The fundamental role of epigenetic regulatory mechanisms involved in neuroplasticity and adaptive... more The fundamental role of epigenetic regulatory mechanisms involved in neuroplasticity and adaptive responses to traumatic brain injury (TBI) is gaining increased recognition. TBI-induced neurodegeneration is associated with several changes in the expression-activity of various epigenetic regulatory enzymes, including histone deacetylases (HDACs). In this study, PET/CT with 6-([18F]trifluoroacetamido)−1- hexanoicanilide ([18F]TFAHA) to image spatial and temporal dynamics of HDACs class IIa expression-activity in brains of adult rats subjected to a weight drop model of diffuse, non-penetrating, mild traumatic brain injury (mTBI). The mTBI model was validated by histopathological and immunohistochemical analyses of brain tissue sections for localization and magnitude of expression of heat-shock protein-70 kDa (HSP70), amyloid precursor protein (APP), cannabinoid receptor-2 (CB2), ionized calcium-binding adapter protein-1 (IBA1), histone deacetylase-4 and −5 (HDAC4 and HDAC5). In comparison to baseline, the expression-activities of HDAC4 and HDAC5 were downregulated in the hippocampus, nucleus accumbens, peri-3rd ventricular part of the thalamus, and substantia nigra at 1–3 days post mTBI, and remained low at 7–8 days post mTBI. Reduced levels of HDAC4 and HDAC5 expression observed in neurons of these brain regions post mTBI were associated with the reduced nuclear and neuropil levels of HDAC4 and HDAC5 with the shift to perinuclear localization of these enzymes. These results support the rationale for the development of therapeutic strategies to upregulate expression-activity of HDACs class IIa post-TBI. PET/CT (MRI) with [18F]TFAHA can facilitate the development and clinical translation of unique therapeutic approaches to upregulate the expression and activity of HDACs class IIa enzymes in the brain after TBI.
Determination of the fate of putative stem cells after transplantation requires development of no... more Determination of the fate of putative stem cells after transplantation requires development of novel cell-labeling and tracing techniques that permit noninvasive whole-body monitoring. Previous methods used in vitro radiolabeling of cells followed by imaging the transplanted radiolabeled cells in vivo, or labeling of cells with supermagnetic agents followed by magnetic resonance imaging with near microscopic resolution. The ex vivo labeling methods provide excellent shortterm results but are not suitable for long-term repetitive imaging because of loss of label owing to radiolabel decay or biological clearance of supermagnetic label. This chapter describes approaches for labeling cells with bioluminescent, fluorescent, and positron emission tomography (PET)-reporter genes for imaging adoptively transplanted cells in vivo. Genetic labeling of cells with different reporter genes allows for long-term, repetitive in vivo imaging using different imaging platforms. These imaging platforms...
L'invention concerne des composes d'imagerie diagnostique in vivo de proliferation cellul... more L'invention concerne des composes d'imagerie diagnostique in vivo de proliferation cellulaire. Ces composes contiennent des L-nucleosides, tels qu'un analogue de nucleoside 2'-desoxy-2'-fluoro-L-arabinofuranosyl pyrimidine. Ces nucleosides sont marques au moyen d'un radio-isotope emettant des positrons. L'invention concerne egalement une methode d'imagerie diagnostique in vivo de proliferation cellulaire.
Epigenetic regulation by histone deacetylase (HDAC) is associated with synaptic plasticity and me... more Epigenetic regulation by histone deacetylase (HDAC) is associated with synaptic plasticity and memory formation, and its aberrant expression has been linked to cognitive disorders, including Alzheimer’s disease (AD). This study aimed to investigate the role of class IIa HDAC expression in AD and monitor it in vivo using a novel radiotracer, 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]TFAHA). A human neural cell culture model with familial AD (FAD) mutations was established and used for in vitro assays. Positron emission tomography (PET) imaging with [18F]TFAHA was performed in a 3xTg AD mouse model for in vivo evaluation. The results showed a significant increase in HDAC4 expression in response to amyloid-β (Aβ) deposition in the cell model. Moreover, treatment with an HDAC4 selective inhibitor significantly upregulated the expression of neuronal memory-/synaptic plasticity-related genes. In [18F]TFAHA-PET imaging, whole brain or regional uptake was significantly higher in 3xTg ...
Optical coherence tomography (OCT), with a high spatial resolution (<10 microns), intermediate... more Optical coherence tomography (OCT), with a high spatial resolution (<10 microns), intermediate penetration depth (~1.5 mm), and volumetric imaging capability is a great candidate to be used as a diagnostic-assistant modality in dermatology. At this time, the accuracy of OCT for melanoma detection is lower than anticipated. In this letter, we studied for the first time, the use of a novel contrast agent consist of ultra-small nanoparticles conjugated to a melanoma biomarker to improve the accuracy of OCT for differentiation of melanoma cells from non-melanoma cells, in vitro. We call this approach SMall nanoparticle Aggregation-enhanced Radiomics of Tumor (SMART)-OCT imaging. This initial proof of concept study is the first step towards the broad utilization of this method for high-accuracy all types of tumor detection applications. This article is protected by copyright. All rights reserved.
Tanyaluck Thientunyakit, Chakmeedaj Sethanandha, Weerasak Muangpaisan, Orasa Chawalparit, Kuntara... more Tanyaluck Thientunyakit, Chakmeedaj Sethanandha, Weerasak Muangpaisan, Orasa Chawalparit, Kuntarat Arunrungvichian, Tossaporn Siriprapa, Thonnapong Thongpraparn, Rujaporn Chanachai and Juri Gelovani, Department of Radiology, Department of Preventive and Social Medicine, Siriraj Hospital, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand and Department of Biomedical Engineering, School of Medicine and College of Engineering, Karmanos Cancer Institute,Wayne State University, Michigan, USA
Infancy is the most critical period in human brain development. Studies demonstrate that subtle b... more Infancy is the most critical period in human brain development. Studies demonstrate that subtle brain abnormalities during this state of life may greatly affect the developmental processes of the newborn infants. One of the rapidly developing methods for early characterization of abnormal brain development is functional connectivity of the brain at rest. While the majority of resting-state studies have been conducted using magnetic resonance imaging (MRI), there is clear evidence that resting-state functional connectivity (rs-FC) can also be evaluated using other imaging modalities. The aim of this review is to compare the advantages and limitations of different modalities used for the mapping of infants' brain functional connectivity at rest. In addition, we introduce photoacoustic tomography, a novel functional neuroimaging modality, as a complementary modality for functional mapping of infants' brain.
Histone deacetylases (HDACs) regulate gene expression by changing histone deacetylation status. N... more Histone deacetylases (HDACs) regulate gene expression by changing histone deacetylation status. Neurotoxicity is one of the major side effects of cisplatin, which reacts with deoxyribonucleic acid (DNA) and has excellent antitumor effects. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor with neuroprotective effects against cisplatin-induced neurotoxicity. We investigated how cisplatin with and without SAHA pretreatment affects HDAC expression/activity in the brain by using 6-([F]fluoroacetamido)-1-hexanoicanilide ([F]FAHA) as a positron emission tomography (PET) imaging agent for HDAC IIa. [F]FAHA and [F]fluoro-2-deoxy-2-D-glucose ([F]FDG) PET studies were done in 24 mice on 2 consecutive days and again 1 week later. The mice were divided into three groups according to drug administration between the first and second imaging sessions (Group A: cisplatin 2 mg/kg, twice; Group B: cisplatin 4 mg/kg, twice; Group C: cisplatin 4 mg/kg, twice, and SAHA 300 mg/kg pretreatment, ...
Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging, Jan 8, 2018
The purpose of this study was to develop a SIRT2-specific substrate-type radiotracer for non-inva... more The purpose of this study was to develop a SIRT2-specific substrate-type radiotracer for non-invasive PET imaging of epigenetic regulatory processes mediated by SIRT2 in normal and disease tissues. A library of compounds containing tert-butyloxycarbonyl-lysine-aminomethylcoumarin backbone was derivatized with fluoroalkyl chains 3-16 carbons in length. SIRT2 most efficiently cleaved the myristoyl, followed by 12-fluorododecanoic and 10-fluorodecanoic groups (K/K 716.5 ± 72.8, 615.4 ± 50.5, 269.5 ± 52.1/s mol, respectively). Radiosynthesis of 12- [F]fluorododecanoic aminohexanoicanilide (12-[F]DDAHA) was achieved by nucleophilic radiofluorination of 12-iododecanoic-AHA precursor. A significantly higher accumulation of 12-[F]DDAHA was observed in MCF-7 and MDA-MB-435 cells in vitro as compared to U87, MiaPaCa, and MCF10A, which was consistent with levels of SIRT2 expression. Initial in vivo studies using 12-[F]DDAHA conducted in a 9L glioma-bearing rats were discouraging, due to rapid ...
Proceedings of the National Academy of Sciences of the United States of America, Mar 28, 2018
Over the past two decades, 33 cases of colonic adenocarcinomas have been diagnosed in rhesus maca... more Over the past two decades, 33 cases of colonic adenocarcinomas have been diagnosed in rhesus macaques () at the nonhuman primate colony of the Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center. The distinctive feature in these cases, based on PET/computed tomography (CT) imaging, was the presence of two or three tumor lesions in different locations, including proximal to the ileocecal juncture, proximal to the hepatic flexure, and/or in the sigmoid colon. These colon carcinoma lesions selectively accumulated [F]fluorodeoxyglucose ([F]FDG) and [F]fluoroacetate ([F]FACE) at high levels, reflecting elevated carbohydrate and fatty acid metabolism in these tumors. In contrast, the accumulation of [F]fluorothymidine ([F]FLT) was less significant, reflecting slow proliferative activity in these tumors. The diagnoses of colon carcinomas were confirmed by endoscopy. The expression of MLH1, MSH2, and MSH6 proteins and the degree of micro...
3079 Background: Targeted therapeutics are highly promising in combination because they are both ... more 3079 Background: Targeted therapeutics are highly promising in combination because they are both well tolerated and interact with the signals that cause cancer. We propose a direct functional screen of combinations in the lab as a complement to the molecular insight based approach. However, with each drug added to the list, the number of possible combinations rises exponentially quickly beyond the capacity of any foreseeable technology to fully screen. We propose the MACS to identify combinations otherwise impossible to be found through a simple screen alone. The foundation of MACS is a genetic algorithm. One of the requirements for MACS will be the presence of some degree of higher order relationships among combinations. This means that knowing the behavior of some combinations formed from a set of drugs enables prediction of the behavior of other combinations formed from the same drugs. However, little is known of the degree of relatedness larger combinations of anticancer agents have. We performed expe...
Cytoskeletal-associated proteins play an active role in coordinating the adhesion and migration m... more Cytoskeletal-associated proteins play an active role in coordinating the adhesion and migration machinery in cancer progression. To identify functional protein networks and potential inhibitors, we screened an internalizing phage (iPhage) display library in tumor cells, and selected LGRFYAASG as a cytosol-targeting peptide. By affinity purification and mass spectrometry, intracellular annexin A2 was identified as the corresponding binding protein. Consistently, annexin A2 and a cell-internalizing, penetratin-fused version of the selected peptide (LGRFYAASG-pen) co-localized and specifically accumulated in the cytoplasm at the cell edges and cell-cell contacts. Functionally, tumor cells incubated with LGRFYAASG-pen showed disruption of filamentous actin, focal adhesions and caveolae-mediated membrane trafficking, resulting in impaired cell adhesion and migration in vitro. These effects were paralleled by a decrease in the phosphorylation of both focal adhesion kinase (Fak) and protei...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1997
Yield not thy neck to fortune's yoke, but let thy dauntless mind still ride in triumph overall mi... more Yield not thy neck to fortune's yoke, but let thy dauntless mind still ride in triumph overall mischance.
Galectin-3 (Gal-3) is a carbohydrate binding protein that is overexpressed in several types of ca... more Galectin-3 (Gal-3) is a carbohydrate binding protein that is overexpressed in several types of cancers, including pancreatic cancer, which makes it a good target for both imaging and therapeutic drug design. A ligand library specialized for (18)F positron emission tomography (PET) has been investigated with molecular dynamics (MD) and free energy methods to determine the relative binding energies of various potential ligands. Our results suggest that traditional docking methods can give good results when complemented by molecular dynamics and free energy methods for these types of ligands. Available experimental binding affinities for a small number of the tested compounds show very good agreement with the calculated energies and provide the rational approach for design of Gal-3 ligands with even higher affinity.
Proceedings of the National Academy of Sciences, 2016
Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and e... more Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging...
The fundamental role of epigenetic regulatory mechanisms involved in neuroplasticity and adaptive... more The fundamental role of epigenetic regulatory mechanisms involved in neuroplasticity and adaptive responses to traumatic brain injury (TBI) is gaining increased recognition. TBI-induced neurodegeneration is associated with several changes in the expression-activity of various epigenetic regulatory enzymes, including histone deacetylases (HDACs). In this study, PET/CT with 6-([18F]trifluoroacetamido)−1- hexanoicanilide ([18F]TFAHA) to image spatial and temporal dynamics of HDACs class IIa expression-activity in brains of adult rats subjected to a weight drop model of diffuse, non-penetrating, mild traumatic brain injury (mTBI). The mTBI model was validated by histopathological and immunohistochemical analyses of brain tissue sections for localization and magnitude of expression of heat-shock protein-70 kDa (HSP70), amyloid precursor protein (APP), cannabinoid receptor-2 (CB2), ionized calcium-binding adapter protein-1 (IBA1), histone deacetylase-4 and −5 (HDAC4 and HDAC5). In comparison to baseline, the expression-activities of HDAC4 and HDAC5 were downregulated in the hippocampus, nucleus accumbens, peri-3rd ventricular part of the thalamus, and substantia nigra at 1–3 days post mTBI, and remained low at 7–8 days post mTBI. Reduced levels of HDAC4 and HDAC5 expression observed in neurons of these brain regions post mTBI were associated with the reduced nuclear and neuropil levels of HDAC4 and HDAC5 with the shift to perinuclear localization of these enzymes. These results support the rationale for the development of therapeutic strategies to upregulate expression-activity of HDACs class IIa post-TBI. PET/CT (MRI) with [18F]TFAHA can facilitate the development and clinical translation of unique therapeutic approaches to upregulate the expression and activity of HDACs class IIa enzymes in the brain after TBI.
Determination of the fate of putative stem cells after transplantation requires development of no... more Determination of the fate of putative stem cells after transplantation requires development of novel cell-labeling and tracing techniques that permit noninvasive whole-body monitoring. Previous methods used in vitro radiolabeling of cells followed by imaging the transplanted radiolabeled cells in vivo, or labeling of cells with supermagnetic agents followed by magnetic resonance imaging with near microscopic resolution. The ex vivo labeling methods provide excellent shortterm results but are not suitable for long-term repetitive imaging because of loss of label owing to radiolabel decay or biological clearance of supermagnetic label. This chapter describes approaches for labeling cells with bioluminescent, fluorescent, and positron emission tomography (PET)-reporter genes for imaging adoptively transplanted cells in vivo. Genetic labeling of cells with different reporter genes allows for long-term, repetitive in vivo imaging using different imaging platforms. These imaging platforms...
L'invention concerne des composes d'imagerie diagnostique in vivo de proliferation cellul... more L'invention concerne des composes d'imagerie diagnostique in vivo de proliferation cellulaire. Ces composes contiennent des L-nucleosides, tels qu'un analogue de nucleoside 2'-desoxy-2'-fluoro-L-arabinofuranosyl pyrimidine. Ces nucleosides sont marques au moyen d'un radio-isotope emettant des positrons. L'invention concerne egalement une methode d'imagerie diagnostique in vivo de proliferation cellulaire.
Epigenetic regulation by histone deacetylase (HDAC) is associated with synaptic plasticity and me... more Epigenetic regulation by histone deacetylase (HDAC) is associated with synaptic plasticity and memory formation, and its aberrant expression has been linked to cognitive disorders, including Alzheimer’s disease (AD). This study aimed to investigate the role of class IIa HDAC expression in AD and monitor it in vivo using a novel radiotracer, 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]TFAHA). A human neural cell culture model with familial AD (FAD) mutations was established and used for in vitro assays. Positron emission tomography (PET) imaging with [18F]TFAHA was performed in a 3xTg AD mouse model for in vivo evaluation. The results showed a significant increase in HDAC4 expression in response to amyloid-β (Aβ) deposition in the cell model. Moreover, treatment with an HDAC4 selective inhibitor significantly upregulated the expression of neuronal memory-/synaptic plasticity-related genes. In [18F]TFAHA-PET imaging, whole brain or regional uptake was significantly higher in 3xTg ...
Optical coherence tomography (OCT), with a high spatial resolution (<10 microns), intermediate... more Optical coherence tomography (OCT), with a high spatial resolution (<10 microns), intermediate penetration depth (~1.5 mm), and volumetric imaging capability is a great candidate to be used as a diagnostic-assistant modality in dermatology. At this time, the accuracy of OCT for melanoma detection is lower than anticipated. In this letter, we studied for the first time, the use of a novel contrast agent consist of ultra-small nanoparticles conjugated to a melanoma biomarker to improve the accuracy of OCT for differentiation of melanoma cells from non-melanoma cells, in vitro. We call this approach SMall nanoparticle Aggregation-enhanced Radiomics of Tumor (SMART)-OCT imaging. This initial proof of concept study is the first step towards the broad utilization of this method for high-accuracy all types of tumor detection applications. This article is protected by copyright. All rights reserved.
Tanyaluck Thientunyakit, Chakmeedaj Sethanandha, Weerasak Muangpaisan, Orasa Chawalparit, Kuntara... more Tanyaluck Thientunyakit, Chakmeedaj Sethanandha, Weerasak Muangpaisan, Orasa Chawalparit, Kuntarat Arunrungvichian, Tossaporn Siriprapa, Thonnapong Thongpraparn, Rujaporn Chanachai and Juri Gelovani, Department of Radiology, Department of Preventive and Social Medicine, Siriraj Hospital, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand and Department of Biomedical Engineering, School of Medicine and College of Engineering, Karmanos Cancer Institute,Wayne State University, Michigan, USA
Infancy is the most critical period in human brain development. Studies demonstrate that subtle b... more Infancy is the most critical period in human brain development. Studies demonstrate that subtle brain abnormalities during this state of life may greatly affect the developmental processes of the newborn infants. One of the rapidly developing methods for early characterization of abnormal brain development is functional connectivity of the brain at rest. While the majority of resting-state studies have been conducted using magnetic resonance imaging (MRI), there is clear evidence that resting-state functional connectivity (rs-FC) can also be evaluated using other imaging modalities. The aim of this review is to compare the advantages and limitations of different modalities used for the mapping of infants' brain functional connectivity at rest. In addition, we introduce photoacoustic tomography, a novel functional neuroimaging modality, as a complementary modality for functional mapping of infants' brain.
Histone deacetylases (HDACs) regulate gene expression by changing histone deacetylation status. N... more Histone deacetylases (HDACs) regulate gene expression by changing histone deacetylation status. Neurotoxicity is one of the major side effects of cisplatin, which reacts with deoxyribonucleic acid (DNA) and has excellent antitumor effects. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor with neuroprotective effects against cisplatin-induced neurotoxicity. We investigated how cisplatin with and without SAHA pretreatment affects HDAC expression/activity in the brain by using 6-([F]fluoroacetamido)-1-hexanoicanilide ([F]FAHA) as a positron emission tomography (PET) imaging agent for HDAC IIa. [F]FAHA and [F]fluoro-2-deoxy-2-D-glucose ([F]FDG) PET studies were done in 24 mice on 2 consecutive days and again 1 week later. The mice were divided into three groups according to drug administration between the first and second imaging sessions (Group A: cisplatin 2 mg/kg, twice; Group B: cisplatin 4 mg/kg, twice; Group C: cisplatin 4 mg/kg, twice, and SAHA 300 mg/kg pretreatment, ...
Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging, Jan 8, 2018
The purpose of this study was to develop a SIRT2-specific substrate-type radiotracer for non-inva... more The purpose of this study was to develop a SIRT2-specific substrate-type radiotracer for non-invasive PET imaging of epigenetic regulatory processes mediated by SIRT2 in normal and disease tissues. A library of compounds containing tert-butyloxycarbonyl-lysine-aminomethylcoumarin backbone was derivatized with fluoroalkyl chains 3-16 carbons in length. SIRT2 most efficiently cleaved the myristoyl, followed by 12-fluorododecanoic and 10-fluorodecanoic groups (K/K 716.5 ± 72.8, 615.4 ± 50.5, 269.5 ± 52.1/s mol, respectively). Radiosynthesis of 12- [F]fluorododecanoic aminohexanoicanilide (12-[F]DDAHA) was achieved by nucleophilic radiofluorination of 12-iododecanoic-AHA precursor. A significantly higher accumulation of 12-[F]DDAHA was observed in MCF-7 and MDA-MB-435 cells in vitro as compared to U87, MiaPaCa, and MCF10A, which was consistent with levels of SIRT2 expression. Initial in vivo studies using 12-[F]DDAHA conducted in a 9L glioma-bearing rats were discouraging, due to rapid ...
Proceedings of the National Academy of Sciences of the United States of America, Mar 28, 2018
Over the past two decades, 33 cases of colonic adenocarcinomas have been diagnosed in rhesus maca... more Over the past two decades, 33 cases of colonic adenocarcinomas have been diagnosed in rhesus macaques () at the nonhuman primate colony of the Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center. The distinctive feature in these cases, based on PET/computed tomography (CT) imaging, was the presence of two or three tumor lesions in different locations, including proximal to the ileocecal juncture, proximal to the hepatic flexure, and/or in the sigmoid colon. These colon carcinoma lesions selectively accumulated [F]fluorodeoxyglucose ([F]FDG) and [F]fluoroacetate ([F]FACE) at high levels, reflecting elevated carbohydrate and fatty acid metabolism in these tumors. In contrast, the accumulation of [F]fluorothymidine ([F]FLT) was less significant, reflecting slow proliferative activity in these tumors. The diagnoses of colon carcinomas were confirmed by endoscopy. The expression of MLH1, MSH2, and MSH6 proteins and the degree of micro...
3079 Background: Targeted therapeutics are highly promising in combination because they are both ... more 3079 Background: Targeted therapeutics are highly promising in combination because they are both well tolerated and interact with the signals that cause cancer. We propose a direct functional screen of combinations in the lab as a complement to the molecular insight based approach. However, with each drug added to the list, the number of possible combinations rises exponentially quickly beyond the capacity of any foreseeable technology to fully screen. We propose the MACS to identify combinations otherwise impossible to be found through a simple screen alone. The foundation of MACS is a genetic algorithm. One of the requirements for MACS will be the presence of some degree of higher order relationships among combinations. This means that knowing the behavior of some combinations formed from a set of drugs enables prediction of the behavior of other combinations formed from the same drugs. However, little is known of the degree of relatedness larger combinations of anticancer agents have. We performed expe...
Cytoskeletal-associated proteins play an active role in coordinating the adhesion and migration m... more Cytoskeletal-associated proteins play an active role in coordinating the adhesion and migration machinery in cancer progression. To identify functional protein networks and potential inhibitors, we screened an internalizing phage (iPhage) display library in tumor cells, and selected LGRFYAASG as a cytosol-targeting peptide. By affinity purification and mass spectrometry, intracellular annexin A2 was identified as the corresponding binding protein. Consistently, annexin A2 and a cell-internalizing, penetratin-fused version of the selected peptide (LGRFYAASG-pen) co-localized and specifically accumulated in the cytoplasm at the cell edges and cell-cell contacts. Functionally, tumor cells incubated with LGRFYAASG-pen showed disruption of filamentous actin, focal adhesions and caveolae-mediated membrane trafficking, resulting in impaired cell adhesion and migration in vitro. These effects were paralleled by a decrease in the phosphorylation of both focal adhesion kinase (Fak) and protei...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1997
Yield not thy neck to fortune's yoke, but let thy dauntless mind still ride in triumph overall mi... more Yield not thy neck to fortune's yoke, but let thy dauntless mind still ride in triumph overall mischance.
Galectin-3 (Gal-3) is a carbohydrate binding protein that is overexpressed in several types of ca... more Galectin-3 (Gal-3) is a carbohydrate binding protein that is overexpressed in several types of cancers, including pancreatic cancer, which makes it a good target for both imaging and therapeutic drug design. A ligand library specialized for (18)F positron emission tomography (PET) has been investigated with molecular dynamics (MD) and free energy methods to determine the relative binding energies of various potential ligands. Our results suggest that traditional docking methods can give good results when complemented by molecular dynamics and free energy methods for these types of ligands. Available experimental binding affinities for a small number of the tested compounds show very good agreement with the calculated energies and provide the rational approach for design of Gal-3 ligands with even higher affinity.
Proceedings of the National Academy of Sciences, 2016
Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and e... more Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging...
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Papers by Juri Gelovani