Evaluation of Peptide-Based Probes toward Diagnostic Imaging of Bacterial Biofilm-Associated Infections.

The clinical management of bacterial biofilm infections represents an enormous challenge in today's healthcare setting. The NIH estimates that 65% of bacterial infections are biofilm-related, and therapeutic outcomes are positively correlated with early intervention. Currently, there is no reliable imaging technique to detect biofilm infections , and current clinical protocols for accurate and direct biofilm identification are nonexistent.

Novel Peptide NIRF Optical Surgical Navigation Agents for HNSCC.

Head and neck squamous cell carcinoma (HNSCC) survival rates have not improved in a decade, with a 63% 5-year recurrence rate after surgery, making HNSCC a compelling indication for optical surgical navigation (OSN). A promising peptide, HN1, targeted and internalized in human HNSCC cells in multiple laboratories, but was slow (24 h) to accumulate. We modified HN1 and explored structural variables to improve the uptake kinetics and create IRdye800 adducts useful for OSN.

Stability Evaluation and Stabilization of a Gastrin-Releasing Peptide Receptor (GRPR) Targeting Imaging Pharmaceutical.

The prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) are identified as important targets on prostate cancer. Receptor-targeting radiolabeled imaging pharmaceuticals with high affinity and specificity are useful in studying and monitoring biological processes and responses. Two potential imaging pharmaceuticals, AMBA agonist (where AMBA = DO3A-CH2CO-G-[4-aminobenzyl]- Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH) and RM1 antagonist (where RM1 = DO3A-CHCO-G-[4-aminobenzyl]-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH), have demonstrated high binding affinity (IC) to GRP receptors and high tumor uptake.

Development of an orthotopic canine prostate cancer model expressing human GRPr.

Background: Ace-1 canine prostate cancer cells grow orthotopically in cyclosporine immunosuppressed laboratory beagles. We previously transfected (human Gastrin-Releasing Peptide Receptor, huGRPr) into Ace-1 cells and demonstrated receptor-targeted NIRF imaging with IR800-G-Abz4-t-BBN, an agonist to huGRPr. Herein, we used the new cell line to develop the first canine prostate cancer model expressing a human growth factor receptor.

Use of a leukocyte-targeted peptide probe as a potential tracer for imaging the tuberculosis granuloma.

Granulomas are the histopathologic hallmark of tuberculosis (TB), both in latency and active disease. Diagnostic and therapeutic strategies that specifically target granulomas have not been developed. Our objective is to develop a probe for imaging relevant immune cell populations infiltrating the granuloma.

Biological Evaluation of a Fluorescent-Imaging Agent for Medullary Thyroid Cancer in an Orthotopic Model.

Context: The primary and definitive treatment of medullary thyroid cancer (MTC) is surgical resection. Recurrent or residual disease is typically a result of incomplete surgical removal.

Objective: Our objective is to develop a compound that assists in intraoperative visualization of cancer, which would have the potential to improve surgical cure rates and outcomes.

A human GRPr-transfected Ace-1 canine prostate cancer model in mice.

Background: A versatile drug screening system was developed to simplify early targeted drug discovery in mice and then translate readily from mice to a dog prostate cancer model that more fully replicates the features of human prostate cancer.

Methods: We stably transfected human cDNA of the GRPr bombesin (BBN) receptor subtype to canine Ace-1 prostate cancer cells (Ace-1(huGRPr) ). Expression was examined by (125) I-Tyr(4) -BBN competition, calcium stimulation assay, and fluorescent microscopy.

A high-affinity near-infrared fluorescent probe to target bombesin receptors.

Purpose: This study aimed to create new optical surgical navigation NIRF probes for prostate and breast cancers.

Procedures: IR800-linker-QWAVGHLM-NH2 with linker = GSG, GGG, and G-Abz4 were synthesized and characterized. IC50 for bombesin receptors (BBN-R) in PC-3 prostate and T47D breast cancer cells, fluorescence microscopy in PC-3 cells, and NIRF imaging in mice PC-3 tumor xenografts were studied.

Development of a calcium-sensing receptor molecular imaging agent.

Background: Calcium-sensing receptor (CaSR) is expressed by parathyroid cells and thyroid C-cells (from which medullary thyroid carcinoma [MTC] is derived). A molecular imaging agent localizing to the CaSR could improve the detection of parathyroids and MTC preoperatively or intraoperatively. We synthesized a novel compound containing a fluorine residue for potential future labeling and demonstrated that the compound inhibited CaSR function in vitro.

Site specific discrete PEGylation of (124)I-labeled mCC49 Fab' fragments improves tumor MicroPET/CT imaging in mice.

The tumor-associated glycoprotein-72 (TAG-72) antigen is highly overexpressed in various human adenocarcinomas and anti-TAG-72 monoclonal antibodies, and fragments are therefore useful as pharmaceutical targeting vectors. In this study, we investigated the effects of site-specific PEGylation with MW 2-4 kDa discrete, branched PEGylation reagents on mCC49 Fab' (MW 50 kDa) via in vitro TAG72 binding, and in vivo blood clearance kinetics, biodistribution, and mouse tumor microPET/CT imaging. mCC49Fab' (Fab'-NEM) was conjugated at a hinge region cysteine with maleimide-dPEG 12-(dPEG24COOH)3 acid (Mal-dPEG-A), maleimide-dPEG12-(dPEG12COOH)3 acid (Mal-dPEG-B), or maleimide-dPEG12-(m-dPEG24)3 (Mal-dPEG-C), and then radiolabeled with iodine-124 ((124)I) in vitro radioligand binding assays and in vivo studies used TAG-72 expressing LS174T human colon carcinoma cells and xenograft mouse tumors.

Localization of CaSR antagonists in CaSR-expressing medullary thyroid cancer.

Objective: Image-based localization of medullary thyroid cancer (MTC) and parathyroid glands would improve the surgical outcomes of these diseases. MTC and parathyroid glands express high levels of calcium-sensing receptor (CaSR). The aim of this study was to prove the concept that CaSR antagonists specifically localize to CaSR-expressing tumors in vivo.

Pharmacokinetic properties of intravitreal I-124-aflibercept in a rabbit model using PET/CT.

Purpose: To determine the anatomic characteristics and pharmacokinetic properties of intravitreally-placed aflibercept in a rabbit model.

Materials And Methods: Four Dutch-belted rabbits underwent intravitreal injection with I-124-aflibercept. Serial imaging with PET/CT imaging was performed on days 0, 2, 5, 7, 14, 21, 28 and 35.

Design, synthesis, and structure-activity relationship of novel CCR2 antagonists.

A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity.

4-Amino-2-alkyl-butyramides as small molecule CCR2 antagonists with favorable pharmacokinetic properties.

A systematic examination of the central aromatic portion of the lead (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-(4-fluorophenyl)-4-(1'H-spiro[indene-1,4'-piperidin]-1'-yl)butanamide (9) led to the discovery of a novel class of CCR2 receptor antagonists, which carry small alicyclic groups such as cyclopropyl, cylobutyl, or cyclopropylmethyl attached at C2 of the carbon backbone. The most potent compound discovered, namely (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-cyclopropyl-4-[(1R,3'R)-3'-methyl-1'H-spiro[indene-1,4'-piperidin]-1'-yl]butanamide (29), showed very high binding affinity (IC50 = 4 nM, human monocyte) and excellent selectivity toward other related chemokine receptors. The excellent pharmacokinetic profile of this new lead compound allows for extensive in vivo evaluation.