Development of the MediBeacon transdermal GFR measurement system

Current methods of kidney function monitoring, based on plasma creatinine concentration, suffer from poor accuracy, lack of sensitivity, and potentially long delay times (24-72 hrs) before detecting acute kidney injury. A kidney function monitor is being developed by MediBeacon, based on transdermally measured fluorescence clearance of the novel fluorescent tracer agent, MB-102. After vascular injection, the agent equilibrates into the extracellular spaces of the body and is cleared exclusively by the kidneys, without being metabolized. Plasma pharmacokinetic (PK) analysis of MB-102 compared to the known GFR agent, iohexol, across subjects with a wide range of chronic kidney disease states, has demonstrated the close equivalence (R2=0.99) of the GFR derived by the two methods. Transdermal monitoring is accomplished using blue (peak ~450 nm) LED excitation to induce green (peak ~560 nm) fluorescence of MB-102. In a pilot study, the full day fluorescent decay kinetics of MB-102 were shown to be directly related to body-size normalized GFR (tGFR). Achieving accurate GFR assessment from shorter time segments is a primary goal, in order to provide near real-time monitoring of kidney function, for example in hospital intensive care units (ICU). The primary interferents to the tGFR measurement are hemoglobin, melanin, and tissue autofluorescence. The focus of the talk will be on the development of several generations of instruments designed to address these challenges, and their performance during clinical studies to date. Business and regulatory challenges faced along the path toward commercialization of this combination device and agent, will also be briefly described. Please click Additional Files below to see the full abstract

Measurement of gut permeability using fluorescent tracer agent technology

Abstract The healthy gut restricts macromolecular and bacterial movement across tight junctions, while increased intestinal permeability accompanies many intestinal disorders. Dual sugar absorption tests, which measure intestinal permeability in humans, present challenges. Therefore, we asked if enterally administered fluorescent tracers could ascertain mucosal integrity, because transcutaneous measurement of differentially absorbed molecules could enable specimen-free evaluation of permeability. We induced small bowel injury in rats using high- (15 mg/kg), intermediate- (10 mg/kg), and low- (5 mg/kg) dose indomethacin. Then, we compared urinary ratios of enterally administered fluorescent tracers MB-402 and MB-301 to urinary ratios of sugar tracers lactulose and rhamnose. We also tested the ability of transcutaneous sensors to measure the ratios of absorbed fluorophores. Urinary fluorophore and sugar ratios reflect gut injury in an indomethacin dose dependent manner. The fluorophores generated smooth curvilinear ratio trajectories with wide dynamic ranges. The more chaotic sugar ratios had narrower dynamic ranges. Fluorophore ratios measured through the skin distinguished indomethacin-challenged from same day control rats. Enterally administered fluorophores can identify intestinal injury in a rat model. Fluorophore ratios are measureable through the skin, obviating drawbacks of dual sugar absorption tests. Pending validation, this technology should be considered for human use

Transdermal fluorescence detection of a dual fluorophore system for noninvasive point-of-care gastrointestinal permeability measurement

The intestinal mucosal barrier prevents macromolecules and pathogens from entering the circulatory stream. Tight junctions in this barrier are compromised in inflammatory bowel diseases, environmental enteropathy, and enteric dysfunction. Dual sugar absorption tests are a standard method for measuring gastrointestinal integrity, however, these are not clinically amenable. Herein, we report on a dual fluorophore system and fluorescence detection instrumentation for which gastrointestinal permeability is determined in a rat small bowel disease model from the longitudinal measured transdermal fluorescence of each fluorophore. This fluorophore technology enables a specimen-free, noninvasive, point-of-care gastrointestinal permeability measurement which should be translatable to human clinical studies

Pre-clinical toxicity evaluation of MB-102, a novel fluorescent tracer agent for real-time measurement of glomerular filtration rate

a b s t r a c t The fluorescent tracer agent 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl}pyrazine, designated MB-102, has been developed with properties and attributes for use as a direct measure of glomerular filtration rate (GFR). In comparison to known standard exogenous GFR agents in animal models, MB-102 has demonstrated an excellent correlation. A battery of toxicity tests has been completed on this new fluorescent tracer agent, including single dose toxicity studies in rats and dogs to determine overall toxicity and toxicokinetics of the compound. Blood compatibility, mutation assay, chromosomal aberration assay, and several other assays were also completed. Toxicity assessments were based on mortality, clinical signs, body weight, food consumption and anatomical pathology. Doses of up to 200-300 times the estimated human dose were administered. No test-article related effects were noted on body weight, food consumption, ophthalmic observations and no abnormal pathology was seen in either macroscopic or microscopic evaluations of any organs or tissues. All animals survived to scheduled sacrifice. Transient discoloration of skin and urine was noted at the higher dose levels in both species as expected from a highly fluorescent compound and was not considered pathological. Thus initial toxicology studies of this new fluorescent tracer agent MB-102 have resulted in negligible demonstrable pathological test article concerns

Functional, cross-linked nanostructures for tandem optical imaging and therapy

The present invention provides optical agents comprising optically functional cross linked supramolecular structures and assemblies useful for tandem optical imaging and therapy. Supramolecular structures and assemblies of the present invention include optically functional shell-cross linked micelles wherein optical functionality is achieved via incorporation of one or more linking groups that include one or more photoactive moieties. The present invention further includes imaging and therapeutic methods using one or more optical agents of the present invention including optically functional shell cross-linked micelles having an associated therapeutic agent.U

Functional, cross-linked nanostructures for tandem optical imaging and therapy

The present invention provides optical agents comprising optically functional cross linked supramolecular structures and assemblies useful for tandem optical imaging and therapy. Supramolecular structures and assemblies of the present invention include optically functional shell-cross linked micelles wherein optical functionality is achieved via incorporation of one or more linking groups that include one or more photoactive moieties. The present invention further includes imaging and therapeutic methods using one or more optical agents of the present invention including optically functional shell cross-linked micelles having an associated therapeutic agent.U

Type 1 Phototherapeutic Agents. 2. Cancer Cell Viability and ESR Studies of Tricyclic Diarylamines

Type 1 phototherapeutic agents based on diarylamines were assessed for free radical generation and evaluated in vitro for cell death efficacy in the U937 leukemia cancer cell line. All of the compounds were found to produce copious free radicals upon photoexcitation with UV-A and/or UV–B light, as determined by electron spin resonance (ESR) spectroscopy. Among the diarylamines, the most potent compounds were acridan (<b>4</b>) and 9-phenylacridan (<b>5</b>), with IC₅₀ values of 0.68 μM and 0.17 μM, respectively