Benign Prostatic Hyperplasia/Hypertrophy is a major health problem in the United States, with one-in-three men having urologic problems. Currently available treatment modalities include alpha-blockers that do not affect the underlying pathologic process, and 5-alpha-reductase inhibitors that have significant systemic side-effects. We have discovered that human prostate endothelial cells express functional androgen receptor, that androgen is a key direct modulator of endothelial cell proliferation and survival, and that the endothelial cells are the prostate cellular compartment most sensitive to androgen deprivation. The goal of this project is to validate that acute androgen deprivation, coupled with a targeted delivery vehicle, provides a selective mechanism to deliver imaging/or and cytostatic/cytotoxic agents to inhibit/reverse BPH at the level of the entire prostate organ. The Specific Aims of this Phase I project will utilize superparamagnetic iron oxide loaded, freeze-dried human platelets (SPIO-StasixTM particles) as the specific targeting vehicle as a proof-of- concept. Aim 1 will establish the optimal time after acute androgen deprivation for maximal binding of the SPIO-StasixTM particles to the damaged human vasculature of primary xenografts of human benign prostate tissue. Aim 2 will validate by MR-imaging, both in vivo and ex vivo, and optical microscopic imaging of tissue specimens, the organ specificity and intra-organ distribution of the SPIO-StasixTM particles within the vascular network of the primary xenografts of human benign prostate tissue and within the organs of the immunocompromised mouse host. Successful completion of the Phase I project showing that platelets selectively localize to the damaged vasculature of the prostate will provide the proof-of-concept that will support a Phase II project that will both explore the utility of SPIO-labeled platelets as mediators of physical modalities of cell killing or thrombosis or as delivery vehicles of cytostatic/cytotoxic/procoagulant agents. The Phase II project would focus on identification of peptides/antibodies/receptor or enzyme ligands that would improve specificity/avidity for the selectively damaged prostate endothelial cells.
Public Health Relevance: Benign Prostatic Hyperplasia (BPH) is an age-related disease that affects a large percentage of the older adult male population in the United States and most developed countries. It is a disease of unknown etiology with current treatments that are only marginally effective yet have a number of undesirable side effects. This proposal will investigate a non-invasive treatment to image the prostate organ to assist in diagnosis as well as develop a targeted vehicle to make current drugs more effective with fewer side effects and open up possibilities for new methods of disease treatment.
Public Health Relevance Statement: Project Narrative Benign Prostatic Hyperplasia (BPH) is an age-related disease that affects a large percentage of the older adult male population in the United States and most developed countries. It is a disease of unknown etiology with current treatments that are only marginally effective yet have a number of undesirable side effects. This proposal will investigate a non-invasive treatment to image the prostate organ to assist in diagnosis as well as develop a targeted vehicle to make current drugs more effective with fewer side effects and open up possibilities for new methods of disease treatment.
NIH Spending Category: Aging; Urologic Diseases
Project Terms: 5 Alpha-Reductase Inhibitor; Acute; Adrenergic alpha-Antagonists; Adult; Adverse effects; Affect; age related; Androgen Receptor; Androgens; Apoptosis; Apoptotic; Avidity; Benign; Benign Prostatic Hypertrophy; Binding (Molecular Function); Blood Platelets; Blood Vessels; Brain Hypoxia-Ischemia; Castration; Cell Death; cell killing; Cell Proliferation; Cells; Cessation of life; Complex; Coupled; Cytostatics; cytotoxic; Cytotoxic agent; deprivation; Developed Countries; Developing Countries; Diagnosis; Disease; Elderly; Endothelial Cells; Enzymes; Epithelial; Epithelial Cells; Etiology; Extravasation; Fc Receptor; feeding; Fibrin; Fibrinogen; Freeze Drying; Goals; Health; Human; Human body; Hyperplasia; Hypertrophy; Image; imaging modality; Immunocompromised Host; improved; in vivo; interstitial; iron oxide; Label; Ligands; Magnetic Resonance Imaging; male; Marketing; Mediating; Mediator of activation protein; men; Methods; Microscopic; Modality; Morbidity - disease rate; Mus; nanoparticle; Optics; Organ; Organ Specificity; Organ Viability; particle; Pathogenesis; Pathologic Processes; Pathology; Peptide antibodies; Pericytes; Pharmaceutical Preparations; Phase; Population; prevent; Prostate; Prostatic; public health relevance; Rattus; repaired; Secondary to; Serum; Specificity; Specimen; Surface; System; targeted delivery; Therapeutic; Thromboplastin; Thrombosis; Time; Tissues; Trees; United States; urologic; Xenograft procedure
