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Start Over Author "Alt K" Publisher american chemical society
6 results on '"Alt K"'

1. Template-Assisted Antibody Assembly: A Versatile Approach for Engineering Functional Antibody Nanoparticles

Author

Hu, Y, Li, J, Ju, Y, Houston, ZH, Fletcher, NL, De Rose, R, Fernandes, S, Hagemeyer, CE, Alt, K, Thurecht, KJ, Cortez-Jugo, C, Caruso, F, Hu, Y, Li, J, Ju, Y, Houston, ZH, Fletcher, NL, De Rose, R, Fernandes, S, Hagemeyer, CE, Alt, K, Thurecht, KJ, Cortez-Jugo, C, and Caruso, F

Abstract

The clinical success of monoclonal antibody therapy has inspired research in understanding the fundamental molecular basis of antibody-antigen interactions and the engineering of antibodies and antibody assemblies with enhanced or novel properties. In particular, colloidally stable antibody assemblies can enhance dosing strategies and enable combined therapy of a mixture of antibodies or biologics. Herein, nanoassemblies of therapeutic antibodies were fabricated with controlled physicochemical properties using a versatile template-mediated assembly method. The antibody nanoparticles (AbNPs) cross-linked with poly(ethylene glycol)-N-hydroxysuccinimide were monodispersed, with particle diameters consistent with the template size (250 nm). When assembled using Herceptin or Kadcyla as a model antibody and antibody-drug conjugate, respectively, the nanoparticles retained the selectivity of the monoclonal antibody and recognized >98% of cells expressing the target receptors on cell membranes. Unlike the free Herceptin antibody, which was predominantly localized at the surface, the AbNPs were internalized via receptor-mediated endocytosis, presenting opportunities for delivering monoclonal antibodies intracellularly at high concentrations and/or against intracellular targets. With the vast array of antibodies that could be applied and different cross-linking chemistries possible, the reported antibody assembly strategy provides a versatile platform for the development of antibody assemblies for therapeutic, diagnostic, and clinical applications.

Published
2022

2. Ligand-Functionalized Poly(ethylene glycol) Particles for Tumor Targeting and Intracellular Uptake.

Author

Cui, J, Alt, K, Ju, Y, Gunawan, ST, Braunger, JA, Wang, T-Y, Dai, Y, Dai, Q, Richardson, JJ, Guo, J, Björnmalm, M, Hagemeyer, CE, Caruso, F, Cui, J, Alt, K, Ju, Y, Gunawan, ST, Braunger, JA, Wang, T-Y, Dai, Y, Dai, Q, Richardson, JJ, Guo, J, Björnmalm, M, Hagemeyer, CE, and Caruso, F

Abstract

Drug carriers typically require both stealth and targeting properties to minimize nonspecific interactions with healthy cells and increase specific interaction with diseased cells. Herein, the assembly of targeted poly(ethylene glycol) (PEG) particles functionalized with cyclic peptides containing Arg-Gly-Asp (RGD) (ligand) using a mesoporous silica templating method is reported. The influence of PEG molecular weight, ligand-to-PEG molecule ratio, and particle size on cancer cell targeting to balance stealth and targeting of the engineered PEG particles is investigated. RGD-functionalized PEG particles (PEG-RGD particles) efficiently target U-87 MG cancer cells under static and flow conditions in vitro, whereas PEG and cyclic peptides containing Arg-Asp-Gly (RDG)-functionalized PEG (PEG-RDG) particles display negligible interaction with the same cells. Increasing the ligand-to-PEG molecule ratio improves cell targeting. In addition, the targeted PEG-RGD particles improve cell uptake via receptor-mediated endocytosis, which is desirable for intracellular drug delivery. The PEG-RGD particles show improved tumor targeting (14% ID g-1) when compared with the PEG (3% ID g-1) and PEG-RDG (7% ID g-1) particles in vivo, although the PEG-RGD particles show comparatively higher spleen and liver accumulation. The targeted PEG particles represent a platform for developing particles aimed at balancing nonspecific and specific interactions in biological systems.

Published
2019

3. Ligand-Functionalized Poly(ethylene glycol) Particles for Tumor Targeting and Intracellular Uptake.

Author

Cui J, Alt K, Ju Y, Gunawan ST, Braunger JA, Wang TY, Dai Y, Dai Q, Richardson JJ, Guo J, Björnmalm M, Hagemeyer CE, and Caruso F

Subjects
Animals, Cell Line, Tumor, Cytoplasm drug effects, Endocytosis drug effects, Humans, Ligands, Oligopeptides chemistry, Polyethylene Glycols chemistry, Signal Transduction drug effects, Silicon Dioxide chemistry, Silicon Dioxide pharmacology, Surface Properties, Drug Delivery Systems, Neoplasms drug therapy, Oligopeptides pharmacology, Polyethylene Glycols pharmacology
Abstract

Drug carriers typically require both stealth and targeting properties to minimize nonspecific interactions with healthy cells and increase specific interaction with diseased cells. Herein, the assembly of targeted poly(ethylene glycol) (PEG) particles functionalized with cyclic peptides containing Arg-Gly-Asp (RGD) (ligand) using a mesoporous silica templating method is reported. The influence of PEG molecular weight, ligand-to-PEG molecule ratio, and particle size on cancer cell targeting to balance stealth and targeting of the engineered PEG particles is investigated. RGD-functionalized PEG particles (PEG-RGD particles) efficiently target U-87 MG cancer cells under static and flow conditions in vitro, whereas PEG and cyclic peptides containing Arg-Asp-Gly (RDG)-functionalized PEG (PEG-RDG) particles display negligible interaction with the same cells. Increasing the ligand-to-PEG molecule ratio improves cell targeting. In addition, the targeted PEG-RGD particles improve cell uptake via receptor-mediated endocytosis, which is desirable for intracellular drug delivery. The PEG-RGD particles show improved tumor targeting (14% ID g -1 ) when compared with the PEG (3% ID g -1 ) and PEG-RDG (7% ID g -1 ) particles in vivo, although the PEG-RGD particles show comparatively higher spleen and liver accumulation. The targeted PEG particles represent a platform for developing particles aimed at balancing nonspecific and specific interactions in biological systems.

Published
2019
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4. Engineering poly(ethylene glycol) particles for improved biodistribution.

Author

Cui J, De Rose R, Alt K, Alcantara S, Paterson BM, Liang K, Hu M, Richardson JJ, Yan Y, Jeffery CM, Price RI, Peter K, Hagemeyer CE, Donnelly PS, Kent SJ, and Caruso F

Subjects
Animals, Cell Line, Granulocytes metabolism, Humans, Mice, Molecular Weight, Monocytes metabolism, Particle Size, Polyethylene Glycols metabolism, Silicon Dioxide chemistry, Structure-Activity Relationship, Tissue Distribution, Engineering, Polyethylene Glycols chemistry, Polyethylene Glycols pharmacokinetics
Abstract

We report the engineering of poly(ethylene glycol) (PEG) hydrogel particles using a mesoporous silica (MS) templating method via tuning the PEG molecular weight, particle size, and the presence or absence of the template and investigate the cell association and biodistribution of these particles. An ex vivo assay based on human whole blood that is more sensitive and relevant than traditional cell-line based assays for predicting in vivo circulation behavior is introduced. The association of MS@PEG particles (template present) with granulocytes and monocytes is higher compared with PEG particles (template absent). Increasing the PEG molecular weight (from 10 to 40 kDa) or decreasing the PEG particle size (from 1400 to 150 nm) reduces phagocytic blood cell association of the PEG particles. Mice biodistribution studies show that the PEG particles exhibit extended circulation times (>12 h) compared with the MS@PEG particles and that the retention of smaller PEG particles (150 nm) in blood, when compared with larger PEG particles (>400 nm), is increased at least 4-fold at 12 h after injection. Our findings highlight the influence of unique aspects of polymer hydrogel particles on biological interactions. The reported PEG hydrogel particles represent a new class of polymer carriers with potential biomedical applications.

Published
2015
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5. Single-chain antibody conjugated to a cage amine chelator and labeled with positron-emitting copper-64 for diagnostic imaging of activated platelets.

Author

Alt K, Paterson BM, Ardipradja K, Schieber C, Buncic G, Lim B, Poniger SS, Jakoby B, Wang X, O'Keefe GJ, Tochon-Danguy HJ, Scott AM, Ackermann U, Peter K, Donnelly PS, and Hagemeyer CE

Subjects
Animals, Blood Platelets metabolism, Carotid Arteries physiopathology, Copper chemistry, Copper Radioisotopes chemistry, Diagnostic Imaging, Disease Models, Animal, Flow Cytometry, Heterocyclic Compounds, 1-Ring chemistry, Inflammation, Ligands, Magnetic Resonance Spectroscopy, Mice, Mice, Inbred BALB C, Platelet Activation, Radiopharmaceuticals, Thrombosis diagnosis, X-Ray Microtomography, Blood Platelets drug effects, Chelating Agents chemistry, Positron-Emission Tomography, Single-Chain Antibodies chemistry
Abstract

Imaging of activated platelets using an activation specific anti-GPIIb/IIIa integrin single-chain antibody (scFvanti-LIBS) conjugated to a positron emitting copper-64 complex of a cage amine sarcophagine chelator (MeCOSar) is reported. This tracer was compared in vitro to a (64)Cu(II) complex of the scFv conjugated to another commonly used macrocycle, DOTA. The scFvanti-LIBS-MeCOSar conjugate was radiolabeled with (64)Cu(II) rapidly under mild conditions and with higher specific activity than scFvanti-LIBS-DOTA. The utility of scFvanti-LIBS-MeCOSar as a diagnostic agent was assessed in vivo in a mouse model of acute thrombosis. The uptake of scFvanti-LIBS-(64)CuMeCOSar in the injured vessel was significantly higher than the noninjured vessel. Positron emission tomography (PET) was used to show accumulation of scFvanti-LIBS-(64)CuMeCOSar with high and specific uptake in the injured vessel. ScFvanti-LIBS-(64)CuMeCOSar is an excellent tool for highly sensitive in vivo detection of activated platelets in PET and has the potential to be used for early diagnosis of acute thrombotic events.

Published
2014
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6. Degradation of 14 C-labeled Diazinon in the rat.

Author

Mücke W, Alt KO, and Esser HO

Subjects
Animals, Carbon Dioxide metabolism, Carbon Isotopes, Cholinesterase Inhibitors pharmacology, Feces analysis, Female, Hydrolysis, Insecticides toxicity, Lethal Dose 50, Male, Organothiophosphorus Compounds toxicity, Oxidation-Reduction, Pyrimidines metabolism, Pyrimidines toxicity, Rats, Urine analysis, Insecticides metabolism, Organothiophosphorus Compounds metabolism
Published
1970
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