ABSTRACT Stroke is one of leading causes of death and disability worldwide, with higher prevalence in the aged population and in patients with comorbid conditions such as diabetes mellitus (DM). Tissue plasminogen activator (tPA), the only Food and Drug Administration (FDA) approved treatment, is limited in its use to < 8.5% of stroke patients. No new treatments have been approved for stroke therapy in twenty years. Therefore, there is a compelling need to develop new and broader utility therapies for acute ischemic stroke. Mast Therapeutics (MT) is currently testing vepoloxamer, a proprietary amphipathic copolymer with rheological and membrane-protective properties, in clinical trials in man. Henry Ford Hospital (HFH) has conducted preliminary studies using vepoloxamer which demonstrated that vepoloxamer reduces infarct volume and improve neurological function in a rat embolic model of middle cerebral artery occlusion (MCAO). In this Phase 1 SBIR application, MT and HFH will collaborate in a study evaluating the combined use of tPA and vepoloxamer in the rat embolic model of MCAO. The specific objective of the study is to determine the feasibility of using vepoloxamer as an adjuvant agent to thrombolytic therapy for acute ischemic stroke. The expected outcome of the Phase 1 SBIR is intended to provide rationale for further pursuing a Phase 2 study that will: 1) establish the combination's therapeutic window, and 2) investigate the effects of the combination treatment in ischemic stroke in female, aged, and diabetic animals, and in another species (i.e., rabbit embolic stroke model) according to the Stroke Therapy Academy Industry Roundtable (STAIR) recommendations. Altogether, the Phase 1 and 2 studies are intended to provide compelling performance data supporting the development of vepoloxamer as new drug modality for use in stroke.