: 10.4274/balkanmedj.galenos.2023.2023-7-87 -
Antimicrobial Agents and Chemotherapy Nov 2022Several pathophysiological changes can alter meropenem pharmacokinetics in critically ill patients, thereby increasing the risk of subtherapeutic concentrations and...
Several pathophysiological changes can alter meropenem pharmacokinetics in critically ill patients, thereby increasing the risk of subtherapeutic concentrations and affecting therapeutic outcomes. This study aimed to characterize the population pharmacokinetic (PPK) parameters of meropenem, evaluate the relationship between the pharmacokinetic/pharmacodynamic index of meropenem and treatment outcomes, and evaluate the different dosage regimens that can achieve 40%, 75%, and 100% of the dosing interval for which the free plasma concentrations remain above the MIC of the pathogens () targets. Critically ill adult patients treated with meropenem were recruited for this study. Five blood samples were collected from each patient. PPK models were developed using a nonlinear mixed-effects modeling approach, and the final model was subsequently used for Monte Carlo simulations to determine the optimal dosage regimens. A total of 247 concentrations from 52 patients were available for analysis. The two-compartment model with linear elimination adequately described the data. The mean PPK parameters were clearance (CL) of 4.8 L/h, central volume of distribution (V) of 11.4 L, peripheral volume of distribution (V) of 14.6 L, and intercompartment clearance of 10.5 L/h. Creatinine clearance was a significant covariate affecting CL, while serum albumin level and shock status were factors influencing V and V, respectively. Although 75% of the drug-resistant infection patients had values of >40%, approximately 83% of them did not survive the infection. Therefore, 40% might not be sufficient for critically ill patients, and a higher target, such as 75 to 100% , should be considered for optimizing therapy. A 75% could be reached using approved doses administered via a 3-h infusion.
Topics: Humans; Adult; Meropenem; Critical Illness; Anti-Bacterial Agents; Monte Carlo Method; Microbial Sensitivity Tests
PubMed: 36226944
DOI: 10.1128/aac.00845-22 -
Pharmaceutics Nov 2022Nanoparticles (NPs) are versatile candidates for nanomedical applications due to their unique physicochemical properties. However, their clinical applicability is... (Review)
Review
Nanoparticles (NPs) are versatile candidates for nanomedical applications due to their unique physicochemical properties. However, their clinical applicability is hindered by their undesirable recognition by the immune system and the consequent immunotoxicity, as well as their rapid clearance in vivo. After injection, NPs are usually covered with layers of proteins, called protein coronas (PCs), which alter their identity, biodistribution, half-life, and efficacy. Therefore, the characterization of the PC is for in predicting the fate of NPs in vivo. The aim of this review was to summarize the state of the art regarding the intrinsic factors closely related to the NP structure, and extrinsic factors that govern PC formation in vitro. In addition, well-known opsonins, including complement, immunoglobulins, fibrinogen, and dysopsonins, such as histidine-rich glycoprotein, apolipoproteins, and albumin, are described in relation to their role in NP detection by immune cells. Particular emphasis is placed on their role in mediating the interaction of NPs with innate and adaptive immune cells. Finally, strategies to reduce PC formation are discussed in detail.
PubMed: 36559099
DOI: 10.3390/pharmaceutics14122605 -
Clinical Pharmacology in Drug... Jan 2020Dalbavancin is indicated for the treatment of acute bacterial skin and skin structure infections caused by susceptible gram-positive microorganisms. This analysis... (Randomized Controlled Trial)
Randomized Controlled Trial
Dalbavancin is indicated for the treatment of acute bacterial skin and skin structure infections caused by susceptible gram-positive microorganisms. This analysis represents the update of the population pharmacokinetics (popPK) modeling and target attainment simulations performed with data from the single-dose safety and efficacy study and an unrelated but substantial revision of the preclinical pharmacokinetic/pharmacodynamic target (fAUC/MIC, free area under concentration-time curve/minimum inhibitory concentration ratio). A 3-compartment distribution model with first-order elimination provided an appropriate fit, with typical dalbavancin clearance of 0.05 L/h and total volume of distribution of ∼15 L. Impact of intrinsic factors was modest, although statistically significant (P < .05) relationships with total clearance were found for the following covariates: creatinine clearance, weight, and albumin - dose adjustment was only indicated for severe renal impairment. Under the new nonclinical target, simulations of the popPK model projected that >99% of subjects would achieve the nonclinical target at MIC values up to and including 2 mg/L.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Area Under Curve; Bacteria; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Models, Biological; Teicoplanin; Young Adult
PubMed: 31087630
DOI: 10.1002/cpdd.695 -
Clinical Pharmacokinetics Mar 2020Risankizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody developed and approved for the treatment of moderate-to-severe plaque psoriasis at a dose of... (Review)
Review
Risankizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody developed and approved for the treatment of moderate-to-severe plaque psoriasis at a dose of 150 mg administered subcutaneously at weeks 0 and 4, and every 12 weeks thereafter. Ongoing trials are investigating the use of risankizumab in other inflammatory autoimmune diseases. Risankizumab exhibits linear pharmacokinetics when administered intravenously (0.01 mg/kg-1200 mg) or subcutaneously (0.25 mg/kg-300 mg), with a long terminal half-life of approximately 28 days. Following subcutaneous administration, peak plasma concentration was reached approximately 3-14 days after dosing, with an estimated bioavailability of 89%. Population pharmacokinetic analyses identified bodyweight, high titers of antidrug antibodies occurring in < 2% of evaluated subjects, baseline serum albumin, baseline high-sensitivity C-reactive protein, and baseline serum creatinine to be statistically correlated with risankizumab clearance, but none of them had a clinically meaningful impact on risankizumab efficacy in psoriasis patients following the clinical dosing regimen. Exposure-response analyses in psoriasis patients demonstrated that the maximum efficacy was achieved with the clinically approved regimen and there was no apparent correlation between risankizumab exposure and safety. A dedicated drug interaction cocktail study in patients with psoriasis demonstrated a lack of therapeutic protein-drug interaction potentials for risankizumab and various cytochrome P450 substrates. In this article, we review the clinical pharmacology data available to date for risankizumab, which supported the clinical development program and ultimately regulatory approvals for risankizumab in the treatment of patients with moderate-to-severe plaque psoriasis.
Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Body Weight; C-Reactive Protein; Clinical Trials as Topic; Creatinine; Drug Interactions; Female; Half-Life; Humans; Immunoglobulin G; Injections, Subcutaneous; Male; Middle Aged; Psoriasis; Safety; Serum Albumin; Severity of Illness Index; Treatment Outcome
PubMed: 31758502
DOI: 10.1007/s40262-019-00842-5