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Dive into the research topics where Jacob W Myerson is active.

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Featured researches published by Jacob W Myerson.


Magnetic Resonance in Medicine | 2008

Gadolinium-modulated 19F signals from perfluorocarbon nanoparticles as a new strategy for molecular imaging.

Anne M. Neubauer; Jacob W Myerson; Shelton D. Caruthers; Franklin D. Hockett; Patrick M. Winter; Junjie Chen; Patrick J. Gaffney; J. David Robertson; Gregory M. Lanza; Samuel A. Wickline

Recent advances in the design of fluorinated nanoparticles for molecular magnetic resonance imaging (MRI) have enabled specific detection of 19F nuclei, providing unique and quantifiable spectral signatures. However, a pressing need for signal enhancement exists because the total 19F in imaging voxels is often limited. By directly incorporating a relaxation agent, gadolinium (Gd), into the lipid monolayer that surrounds the perfluorocarbon (PFC), a marked augmentation of the 19F signal from 200‐nm nanoparticles was achieved. This design increases the magnetic relaxation rate of the 19F nuclei fourfold at 1.5 T and effects a 125% increase in signal—an effect that is maintained when they are targeted to human plasma clots. By varying the surface concentration of Gd, the relaxation effect can be quantitatively modulated to tailor particle properties. This novel strategy dramatically improves the sensitivity and range of 19F MRI/MRS and forms the basis for designing contrast agents capable of sensing their surface chemistry. Magn Reson Med 60:1066–1072, 2008.


Journal of Thrombosis and Haemostasis | 2011

Thrombin‐inhibiting perfluorocarbon nanoparticles provide a novel strategy for the treatment and magnetic resonance imaging of acute thrombosis

Jacob W Myerson; Li He; Gregory M. Lanza; Douglas M. Tollefsen; Samuel A. Wickline

Summary.  Background: As a regulator of the penultimate step in the coagulation cascade, thrombin represents a principal target of direct and specific anticoagulants. Objective: A potent thrombin inhibitor complexed with a colloidal nanoparticle was devised as a first‐in‐class anticoagulant with prolonged and highly localized therapeutic impact conferred by its multivalent thrombin‐absorbing particle surface. Methods: PPACK (Phe[D]‐Pro‐Arg‐Chloromethylketone) was secured covalently to the surface of perfluorocarbon‐core nanoparticle structures. PPACK and PPACK nanoparticle inhibition of thrombin were assessed in vitro via thrombin activity against a chromogenic substrate. In vivo antithrombotic activity of PPACK, heparin, non‐functionalized nanoparticles and PPACK nanoparticles was assessed through intravenous (i.v.) administration prior to acute photochemical injury of the common carotid artery. Perfluorocarbon particle retention in extracted carotid arteries from injured mice was assessed via 19F magnetic resonance spectroscopy (MRS) and imaging (MRI) at 11.7 T. Activated partial thromboplastin time (APTT) measurements determined the systemic effects of the PPACK nanoparticles at various times after injection. Results: An optical assay verified that PPACK nanoparticles exceeded PPACK’s intrinsic activity against thrombin. Application of an in vivo acute arterial thrombosis model demonstrated that PPACK nanoparticles outperformed both heparin (P = 0.001) and uncomplexed PPACK (P = 0.0006) in inhibiting thrombosis. 19F MRS confirmed that PPACK nanoparticles specifically bound to sites of acute thrombotic injury. APTT normalized within 20 min of PPACK nanoparticles injection. Conclusions: PPACK nanoparticles present thrombin‐inhibiting surfaces at sites of acutely forming thrombi that continue to manifest local clot inhibition even as systemic effects rapidly diminish and thus represent a new platform for localized control of acute thrombosis.


The FASEB Journal | 2013

Programmable nanoparticle functionalization for in vivo targeting

Hua Pan; Jacob W Myerson; Lingzhi Hu; Jon N. Marsh; Kirk K. Hou; Michael J. Scott; John S. Allen; Grace Hu; Susana San Roman; Gregory M. Lanza; Robert D. Schreiber; Paul H. Schlesinger; Samuel A. Wickline

The emerging demand for programmable functionalization of existing base nanocarriers necessitates development of an efficient approach for cargo loading that avoids nanoparticle redesign for each individual application. Herein, we demonstrate in vivo a postformulation strategy for lipidic nanocarrier functionalization with the use of a linker peptide, which rapidly and stably integrates cargos into lipidic membranes of nanocarriers after simple mixing through a self‐assembling process. We exemplified this strategy by generating a VCAM‐1‐targeted perfluorocarbon nanoparticle for in vivo targeting in atherosclerosis (ApoE‐deficient) and breast cancer (STAT‐1‐deficient) models. In the atherosclerotic model, a 4.1‐fold augmentation in binding to affected aortas was observed for targeted vs. nontargeted nanoparticles (P<0.0298). Likewise, in the breast cancer model, a 4.9‐fold increase in the nanoparticle signal from tumor vasculature was observed for targeted vs. nontargeted nanoparticles (P<0.0216). In each case, the nanoparticle was registered with fluorine (19F) magnetic resonance spectroscopy of the nanoparticle perfluorocarbon core, yielding a quantitative estimate of the number of tissue‐bound nanoparticles. Because other common nanocarriers with lipid coatings (e.g., liposomes, micelles, etc.) can employ this strategy, this peptide linker postformulation approach is applicable to more than half of the available nanosystems currently in clinical trials or clinical uses.—Pan, H., Myerson, J. W., Hu, L., Marsh, J. N., Hou K., Scott, M. J., Allen, J. S., Hu, G., San Roman, S., Lanza, G. M., Schreiber, R. D., Schlesinger, P. H., Wickline, S. A. Programmable nanoparticle functionalization for in vivo targeting. FASEB J. 27, 255–264 (2013). www.fasebj.org


The FASEB Journal | 2014

Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function

Kristin Bibee; Ya-Jian Cheng; James Kain Ching; Jon N. Marsh; Allison J. Li; Richard M. Keeling; Anne M. Connolly; Paul T. Golumbek; Jacob W Myerson; Grace Hu; Junjie Chen; William D. Shannon; Gregory M. Lanza; Conrad C. Weihl; Samuel A. Wickline

Duchenne muscular dystrophy in boys progresses rapidly to severe impairment of muscle function and death in the second or third decade of life. Current supportive therapy with corticosteroids results in a modest increase in strength as a consequence of a general reduction in inflammation, albeit with potential untoward long‐term side effects and ultimate failure of the agent to maintain strength. Here, we demonstrate that alternative approaches that rescue defective autophagy in mdx mice, a model of Duchenne muscular dystrophy, with the use of rapamycin‐loaded nanoparticles induce a reproducible increase in both skeletal muscle strength and cardiac contractile performance that is not achievable with conventional oral rapamycin, even in pharmacological doses. This increase in physical performance occurs in both young and adult mice, and, surprisingly, even in aged wild‐type mice, which sets the stage for consideration of systemic therapies to facilitate improved cell function by autophagic disposal of toxic byproducts of cell death and regeneration.—Bibee, K. P., Cheng, Y.‐J., Ching, J. K., Marsh, J. N., Li, A. J., Keeling, R. M., Connolly, A. M., Golumbek, P. T., Myerson, J. W., Hu, G., Chen, J., Shannon, W. D., Lanza, G. M., Weihl, C. C., Wickline, S. A. Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function. FASEB J. 28, 2047–2061 (2014). www.fasebj.org


The FASEB Journal | 2010

Lipid membrane editing with peptide cargo linkers in cells and synthetic nanostructures

Hua Pan; Jacob W Myerson; Olena Ivashyna; Neelesh R. Soman; Jon N. Marsh; Joshua L. Hood; Gregory M. Lanza; Paul H. Schlesinger; Samuel A. Wickline

Current strategies for deploying synthetic nanocarriers involve the creation of agents that incorporate targeting ligands, imaging agents, and/or therapeutic drugs into particles as an integral part of the formulation process. Here we report the development of an amphipathic peptide linker that enables postformulation editing of payloads without the need for reformulation to achieve multiplexing capability for lipidic nanocarriers. To exemplify the flexibility of this peptide linker strategy, 3 applications were demonstrated: converting nontargeted nanoparticles into targeting vehicles;adding cargo to preformulated targeted nanoparticles for in vivo site‐specific delivery;and labeling living cells for in vivo tracking. This strategy is expected to enhance the clinical application of molecular imaging and/or targeted therapeutic agents by offering extended flexibility for multiplexing targeting ligands and/or drug payloads that can be selected after base nanocarrier formulation.—Pan, H., Myerson, J. W., Ivashyna, O., Soman, N. R., Marsh, J. N., Hood, J. L., Lanza, G. M., Schlesinger, P. H., Wickline, S. A.. Lipid membrane editing with peptide cargo linkers in cells and synthetic nanostructures. FASEB J. 24, 2928–2937 (2010). www.fasebj.org


PLOS ONE | 2011

Quantifying the Evolution of Vascular Barrier Disruption in Advanced Atherosclerosis with Semipermeant Nanoparticle Contrast Agents

Huiying Zhang; Lei Zhang; Jacob W Myerson; Kristin Bibee; Michael J. Scott; John S. Allen; Gregorio A. Sicard; Gregory M. Lanza; Samuel A. Wickline

Rationale Acute atherothrombotic occlusion in heart attack and stroke implies disruption of the vascular endothelial barrier that exposes a highly procoagulant intimal milieu. However, the evolution, severity, and pathophysiological consequences of vascular barrier damage in atherosclerotic plaque remain unknown, in part because quantifiable methods and experimental models are lacking for its in vivo assessment. Objective To develop quantitative nondestructive methodologies and models for detecting vascular barrier disruption in advanced plaques. Methods and Results Sustained hypercholesterolemia in New Zealand White (NZW) rabbits for >7–14 months engendered endothelial barrier disruption that was evident from massive and rapid passive penetration and intimal trapping of perfluorocarbon-core nanoparticles (PFC-NP: ∼250 nm diameter) after in vivo circulation for as little as 1 hour. Only older plaques (>7 mo), but not younger plaques (<3 mo) demonstrated the marked enhancement of endothelial permeability to these particles. Electron microscopy revealed a complex of subintimal spongiform channels associated with endothelial apoptosis, superficial erosions, and surface-penetrating cholesterol crystals. Fluorine (19F) magnetic resonance imaging and spectroscopy (MRI/MRS) enabled absolute quantification (in nanoMolar) of the passive permeation of PFC-NP into the disrupted vascular lesions by sensing the unique spectral signatures from the fluorine core of plaque-bound PFC-NP. Conclusions The application of semipermeant nanoparticles reveals the presence of profound barrier disruption in later stage plaques and focuses attention on the disrupted endothelium as a potential contributor to plaque vulnerability. The response to sustained high cholesterol levels yields a progressive deterioration of the vascular barrier that can be quantified with fluorine MRI/MRS of passively permeable nanostructures. The possibility of plaque classification based on the metric of endothelial permeability to nanoparticles is suggested.


Arteriosclerosis, Thrombosis, and Vascular Biology | 2016

Inhibition of Thrombin With PPACK-Nanoparticles Restores Disrupted Endothelial Barriers and Attenuates Thrombotic Risk in Experimental Atherosclerosis

Rohun U. Palekar; Andrew P. Jallouk; Jacob W Myerson; Hua Pan; Samuel A. Wickline

Objective— A role for thrombin in the pathogenesis of atherosclerosis has been suggested through clinical and experimental studies revealing a critical link between the coagulation system and inflammation. Although approved drugs for inhibition of thrombin and thrombin-related signaling have demonstrated efficacy, their clinical application to this end may be limited because of significant potential for bleeding side effects. Thus, we sought to implement a plaque-localizing nanoparticle-based approach to interdict thrombin-induced inflammation and hypercoagulability in atherosclerosis. Approach and Results— We deployed a novel magnetic resonance spectroscopic method to quantify the severity of endothelial damage for correlation with traditional metrics of vessel procoagulant activity after dye-laser injury in fat-fed apolipoprotein E-null mice. We demonstrate that a 1-month course of treatment with antithrombin nanoparticles carrying the potent thrombin inhibitor PPACK (D-phenylalanyl-L-prolyl-L-arginyl chloromethylketone) nanoparticle (1) reduces the expression and secretion of proinflammatory and procoagulant molecules, (2) diminishes plaque procoagulant activity without the need for systemic anticoagulation, (3) rapidly restores disrupted vascular endothelial barriers, and (4) retards plaque progression in lesion-prone areas. Conclusions— These observations illustrate the role of thrombin as a pleiotropic atherogenic molecule under conditions of hypercholesterolemia and suggest the utility of its inhibition with locally acting antithrombin nanoparticle therapeutics as a rapid-acting anti-inflammatory strategy in atherosclerosis to reduce thrombotic risk.


Nanotechnology | 2014

Thrombin-inhibiting nanoparticles rapidly constitute versatile and detectable anticlotting surfaces

Jacob W Myerson; Li He; John S. Allen; Todd A. Williams; Gregory M. Lanza; Douglas M. Tollefsen; Shelton D. Caruthers; Samuel A. Wickline

Restoring an antithrombotic surface to suppress ongoing thrombosis is an appealing strategy for treatment of acute cardiovascular disorders such as erosion of atherosclerotic plaque. An antithrombotic surface would present an alternative to systemic anticoagulation with attendant risks of bleeding. We have designed thrombin-targeted nanoparticles (NPs) that bind to sites of active clotting to extinguish local thrombin activity and inhibit platelet deposition while exhibiting only transient systemic anticoagulant effects. Perfluorocarbon nanoparticles (PFC NP) were functionalized with thrombin inhibitors (either D-phenylalanyl-L-prolyl-L-arginyl-chloromethyl ketone or bivalirudin) by covalent attachment of more than 15 000 inhibitors to each PFC NP. Fibrinopeptide A (FPA) ELISA demonstrated that thrombin-inhibiting NPs prevented cleavage of fibrinogen by both free and clot-bound thrombin. Magnetic resonance imaging (MRI) confirmed that a layer of thrombin-inhibiting NPs prevented growth of clots in vitro. Thrombin-inhibiting NPs were administered in vivo to C57BL6 mice subjected to laser injury of the carotid artery. NPs significantly delayed thrombotic occlusion of the artery, whereas an equivalent bolus of free inhibitor was ineffective. For thrombin-inhibiting NPs, only a short-lived (∼10 min) systemic effect on bleeding time was observed, despite prolonged clot inhibition. Imaging and quantification of in vivo antithrombotic NP layers was demonstrated by MRI of the PFC NP. (19)F MRI confirmed colocalization of particles with arterial thrombi, and quantitative (19)F spectroscopy demonstrated specific binding and retention of thrombin-inhibiting NPs in injured arteries. The ability to rapidly form and image a new antithrombotic surface in acute vascular syndromes while minimizing risks of bleeding would permit a safer method of passivating active lesions than current systemic anticoagulant regimes.


The FASEB Journal | 2015

Quantifying progression and regression of thrombotic risk in experimental atherosclerosis

Rohun U. Palekar; Andrew P. Jallouk; Matthew J. Goette; Junjie Chen; Jacob W Myerson; John S. Allen; Antonina Akk; Lihua Yang; Yizheng Tu; Mark J. Miller; Christine T. N. Pham; Samuel A. Wickline; Hua Pan

Currently, there are no generally applicable noninvasive methods for defining the relationship between atherosclerotic vascular damage and risk of focal thrombosis. Herein, we demonstrate methods to delineate the progression and regression of vascular damage in response to an atherogenic diet by quantifying the in vivo accumulation of semipermeable 200‐300 nm per‐fluorocarbon core nanoparticles (PFC‐NP) in ApoE null mouse plaques with [19F] magnetic resonance spectroscopy (MRS). Permeability to PFC‐NP remained minimal until 12 weeks on diet, then increased rapidly following 12 weeks, but regressed to baseline within 8 weeks after diet normalization. Markedly accelerated clotting (53.3% decrease in clotting time) was observed in carotid artery preparations of fat‐fed mice subjected to photochemical injury as defined by the time to flow cessation. For all mice on and off diet, an inverse linear relationship was observed between the permeability to PFC‐NP and accelerated thrombosis (P = 0.02). Translational feasibility for quantifying plaque permeability and vascular damage in vivo was demonstrated with clinical 3 T MRI of PFC‐NP accumulating in plaques of atherosclerotic rabbits. These observations suggest that excessive permeability to PFC‐NP may indicate prothrombotic risk in damaged atherosclerotic vasculature, which resolves within weeks after dietary therapy.—Palekar, R. U., Jallouk, A. P., Goette, M. J., Chen, J., Myerson, J. W., Allen, J. S., Akk, A., Yang, L., Tu, Y., Miller, M. J., Pham, C. T. N., Wickline, S. A., Pan, H. Quantifying progression and regression of thrombotic risk in experimental atherosclerosis. FASEB J. 29, 3100‐3109 (2015). www.fasebj.org


Journal of Cardiovascular Magnetic Resonance | 2014

Atherosclerosis endothelial activation quantification in vivo with fluorine magnetic resonance imaging and spectroscopy

Hua Pan; Jacob W Myerson; Xiaoxia Yang; Gregory M. Lanza; Samuel A. Wickline

Background Endothelial activation is one of the necessary initial steps in the formation of atherosclerotic plaque that facilitates immune cell recruitment and retention. To image and quantify early markers of endothelial inflammation, we recently developed a multiplexing peptide-based targeting system for post-formulation functionalization of perfluorocarbon (19F) nanoparticles (PFC NP) that is intrinsically quantifiable at a binding site based on magnetic resonance spectroscopy. The approach is now demonstrated in vivo to detect and quantify VCAM-1 in ApoE-/- mouse aorta. Methods

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Samuel A. Wickline

Washington University in St. Louis

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Gregory M. Lanza

Washington University in St. Louis

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Hua Pan

Washington University in St. Louis

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Douglas M. Tollefsen

Washington University in St. Louis

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John S. Allen

Washington University in St. Louis

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Li He

Washington University in St. Louis

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Shelton D. Caruthers

Washington University in St. Louis

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Junjie Chen

Washington University in St. Louis

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Rohun U. Palekar

Washington University in St. Louis

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Jon N. Marsh

Washington University in St. Louis

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