Biomedical subjects

Alexei A Bogdanov

Publications and source records attributed to Alexei A Bogdanov.

6 recordsLinked to original sources

PubMed2006

A paramagnetic contrast agent with myeloperoxidase-sensing properties.

Myeloperoxidase (MPO) is an essential component of inflammatory response in norm and pathology. With an ultimate goal of non-invasive imaging of MPO we used a gadolinium-chelating bis(5-hydroxytrytamide) derivative of diethylenetetraamine pentaacetic acid (L1-Gd3+ salt) as a paramagnetic sensor of enzymatic activity. We tested whether L1-Gd3+ is active in reducing the oxidized form of myeloperoxidase, generated as a result of hydrogen peroxide reduction by the enzyme. We expected that upon activation by MPO/H2O2 L1-Gd3+ would not only oligomerise but also bind to other macromolecules present in the media and that the overall process will give rise to a net T1-weighted MRI signal increase.

Contrast Media↗

PubMed2006

Targeted imaging of human endothelial-specific marker in a model of adoptive cell transfer.

Imaging of endothelial-specific markers is critically important in non-invasive detection of early signs of vascular pathologies (eg inflammation, atherosclerosis and angiogenesis). A model of adoptive human endothelial cell (HUVEC) transfer was used to test-specific imaging probes for human vascular disease consisting of cross-linked iron oxide (CLIO) nanoparticles conjugated to anti-human E-selectin (CLIO-F(ab')(2)). To perform in vivo imaging of E-selectin expression in functional blood vessels, human vascular endothelium cells (HUVECs) were implanted in athymic mice in Matrigel solution, which served as a temporary neovascularization scaffold after the solidification. The formation of HUVEC-containing vessels was established by histology and microscopy. CLIO-F(ab')(2) probes were administered via an i.v. injection following the induction of E-selectin expression by IL-1beta. High-resolution MR images were obtained before and after the administration of CLIO-F(ab')(2), which showed specific hypointensity only if treated with IL-1beta. A three-times higher CLIO-induced MR signal decrease on T2(*) images was measured in HUVEC implants in response to IL-1beta treatment. Image signal intensity did not change in control animals that: (1) harbored Matrigel alone, (2) in the absence of IL-1beta treatment or (3) in animals injected with CLIO linked to the idiotype-matched control F(ab')(2). Experiments in an adoptive transfer model demonstrated that HUVEC-containing neovessels are perfused and that IL-1beta inducible E-selectin expression in these vessels is detectable with non-invasive imaging by using targeted nanoparticles.

Adoptive Transfer↗

PubMed2005

Detection of early antiangiogenic effects in human colon adenocarcinoma xenografts: in vivo changes of tumor blood volume in response to experimental VEGFR tyrosine kinase inhibitor.

Antiangiogenesis is emerging as efficient strategy for targeting and potentially eliminating neoplastic tumor vessels. The main goal of this study was to establish whether absolute tumor blood volume (V(b)) change could be used as an early predictor of antiangiogenesis in ectopic and orthotopic colon carcinomas. To assess therapy-induced changes of V(b), we did comparative analysis of signal intensities in tumors and muscle using steady-state magnetic resonance imaging (MRI) assisted with an intravascular paramagnetic contrast agent [gadolinium-labeled protected graft copolymer (PGC-Gd)]. Athymic mice with implanted human MV522 tumors were treated with vascular endothelial growth factor type 2 receptor tyrosine kinase inhibitor (VEGFR2-TKI) that has been shown to inhibit VEGFR2 phosphorylation and tumor growth in vivo. Animals were imaged either after a single day or after a 1-week course of treatments. The measured V(b) in ectopic tumors was 2.5 +/- 1.5% of total tissue volume 1 week after the implantation (n = 8). Two doses of VEGFR2-TKI (25 mg/kg, p.o., b.i.d.) resulted in a decrease of V(b) to 1.3 +/- 0.3%. In orthotopic tumors, the measured V(b) was initially higher (11.9 +/- 2.0%); however, VEGFR2-TKI treatment also resulted in a statistically significant decrease of V(b). The absolute V(b) was not affected in the muscle as a result of treatments. MRI measurements were corroborated by using isotope and correlative histology experiments. Our results show that steady-state MRI is highly sensitive to early antiangiogenic effects caused by small molecule drugs.

Adenocarcinoma↗

PubMed2002

Viral imaging in gene therapy noninvasive demonstration of gene delivery and expression.

Gene therapy is a rapidly developing modality of treatment, with applications in acquired and inherited disorders. Gene delivery vehicles ("vectors") are the main impediment in the evolution of gene therapy into a clinically acceptable mainstream therapy. Vectors based on viral particles are the most commonly used vehicles to carry genes to the organs and tissues of interest. Despite initial promise and substantial progress in the development of experimental gene therapy protocols, human gene therapy still is based on technologies that so far do not allow for routine clinical use. Recent progress in viral vector production and better understanding of molecular aspects of vector delivery and targeting issues has created the need for imaging techniques that would be useful in addressing the problems and opportunities inherent in viral gene therapy development. Two integral components of gene therapy monitoring, the imaging of gene delivery and the imaging of resultant exogenous gene expression, are recognized. These molecular imaging components provide a realistic means for assessment of safety and efficacy of preclinical and clinical development of gene therapy.

Animals↗

PubMedDate not supplied

Myeloperoxidase activity imaging using (67)Ga labeled substrate.

PURPOSE: The aim of the study is to assess the feasibility of imaging specific activity of myeloperoxidase (MPO), a leukocyte enzyme with important roles in inflammation and atherosclerosis, by single photon emission computed tomography (SPECT) using a novel (67)Ga-labeled radiotracer obtained by conjugating desferrioxamine (DF) and hydroxyindolyl acetic acid in vivo. MATERIALS AND METHODS: A reducing substrate of MPO (I) was synthesized by reacting commercially available DF with 2-(5-hydroxy-1H-indol-3-yl) acetic acid in the presence of a coupling agent [dicyclohexyl carbodiimide (DCC)]. The chelating unit was labeled with (67)Ga, and its interaction with MPO was characterized using MALDI-TOF and UV-vis. Mice with Matrigel implants containing human MPO were used to model diseased tissues rich in MPO. Three hours after the injection of (67)Ga-I, SPECT/computed tomography (CT) imaging was performed on a high-resolution Gamma Medica X-SPECT system. Biodistribution studies were performed six hours after the injection of the radiotracer. RESULTS: The feasibility of compound I oligomerization in the presence of MPO and MPO-mediated cross-linking with proteins was initially confirmed in vitro. In vivo, a 2.7-fold increase in target-to-muscle ratio could be measured in MPO-containing Matrigel implants in mice. Biodistribution experiments demonstrated a 60% increase of radioactivity in MPO-containing vs. control (contralateral) Matrigel implants. CONCLUSION: (67)Ga-I can be used to image MPO activity in a model system. The accumulation mechanism is based on a differential pharmacokinetics because of the size increase resulting from (67)Ga-I interaction with the target enzyme.

Animals↗

PubMedDate not supplied

Cellular activation of the self-quenched fluorescent reporter probe in tumor microenvironment.

The effect of intralysosomal proteolysis of near-infrared fluorescent (NIRF) self-quenched macromolecular probe (PGC-Cy5.5) has been previously reported and used for tumor imaging. Here we demonstrate that proteolysis can be detected noninvasively in vivo at the cellular level. A codetection of GFP fluorescence (using two-photon excitation) and NIRF was performed in tumor-bearing animals injected with PGC-Cy5.5. In vivo microscopy of tumor cells in subdermal tissue layers (up to 160 microm) showed a strong Cy5.5 dequenching effect in GFP-negative cells. This observation was corroborated by flow cytometry, sorting, and reverse transcription polymerase chain reaction analysis of tumor-isolated cells. Both GFP-positive (81% total) and GFP-negative (19% total) populations contained Cy5.5-positive cells. The GFP-negative cells were confirmed to be host mouse cells by the absence of rat cathepsin mRNA signal. The subfraction of GFP-negative cells (2.5-3.0%) had seven times higher NIRF intensity than the majority of GFP-positive or GFP-negative cells (372 and 55 AU, respectively). Highly NIRF-positive, FP-negative cells were CD45- and MAC3-positive. Our results indicate that: 1) intracellular proteolysis can be imaged in vivo at the cellular level using cathepsin-sensitive probes; 2) tumor-recruited cells of hematopoetic origin participate most actively in uptake and degradation of long-circulating macromolecular probes.

Animals↗