University System of Maryland

Johns Hopkins University

Jeffrey A Winkles

Graeme F Woodworth

Anthony J Kim

Aniket Wadajkar

Justin Scot Hanes

Manuel S Yepes

Craig S Schneider

Metastatic triple negative breast cancer (TNBC) still carries a dismal prognosis with the current treatment paradigms. The effectiveness of drug treatment for many solid tumors such as TNBC is limited by tumor heterogeneity, lack of tumor specificity, off-target toxicities, and transient therapeutic action(s). Strategies that provide tumor-specific, sustained concentrations of drugs to the tumors and tumor receptor-specific binding, while reducing off-target effects are needed to ensure sufficient tumor cell uptake within the primary and metastatic tumor microenvironment. The decreased non-specific adhesivity, receptor-targeted nanoparticle formulations ('DART' nanoparticles) of the invention were assessed for clinical potential in directing biological agents to the cell surface receptor Fn14, which is expressed in many solid cancer types, including TNBC primary tumors and metastatic lesions. They are contemplated for use against solid tumors, particularly brain tumors such as glioblastoma and breast cancer, including metastatic breast cancer.

Decreased adhesivity receptor-targeted nanoparticles for Fn14-positive tumors

Provided are targeted structure-specific particulate-based delivery systems comprising: a nanoparticle; a PEG polymer coating on the surface of the nanoparticle; a targeting moiety conjugated on a surface of the nanoparticle and configured to promote specific binding to a cell surface molecule expressed by a target cell; and a biologically active agent in or on the nanoparticle, wherein the biologically active agent is selected to enhance a desired response in a target cell intracellularly or extracellularly. Methods of treating a disease or disorder administering the delivery system are contemplated.

Targeted structure-specific particulate delivery systems

The present invention is directed to compositions and methods for treating cerebral edema and cell death in neurological conditions characterized by disruption of the architecture of the neurovascular unit with increase in the permeability of the NVU, particularly for treating stroke. One aspect of the present invention relates to a composition comprising an agent that interferes with a TWEAK-mediated signaling pathway. Another aspect of the present invention relates to a method of using a composition which comprises an agent that inhibits Fn14 activity or Fn14 expression for the prevention and/or treatment of cerebral edema and cell death occurring in certain neurological conditions such as cerebral ischemia.

TWEAK as a therapeutic target for treating central nervous system diseases associated with cerebral edema and cell death

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Frederick, MD, United States of America

Jeffrey A Winkles