Evaluation of Developmental and Reproductive Toxicity in Rabbits for MB-102, a Fluorescent Tracer Agent Designed for Real-Time Measurement of Glomerular Filtration Rate.

The fluorescent tracer, MB-102, has been designed for the direct, real-time measurement of glomerular filtration rate. Previous studies, both and (rats, rabbits and dogs), were conducted to assess potential toxicity including single dose toxicity, mutation assay, chromosomal aberration assay, phototoxicity, local tolerance study, micronuclease assay, hERG channel changes, CNS and cardiovascular safety. The results of these studies led to a safety/toxicology profile for this agent deemed sufficient by the FDA to conduct Phase I and Phase II human clinical studies.

Absence of developmental or reproductive toxicity in rats for MB-102, a fluorescent tracer agent for point-of-care measurement of glomerular filtration rate.

The fluorescent tracer agent MB-102 was designed for the direct, real-time measurement of glomerular filtration rate. Previous studies, both in vitro and in vivo (rats, rabbits and dogs) have assessed single dose toxicity, phototoxicity, local tolerance, hERG channel changes, mutation, chromosomal aberration, micronuclease assays, and CNS and cardiovascular safety. The resulting safety/toxicology profile allowed FDA clearance to conduct Phase I and II human clinical studies.

Next tier in vitro and in vivo nonclinical studies further elucidating the safety and toxicity profile of MB-102, a novel fluorescent tracer agent for measurement of glomerular filtration rate.

MB-102 was designed for measurement of real-time glomerular filtration rate (GFR). Previously reported in vitro and in vivo nonclinical studies clearly demonstrated negligible toxicity, resulting in FDA clearance for First-in Human, proof of concept clinical studies. The next tier of safety and toxicity studies are reported herein.

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

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.

18FDG-PET predicts pharmacodynamic response to OSI-906, a dual IGF-1R/IR inhibitor, in preclinical mouse models of lung cancer.

Purpose: To evaluate 2-deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography imaging ((18)FDG-PET) as a predictive, noninvasive, pharmacodynamic (PD) biomarker of response following administration of a small-molecule insulin-like growth factor-1 receptor and insulin receptor (IGF-1R/IR) inhibitor, OSI-906.

Experimental Design: In vitro uptake studies of (3)H-2-deoxy glucose following OSI-906 exposure were conducted evaluating correlation of dose with inhibition of IGF-1R/IR as well as markers of downstream pathways and glucose metabolism. Similarly, in vivo PD effects were evaluated in human tumor cell line xenografts propagated in athymic nude mice by (18)FDG-PET at 2, 4, and 24 hours following a single treatment of OSI-906 for the correlation of inhibition of receptor targets and downstream markers.

Novel approach in radionuclide tumor therapy: dose enhancement by high Z-element contrast agents.

Purpose: The aim of this study was to first calculate the dose-enhancement effect from internalized radiation by the presence of exogenous contrast media using Monte Carlo simulations, and then provide in vitro proof-of-concept for this novel method of radiation-dose enhancement.

Materials And Methods: The Monte Carlo program EGSnrc (Electron Gamma Shower) was used to simulate the interaction of internalizing radiation with iodine (I) or gadolinium (Gd) containing contrast media. Experimentally, the doseenhancement effect induced by I or Gd was evaluated in cell culture assays using internalizing peptides chelated with beta- emitting radionuclides and clinically available contrast media.

Novel bioactive and stable neurotensin peptide analogues capable of delivering radiopharmaceuticals and molecular beacons to tumors.

The prevalence of neurotensin receptor (NTR) in several human tumors makes it an attractive target for the delivery of cytotoxic drugs and imaging agents. Native neurotensin (NT) is a tridecapeptide that binds to NTR and induces tumor growth. Unfortunately, NT has a short plasma half-life, which hinders its use for in vivo biomedical applications.

Preclinical comparison of (111)In-labeled DTPA- or DOTA-bombesin analogs for receptor-targeted scintigraphy and radionuclide therapy.

Unlabelled: The 14-amino-acid peptide bombesin (BN) has a high affinity for the gastrin-releasing peptide (GRP) receptor that is expressed by a variety of tumors. Recently, high densities of GRP receptors were identified by in vitro receptor autoradiography in human prostate and breast carcinomas using [(125)I-Tyr(4)]BN as radioligand. Radiometal-labeled diethylenetriaminepentaacetic acid (DTPA)-BN derivatives are potentially useful radioligands for receptor-targeted scintigraphy and radiotherapy of GRP receptor-expressing tumors.

DOTA-D-Tyr(1)-octreotate: a somatostatin analogue for labeling with metal and halogen radionuclides for cancer imaging and therapy.

The goal of this study was to evaluate a somatostatin receptor ligand, DOTA-D-Tyr(1)-octreotate (DOTA-DY1-TATE), that has the chelator 1,4,7,10-tetraazacyclotetradecane-N,N',N'',N'"-tetraacetic acid (DOTA) attached to the D-Tyr(1) residue, allowing radiolabeling with both radiohalogens and radiometals. A potential advantage of having a chelator attached to the Tyr(1) residue is that halogen radiolabels may residualize or remain trapped in tumor cells rather than clear from the tumor. DOTA-DY1-TATE was synthesized by solid-phase methods and radiolabeled with (61)Cu, (64)Cu, and (125)I in high radiochemical purity and specific activity.

Synthesis, in vitro receptor binding, and in vivo evaluation of fluorescein and carbocyanine peptide-based optical contrast agents.

Site-specific delivery of drugs and contrast agents to tumors protects normal tissues from the cytotoxic effects of drugs and enhances the contrast between normal and pathologic tissues. One approach to achieve selectivity is to target overexpressed receptors on the membranes of tumor cells and to visualize the tumors by a noninvasive optical imaging method. Accordingly, we conjugated fluorescein and carbocyanine dyes to somatostatin and bombesin receptor-avid peptides and examined their receptor binding affinities.