SBIR-STTR Award

?This project entails the development of a novel dual-component MRI contrast agent formulation for the detecting permeability in the luminal surface of the urinary bladder. The purpose of having such a test is ultimately to allow clinicians, in certain circumstances, to differentially diagnose a chronic, non-infectious inflammation of the urinary bladder from a pelvic floor defect. The two components of the formulation permit the simultaneous tracking of the bladder wall via one component that is composed of particles having a larger particle size, as well as map the local permeability of the wall via the second component composed of particles having a much smaller particle size, wherein each of the two components can be tracked independently. The proposed project is segmented into two aims. The first aim is an animal protocol where bladder wall permeability can be chemically influenced, and the second aim is a pilot clinical protocol designed to assess the feasibility of a human diagnostic test. For aim 1, a mouse model that works well with the available bladder instillation and animal imaging equipment is proposed. Protamine sulfate is the proposed drug for inducing bladder wall permeability, not necessarily because it is the best model of bladder disease, but because it provides the best-controlled inflammatory effects in the time frames logistically available for the proposed imaging experiments. Different levels of permeability induction as well as different levels of bladder distension are proposed as effectors to be tested. Since the components used in the formulation are already FDA-approved for parenteral route of administration, IND approval to study true cystitis in human subjects will be available. This proposal thus includes aim 2, the test of clinical feasibility in six human subjects. These six human sub- jects are divided into three cohorts: two healthy control subjects, two subjects with interstitial cystitis bladder pain syndrome (IC/BPS), and two IC/BPS subjects also having Hunner's ulcer. We anticipate that the results of the both aims of this proposed Phase-1 study will provide the foundation for the development of a subse- quent Phase-2 proposal in which we would propose the further clinical development of the formulation and diagnostic method. If successful, this research could ultimately lead to a product that may be helpful in diagnosing inflammatory conditions of the urinary bladder, such as IC/BPS, a diagnostic test which has been long sought after by the urology community.

Public Health Relevance Statement:


Public Health Relevance:
Interstitial Cystitis / Bladder Pain Syndrome (IC/BPS) is an incurable chronic, debilitating disease of the urinary bladder that involves urinary urgency, frequency of urination and chronic pelvic pain. Estimates of the prevalence of IC/BPS in the U.S. range from 10 to 500 cases per 100,000 persons. Historically, increased bladder permeability is suggested to be the key determinant of bladder pathology and IC/BPS symptoms. However, there is a current lack of acceptable methods for direct measurement of bladder permeability in IC/BPS patients, and this proposal will develop a new objective MRI test for direct measurement of bladder permeability.

NIH Spending Category:
Clinical Research; Diagnostic Radiology; Interstitial Cystitis; Pain Conditions - Chronic; Pain Research; Urologic Diseases

Project Terms:
animal imaging; Animals; Biological Assay; Biological Models; Bladder; Bladder Diseases; Bladder Tissue; Blood; Chemicals; Chronic; chronic pelvic pain; Clinical; Clinical Protocols; cohort; Communities; Contrast Media; Cystitis; Data; Defect; design; Development; Diagnosis; Diagnostic Procedure; Diagnostic tests; Dialysis procedure; Diffusion; Disease; Dosage Forms; Drug Formulations; Equipment; FDA approved; follow-up; Foundations; Frequencies (time pattern); Gadolinium DTPA; Human; Human body; human data; human study; human subject; Image; Imaging Techniques; in vivo; Inflammation; Inflammatory; Interstitial Cystitis; Intravesical Instillation; Lead; Legal patent; Magnetic Resonance Imaging; Maps; Measurement; Measures; membrane model; Methods; micturition urgency; Modeling; Motivation; mouse model; Mus; Nature; novel; novel diagnostics; particle; Particle Size; Pathology; Patients; Pelvic floor structure; Permeability; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; phase 1 study; Positioning Attribute; Prevalence; Protamine Sulfate; Protocols documentation; public health relevance; Reagent; Research; research study; Route; Services; Signal Transduction; Small Business Technology Transfer Research; small molecule; solute; Source; Staging; Sterility; Surface; Symptoms; System; Techniques; Testing; Time; Ulcer; Urination; Urine; Urology; Work

This Phase II SBIR proposal leverages the progress made in Phase I on the development of a novel con- trast mixture enhanced T1-weighted MRI technique as a safe, sensitive, and objective diagnostic test for the increased permeability in the luminal surface of the urinary bladder in Interstitial Cystitis/Bladder Pain Syn- drome (IC/BPS) patients. The purpose of having such a test is ultimately to allow clinicians, in certain cir- cumstances, to differentially diagnose a chronic, non-infectious inflammation of the urinary bladder from a pelvic floor defect. Phase I support was utilized to demonstrate that the novel contrast mixture is superior to individual instillation of either FDA approved gadolinium chelate (Gadovist) or superparamagnetic iron oxide nanoparticles (Feraheme) in segmenting the rat bladder wall from lumen. The contrast mixture relies on the differences in particle size and contrast mechanisms of the two contrast agents for improved image contrast of the bladder wall. Gadovist shortens the local T1 and Feraheme shortens the local T2, wherein each of the two components can be tracked independently. Quantitative T1 measurements can thus become a bi- omarker for Gd contrast permeability, albeit the quantitative relationship would have to be carefully deter- mined. The rat studies in Phase I were performed at a high field strength of 7T. When transitioning to imag- ing of human subjects in clinical field strength scanners at 3T, the novel contrast mixture was safely tolerat- ed by human subjects, whose 3 mm thick bladder wall could be imaged by a series of single-breath-hold FLASH sequences in a clinically acceptable imaging time (<1 h total). For Phase 1, the novel contrast mix- ture was extemporaneously compounded, and therefore, we need to develop a unit dosage form of novel contrast mixture suitable for an FDA filing and optimize its imaging properties in clinical strength magnet us- ing cat. We will also validate the tissue signal enhancement in bladder and perivesical organs by gadolinium measurement by inductively coupled plasma mass spectrometry (ICP-MS). Our long-term goal is to develop contrast agents for improved patient care of IC patients by optimizing, validating, and extending quantitative MRI methods for identifying IC patients with bladder permeability versus pelvic floor tonicity.