2013 IEEE Nuclear Science Symposium and Medical Imaging Conference (2013 NSS/MIC), 2013
A quick localization of the tumor site to guide the therapeutic administration is important for a... more A quick localization of the tumor site to guide the therapeutic administration is important for an image guided cancer therapy to decrease both mortalityand morbidity, especially in prolonged procedures, such as photodynamic and photothermal therapies. Consequently, the images have to be updated quickly enough to capture the patient motion and the movement of therapeutic device, which poses a significant challenge on functional imaging probes. Besides increasing the sensitivity of imaging detectors, advanced image processing methods may play an important role to overcome this challenge. In this work, we investigate the effectiveness of the spatiotemporal processing to shorten the acquisition time of each image frame to be able to capture the object motion with good image quality. The simulation study of beta imaging of a moving tumor phantom at different imaging dose levels demonstrates that the spatiotemporal processing can yield superior image quality compared to either a short ac...
ABSTRACT Objectives: Gold nanoparticles (AuNPs) have gained significant attention in biomedical a... more ABSTRACT Objectives: Gold nanoparticles (AuNPs) have gained significant attention in biomedical applications due to their ease of synthesis, unique physico-chemical properties, and modifiable surface. Copper-64 is an attractive radioisotope in PET research due to its low positron range, availability, and reasonably long half-life (t1/2 = 12.7 hr). It is principally a suitable candidate for the development of AuNP-based in vivo theranostic agents. Herewith, we investigated a facile synthetic approach to incorporate 64Cu into the core of PEGylated AuNPs by metallic doping technique as against to macrocyclic chelation tactic followed in earlier reports. Methods: Synthetic methodology to prepare radioactive AuNPs was developed and optimized. The in vivo integrity of developed [64Cu]AuNPs was also evaluated by a comparative biodistribution study using both radioactive gamma counting (64Cu) and ICP-MS (Au). Results: Our optimized synthesis methodology produced stable, biocompatible (<1% hemolytic) and nanometric [64Cu]AuNPs (51.45±2.73 nm) within 150 min in high yields (>70%). ICP-MS based Au biodistribution pattern was found to be in agreement with 64Cu gamma counting report inferring retention of radio-chemical integrity following in vivo administration. The retention of radiochemical integrity can be ascribed to the direct integration of 64Cu into the lattice structure of AuNPs during synthesis. Further, CT imaging done at 24 hr p.i. showed enhancement in tumor CT signal from 194.1 HU to 233.2 HU (20% CT contrast enhancement), which can be envisaged to the localization of AuNPs in the tumor mass. Conclusions: This investigation reports effective synthesis of stabile, biocompatibile and nanometric gold nanoparticles with high radiolabelling efficiency. High tumor localization, significantly high tumor CT contrast (p<0.005) as well as retention of radio-chemical integrity under in vivo environment submits the prospective potential of developed nanoparticles for preclinical translational applications in tumor imaging and diagnosis.
Mouse models of experimental anti-glomerular basement membrane (anti-GBM) nephritis provide an an... more Mouse models of experimental anti-glomerular basement membrane (anti-GBM) nephritis provide an analytical tool for studying spontaneous lupus nephritis. The potential of Positron Emission Tomography (PET) was evaluated using 2-deoxy-2-[ 18 F]fluoro-d-glucose (FDG) as a probe to monitor the progression of anti-GBM induced nephritis in a mouse model. The imaging results were compared to conventional measures of renal function and pathological changes. Serum and urinary vascular cell adhesion molecule-1 (VCAM-1) levels were used as measures of endothelial cell activation and inflammation. Following a challenge with anti-glomerular antibodies, mice exhibited peak changes in serum creatinine, proteinuria, and glomerulonephritis score at 14 days post-challenge (p.c.). In contrast, VCAM levels peaked at day 7 p.c. On dynamic PET images (0-60 min) of day 7, kidneys of the anti-GBM nephritis mice demonstrated a unique pattern of FDG uptake. Compared to the time activity curve (TAC) prior to challenge, a rightward shift was observed after the challenge. By day 10 p.c., kidney FDG uptake was lower than baseline and remained so until the study ended at 21 days p.c. During this time frame measures of renal dysfunction remained high but VCAM-1 levels declined. These changes were accompanied by an increase in kidney volume as measured by Computed Tomography (CT) and intra-abdominal fluid collection. Our results suggest that FDG-PET-CT can be used as a non-invasive imaging tool to longitudinally monitor the progression of renal disease activity in antibody mediated nephritis and the magnitude of renal FDG retention correlates better with early markers of renal inflammation than renal dysfunction.
To image implant-surrounding activated macrophages, a macrophage-specific PET probe was prepared ... more To image implant-surrounding activated macrophages, a macrophage-specific PET probe was prepared by conjugating folic acid (FA) and 2,2′,2″,2‴-(1,4,7,10tetraazacyclododecane-1,4,7,10-tetrayl) tetracetic acid (DOTA) to polyethylene glycol (PEG) and then labeling the conjugate with Ga-68. In vivo PET imaging evaluations demonstrate that the probe is able to detect foreign body reactions, and more importantly, quantify the degree of inflammatory responses to an implanted medical device. These results were further validated by histological analysis.
American journal of nuclear medicine and molecular imaging, 2011
Non-invasive detection of vascular endothelial growth factor receptor 2 (VEGFR2) by positron emis... more Non-invasive detection of vascular endothelial growth factor receptor 2 (VEGFR2) by positron emission tomography (PET) would allow the evaluation of tumor vascular activity in vivo. Recently, a dimeric peptoid, GU40C4, was reported as a highly potent antagonist of VEGFR2 activation inhibiting angiogenesis and tumor growth in vivo. The purpose of this work was to evaluate the potential of this peptoid for PET imaging of VEGFR2 expression. To label GU40C4 and a control peptoid with a positron emitter, (64)Cu (t(1/2) = 12.7 h; β(+): 0.653 MeV, 17.4%), a cysteine was introduced to the C-terminus of the peptoids and then conjugated to a bifunctional chelator (DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) through the maleimide-thiol coupling chemistry. The in vitro binding assay showed a negligible effect of the DOTA conjugation on the VEGFR2 binding affinity of GU40C4. Both peptoid conjugates were efficiently labeled with (64)Cu in high radiochemical yields (> 90%); ...
Non-invasive detection of prostate cancer or metastases still remains a challenge in the field of... more Non-invasive detection of prostate cancer or metastases still remains a challenge in the field of molecular imaging. In our recent work of screening arginine- or lysine-rich peptides for intracellular delivery of a therapeutic agent into prostate cancer cells, an arginine-rich cell permeable peptide (NH(2)GR(11)) was found with an unexpectedly preferential uptake in prostate cancer cell lines. The goal of this work was to develop this peptide as a positron emission tomography (PET) imaging probe for specific detection of distant prostate cancer metastases. The optimal length of arginine-rich peptides was evaluated by the cell uptake efficiency of three fluorescein isothiocyanate (FITC)-tagged oligoarginines (NHGR(9), NHGR(11), and NHGR(13)) in four human prostate cell lines (LNCaP, PZ-HPV-7, DU145, and PC3). Of the three oligoarginines, NH(2)GR(11) showed the highest cell uptake and internalization efficiency with its subcellular localization in cytosol. The biodistribution of FITC-NHGR(9), FITC-NHGR(11), and FITC-NHGR(13) performed in control nude mice displayed the unique preferential accumulation of FITC-NHGR(11) in the prostate tissue. Further in vivo evaluation of FITC-NHGR(11) in PC3 tumor-bearing nude mice revealed elevated uptake of this peptide in tumors as compared to other organs. In vivo pharmacokinetics evaluated with (64)Cu-labeled NH(2)GR(11) showed that the peptide was rapidly cleared from the blood (t(1/2) = 10.7 min) and its elimination half-life was 17.2 h. The PET imaging specificity of (64)Cu-labled NH(2)GR(11) was demonstrated for the detection of prostate cancer in a comparative imaging experiment using two different human cancer xenograft models.
In this study, we report the preparation, luminescence, and targeting properties of folic acid-Cd... more In this study, we report the preparation, luminescence, and targeting properties of folic acid-CdTe quantum dot conjugates. Water-soluble CdTe quantum dots were synthesized and conjugated with folic acid using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-Nhydroxysuccinimide chemistry. The influence of folic acid on the luminescence properties of CdTe quantum dots was investigated, and no energy transfer between them was observed. To investigate the efficiency of folic acid-CdTe nanoconjugates for tumor targeting, pure CdTe quantum dots and folic acid-coated CdTe quantum dots were incubated with human nasopharyngeal epidermal carcinoma cell line with positive expressing folic acid receptors (KB cells) and lung cancer cells without expression of folic acid receptors (A549 cells). For the cancer cells with positive folate receptors (KB cells), the uptake for CdTe quantum dots is very low, but for folic acid-CdTe nanoconjugates, the uptake is very high. For the lung cancer cells without folate receptors (A549 cells), the uptake for folic acid-CdTe nanoconjugates is also very low. The results indicate that folic acid is an effective targeting molecule for tumor cells with overexpressed folate receptors.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 27, 2014
Despite promise for the use of antibodies as molecular imaging agents in PET, their long in vivo ... more Despite promise for the use of antibodies as molecular imaging agents in PET, their long in vivo half-lives result in poor contrast and radiation damage to normal tissue. This study describes an approach to overcome these limitations. Mice bearing human epidermal growth factor receptor type 2 (HER2)-overexpressing tumors were injected with radiolabeled ((124)I, (125)I) HER2-specific antibody (pertuzumab). Pertuzumab injection was followed 8 h later by the delivery of an engineered, antibody-based inhibitor of the receptor, FcRn. Biodistribution analyses and PET were performed at 24 and 48 h after pertuzumab injection. The delivery of the engineered, antibody-based FcRn inhibitor (or Abdeg, for antibody that enhances IgG degradation) results in improved tumor-to-blood ratios, reduced systemic exposure to radiolabel, and increased contrast during PET. Abdegs have considerable potential as agents to stringently regulate antibody dynamics in vivo, resulting in increased contrast during ...
Proceedings of the National Academy of Sciences, 2010
A single nucleotide polymorphism in the DAB2IP gene is associated with risk of aggressive prostat... more A single nucleotide polymorphism in the DAB2IP gene is associated with risk of aggressive prostate cancer (PCa), and loss of DAB2IP expression is frequently detected in metastatic PCa. However, the functional role of DAB2IP in PCa remains unknown. Here, we show that the loss of DAB2IP expression initiates epithelial-to-mesenchymal transition (EMT), which is visualized by repression of E-cadherin and up-regulation of vimentin in both human normal prostate epithelial and prostate carcinoma cells as well as in clinical prostate-cancer specimens. Conversely, restoring DAB2IP in metastatic PCa cells reversed EMT. In DAB2IP knockout mice, prostate epithelial cells exhibited elevated mesenchymal markers, which is characteristic of EMT. Using a human prostate xenograft-mouse model, we observed that knocking down endogenous DAB2IP in human carcinoma cells led to the development of multiple lymph node and distant organ metastases. Moreover, we showed that DAB2IP functions as a scaffold protein in regulating EMT by modulating nuclear β-catenin/Tcell factor activity. These results show the mechanism of DAB2IP in EMT and suggest that assessment of DAB2IP may provide a prognostic biomarker and potential therapeutic target for PCa metastasis. P rostate cancer (PCa) has surpassed lung cancer as the leading cancer among American men (1). In the absence of metastasis, prostate cancer is largely a treatable disease. Thus, early diagnosis of patients who will develop PCa metastasis could reduce the mortality and morbidity associated with this disease. The development of metastasis depends on the migration and invasion of cancer cells from the primary tumor into the surrounding tissue. To acquire such invasive abilities, carcinoma cells may acquire unique phenotypic changes such as epithelial-tomesenchymal transition (EMT). EMT is a highly conserved cellular process that allows polarized, generally immotile epithelial cells to convert to motile mesenchymal-appearing cells. This process was initially recognized during several critical stages of embryonic development and has more recently been implicated in promoting carcinoma invasion and metastasis (2-4). During EMT, three major changes occur: (i) morphological changes from a cobblestone-like monolayer of epithelial cells to dispersed, spindle-shaped mesenchymal cells with migratory protrusions; (ii) changes of differentiation markers from cell-cell junction proteins and cytokeratin intermediate filaments to vimentin filaments and fibronectin; and (iii) acquisition of invasiveness through the extracellular matrix (4). Decreased E-cadherin expression or gain of vimentin expression is closely correlated with various indices of PCa progression, including grade, local invasiveness, dissemination into the blood, and tumor relapse after radiotherapy (5-8).
Two bicyclic compounds containing Arg-Gly-Asp (RGD) motifs (RGDf and RGD) were synthesized by cyc... more Two bicyclic compounds containing Arg-Gly-Asp (RGD) motifs (RGDf and RGD) were synthesized by cyclizing the peptide sequence across the macrocyclic ring of DOTA via two non-adjacent carboxylate pendent arms. The Lu(3+) or Cu(2+) complexes of these compounds, c(DOTA-RGDf) and c(DOTA-RGD), showed a metal dependent affinity towards integrin α(v)β(3)in vitro and the (177)Lu(3+) or (64)Cu(2+) labelled derivatives showed specific tumour uptake in MCF7 and U87MG tumour bearing mice.
Driven by the ever-increasing availability of preclinical and clinical positron emission tomograp... more Driven by the ever-increasing availability of preclinical and clinical positron emission tomography (PET) scanners, the use of non-standard PET nuclides has been growing exponentially in the past decade. Largely complementary to the roles of the four standard PET nuclides ((15)O, (13)N, (11)C, and (18)F) in PET, non-standard PET nuclides enable the novel design and synthesis of a wider range of PET tracers to probe a variety of biological events. However, characterized by emitting high energy positrons and cascade gamma rays, non-standard PET nuclides with half-lives ranging from seconds to days must be judiciously chosen for specific applications. Generally, chemistries with non-standard PET nuclides are more manageable given a wealthy of existing standard operation procedures for the preparation of radiotracers for gamma scintigraphy or single photon emission tomography (SPECT). This review describes most of the non-standard PET nuclides that have recently been reported for basic PET research or clinical studies with focus on the unique features of their productions, radiochemical procedures, and applications. The main drawbacks of each nuclide are also discussed along with special considerations that must be given towards its practice use in PET.
Positron emission tomography (PET), a nuclear imaging technique, has become a standard-of-care to... more Positron emission tomography (PET), a nuclear imaging technique, has become a standard-of-care tool for diagnosis, staging treatment planning, and therapeutic efficacy monitoring of patients with cancer or other diseases. 1À5 In addition to clinical applications, PET is also widely used in laboratory research to study the underlying mechanisms of diseases and to facilitate the discovery of new treatments. 6 Development and application of PET imaging probes from the standard PET radionuclides ( 15 O: t 1/2 = 2.04 min; 13 N: t 1/2 = 9.96 min; 11 C: t 1/2 = 20.4 min; and 18 F: t 1/2 = 110 min) suffers from the short half-lives of the radionuclides, which mandates the presence of a radiochemistry laboratory in close proximity to a cyclotron facility. 7 To date, PET probe development using nonstandard PET radionuclides (e.g., Cu, 68 Ga, 89 Zr, 124 I) has drawn considerable interest given its independence from a cyclotron facility. 8,9 Among the nonstandard PET radionuclides, 68 Ga (t 1/2 = 68 min, 89% β + , E β+max = 1.92 MeV, 11% EC) has the most clinical significance as it can be obtained on as-needed basis from a benchtop 68 Ge/ 68 Ga generator system thereby negating the onsite cyclotron requirement. 10À14 Compared to 18 F, the shorter half-life of 68 Ga is not necessarily a hindrance in preclinical or clinical applications because its well-established coordination chemistry enables rapid radiolabeling with high radiochemical yields, 15,16 which provides an opportunity to develop commercial kits to prepare PET probes onsite for diagnostic and prognostic imaging of diseases.
ABSTRACT Objectives: Gold nanoparticles (AuNPs) have gained significant attention in biomedical a... more ABSTRACT Objectives: Gold nanoparticles (AuNPs) have gained significant attention in biomedical applications due to their ease of synthesis, unique physico-chemical properties, and modifiable surface. Copper-64 is an attractive radioisotope in PET research due to its low positron range, availability, and reasonably long half-life (t1/2 = 12.7 hr). It is principally a suitable candidate for the development of AuNP-based in vivo theranostic agents. Herewith, we investigated a facile synthetic approach to incorporate 64Cu into the core of PEGylated AuNPs by metallic doping technique as against to macrocyclic chelation tactic followed in earlier reports. Methods: Synthetic methodology to prepare radioactive AuNPs was developed and optimized. The in vivo integrity of developed [64Cu]AuNPs was also evaluated by a comparative biodistribution study using both radioactive gamma counting (64Cu) and ICP-MS (Au). Results: Our optimized synthesis methodology produced stable, biocompatible (<1% hemolytic) and nanometric [64Cu]AuNPs (51.45±2.73 nm) within 150 min in high yields (>70%). ICP-MS based Au biodistribution pattern was found to be in agreement with 64Cu gamma counting report inferring retention of radio-chemical integrity following in vivo administration. The retention of radiochemical integrity can be ascribed to the direct integration of 64Cu into the lattice structure of AuNPs during synthesis. Further, CT imaging done at 24 hr p.i. showed enhancement in tumor CT signal from 194.1 HU to 233.2 HU (20% CT contrast enhancement), which can be envisaged to the localization of AuNPs in the tumor mass. Conclusions: This investigation reports effective synthesis of stabile, biocompatibile and nanometric gold nanoparticles with high radiolabelling efficiency. High tumor localization, significantly high tumor CT contrast (p<0.005) as well as retention of radio-chemical integrity under in vivo environment submits the prospective potential of developed nanoparticles for preclinical translational applications in tumor imaging and diagnosis.
2013 IEEE Nuclear Science Symposium and Medical Imaging Conference (2013 NSS/MIC), 2013
A quick localization of the tumor site to guide the therapeutic administration is important for a... more A quick localization of the tumor site to guide the therapeutic administration is important for an image guided cancer therapy to decrease both mortalityand morbidity, especially in prolonged procedures, such as photodynamic and photothermal therapies. Consequently, the images have to be updated quickly enough to capture the patient motion and the movement of therapeutic device, which poses a significant challenge on functional imaging probes. Besides increasing the sensitivity of imaging detectors, advanced image processing methods may play an important role to overcome this challenge. In this work, we investigate the effectiveness of the spatiotemporal processing to shorten the acquisition time of each image frame to be able to capture the object motion with good image quality. The simulation study of beta imaging of a moving tumor phantom at different imaging dose levels demonstrates that the spatiotemporal processing can yield superior image quality compared to either a short ac...
ABSTRACT Objectives: Gold nanoparticles (AuNPs) have gained significant attention in biomedical a... more ABSTRACT Objectives: Gold nanoparticles (AuNPs) have gained significant attention in biomedical applications due to their ease of synthesis, unique physico-chemical properties, and modifiable surface. Copper-64 is an attractive radioisotope in PET research due to its low positron range, availability, and reasonably long half-life (t1/2 = 12.7 hr). It is principally a suitable candidate for the development of AuNP-based in vivo theranostic agents. Herewith, we investigated a facile synthetic approach to incorporate 64Cu into the core of PEGylated AuNPs by metallic doping technique as against to macrocyclic chelation tactic followed in earlier reports. Methods: Synthetic methodology to prepare radioactive AuNPs was developed and optimized. The in vivo integrity of developed [64Cu]AuNPs was also evaluated by a comparative biodistribution study using both radioactive gamma counting (64Cu) and ICP-MS (Au). Results: Our optimized synthesis methodology produced stable, biocompatible (<1% hemolytic) and nanometric [64Cu]AuNPs (51.45±2.73 nm) within 150 min in high yields (>70%). ICP-MS based Au biodistribution pattern was found to be in agreement with 64Cu gamma counting report inferring retention of radio-chemical integrity following in vivo administration. The retention of radiochemical integrity can be ascribed to the direct integration of 64Cu into the lattice structure of AuNPs during synthesis. Further, CT imaging done at 24 hr p.i. showed enhancement in tumor CT signal from 194.1 HU to 233.2 HU (20% CT contrast enhancement), which can be envisaged to the localization of AuNPs in the tumor mass. Conclusions: This investigation reports effective synthesis of stabile, biocompatibile and nanometric gold nanoparticles with high radiolabelling efficiency. High tumor localization, significantly high tumor CT contrast (p<0.005) as well as retention of radio-chemical integrity under in vivo environment submits the prospective potential of developed nanoparticles for preclinical translational applications in tumor imaging and diagnosis.
Mouse models of experimental anti-glomerular basement membrane (anti-GBM) nephritis provide an an... more Mouse models of experimental anti-glomerular basement membrane (anti-GBM) nephritis provide an analytical tool for studying spontaneous lupus nephritis. The potential of Positron Emission Tomography (PET) was evaluated using 2-deoxy-2-[ 18 F]fluoro-d-glucose (FDG) as a probe to monitor the progression of anti-GBM induced nephritis in a mouse model. The imaging results were compared to conventional measures of renal function and pathological changes. Serum and urinary vascular cell adhesion molecule-1 (VCAM-1) levels were used as measures of endothelial cell activation and inflammation. Following a challenge with anti-glomerular antibodies, mice exhibited peak changes in serum creatinine, proteinuria, and glomerulonephritis score at 14 days post-challenge (p.c.). In contrast, VCAM levels peaked at day 7 p.c. On dynamic PET images (0-60 min) of day 7, kidneys of the anti-GBM nephritis mice demonstrated a unique pattern of FDG uptake. Compared to the time activity curve (TAC) prior to challenge, a rightward shift was observed after the challenge. By day 10 p.c., kidney FDG uptake was lower than baseline and remained so until the study ended at 21 days p.c. During this time frame measures of renal dysfunction remained high but VCAM-1 levels declined. These changes were accompanied by an increase in kidney volume as measured by Computed Tomography (CT) and intra-abdominal fluid collection. Our results suggest that FDG-PET-CT can be used as a non-invasive imaging tool to longitudinally monitor the progression of renal disease activity in antibody mediated nephritis and the magnitude of renal FDG retention correlates better with early markers of renal inflammation than renal dysfunction.
To image implant-surrounding activated macrophages, a macrophage-specific PET probe was prepared ... more To image implant-surrounding activated macrophages, a macrophage-specific PET probe was prepared by conjugating folic acid (FA) and 2,2′,2″,2‴-(1,4,7,10tetraazacyclododecane-1,4,7,10-tetrayl) tetracetic acid (DOTA) to polyethylene glycol (PEG) and then labeling the conjugate with Ga-68. In vivo PET imaging evaluations demonstrate that the probe is able to detect foreign body reactions, and more importantly, quantify the degree of inflammatory responses to an implanted medical device. These results were further validated by histological analysis.
American journal of nuclear medicine and molecular imaging, 2011
Non-invasive detection of vascular endothelial growth factor receptor 2 (VEGFR2) by positron emis... more Non-invasive detection of vascular endothelial growth factor receptor 2 (VEGFR2) by positron emission tomography (PET) would allow the evaluation of tumor vascular activity in vivo. Recently, a dimeric peptoid, GU40C4, was reported as a highly potent antagonist of VEGFR2 activation inhibiting angiogenesis and tumor growth in vivo. The purpose of this work was to evaluate the potential of this peptoid for PET imaging of VEGFR2 expression. To label GU40C4 and a control peptoid with a positron emitter, (64)Cu (t(1/2) = 12.7 h; β(+): 0.653 MeV, 17.4%), a cysteine was introduced to the C-terminus of the peptoids and then conjugated to a bifunctional chelator (DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) through the maleimide-thiol coupling chemistry. The in vitro binding assay showed a negligible effect of the DOTA conjugation on the VEGFR2 binding affinity of GU40C4. Both peptoid conjugates were efficiently labeled with (64)Cu in high radiochemical yields (> 90%); ...
Non-invasive detection of prostate cancer or metastases still remains a challenge in the field of... more Non-invasive detection of prostate cancer or metastases still remains a challenge in the field of molecular imaging. In our recent work of screening arginine- or lysine-rich peptides for intracellular delivery of a therapeutic agent into prostate cancer cells, an arginine-rich cell permeable peptide (NH(2)GR(11)) was found with an unexpectedly preferential uptake in prostate cancer cell lines. The goal of this work was to develop this peptide as a positron emission tomography (PET) imaging probe for specific detection of distant prostate cancer metastases. The optimal length of arginine-rich peptides was evaluated by the cell uptake efficiency of three fluorescein isothiocyanate (FITC)-tagged oligoarginines (NHGR(9), NHGR(11), and NHGR(13)) in four human prostate cell lines (LNCaP, PZ-HPV-7, DU145, and PC3). Of the three oligoarginines, NH(2)GR(11) showed the highest cell uptake and internalization efficiency with its subcellular localization in cytosol. The biodistribution of FITC-NHGR(9), FITC-NHGR(11), and FITC-NHGR(13) performed in control nude mice displayed the unique preferential accumulation of FITC-NHGR(11) in the prostate tissue. Further in vivo evaluation of FITC-NHGR(11) in PC3 tumor-bearing nude mice revealed elevated uptake of this peptide in tumors as compared to other organs. In vivo pharmacokinetics evaluated with (64)Cu-labeled NH(2)GR(11) showed that the peptide was rapidly cleared from the blood (t(1/2) = 10.7 min) and its elimination half-life was 17.2 h. The PET imaging specificity of (64)Cu-labled NH(2)GR(11) was demonstrated for the detection of prostate cancer in a comparative imaging experiment using two different human cancer xenograft models.
In this study, we report the preparation, luminescence, and targeting properties of folic acid-Cd... more In this study, we report the preparation, luminescence, and targeting properties of folic acid-CdTe quantum dot conjugates. Water-soluble CdTe quantum dots were synthesized and conjugated with folic acid using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-Nhydroxysuccinimide chemistry. The influence of folic acid on the luminescence properties of CdTe quantum dots was investigated, and no energy transfer between them was observed. To investigate the efficiency of folic acid-CdTe nanoconjugates for tumor targeting, pure CdTe quantum dots and folic acid-coated CdTe quantum dots were incubated with human nasopharyngeal epidermal carcinoma cell line with positive expressing folic acid receptors (KB cells) and lung cancer cells without expression of folic acid receptors (A549 cells). For the cancer cells with positive folate receptors (KB cells), the uptake for CdTe quantum dots is very low, but for folic acid-CdTe nanoconjugates, the uptake is very high. For the lung cancer cells without folate receptors (A549 cells), the uptake for folic acid-CdTe nanoconjugates is also very low. The results indicate that folic acid is an effective targeting molecule for tumor cells with overexpressed folate receptors.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 27, 2014
Despite promise for the use of antibodies as molecular imaging agents in PET, their long in vivo ... more Despite promise for the use of antibodies as molecular imaging agents in PET, their long in vivo half-lives result in poor contrast and radiation damage to normal tissue. This study describes an approach to overcome these limitations. Mice bearing human epidermal growth factor receptor type 2 (HER2)-overexpressing tumors were injected with radiolabeled ((124)I, (125)I) HER2-specific antibody (pertuzumab). Pertuzumab injection was followed 8 h later by the delivery of an engineered, antibody-based inhibitor of the receptor, FcRn. Biodistribution analyses and PET were performed at 24 and 48 h after pertuzumab injection. The delivery of the engineered, antibody-based FcRn inhibitor (or Abdeg, for antibody that enhances IgG degradation) results in improved tumor-to-blood ratios, reduced systemic exposure to radiolabel, and increased contrast during PET. Abdegs have considerable potential as agents to stringently regulate antibody dynamics in vivo, resulting in increased contrast during ...
Proceedings of the National Academy of Sciences, 2010
A single nucleotide polymorphism in the DAB2IP gene is associated with risk of aggressive prostat... more A single nucleotide polymorphism in the DAB2IP gene is associated with risk of aggressive prostate cancer (PCa), and loss of DAB2IP expression is frequently detected in metastatic PCa. However, the functional role of DAB2IP in PCa remains unknown. Here, we show that the loss of DAB2IP expression initiates epithelial-to-mesenchymal transition (EMT), which is visualized by repression of E-cadherin and up-regulation of vimentin in both human normal prostate epithelial and prostate carcinoma cells as well as in clinical prostate-cancer specimens. Conversely, restoring DAB2IP in metastatic PCa cells reversed EMT. In DAB2IP knockout mice, prostate epithelial cells exhibited elevated mesenchymal markers, which is characteristic of EMT. Using a human prostate xenograft-mouse model, we observed that knocking down endogenous DAB2IP in human carcinoma cells led to the development of multiple lymph node and distant organ metastases. Moreover, we showed that DAB2IP functions as a scaffold protein in regulating EMT by modulating nuclear β-catenin/Tcell factor activity. These results show the mechanism of DAB2IP in EMT and suggest that assessment of DAB2IP may provide a prognostic biomarker and potential therapeutic target for PCa metastasis. P rostate cancer (PCa) has surpassed lung cancer as the leading cancer among American men (1). In the absence of metastasis, prostate cancer is largely a treatable disease. Thus, early diagnosis of patients who will develop PCa metastasis could reduce the mortality and morbidity associated with this disease. The development of metastasis depends on the migration and invasion of cancer cells from the primary tumor into the surrounding tissue. To acquire such invasive abilities, carcinoma cells may acquire unique phenotypic changes such as epithelial-tomesenchymal transition (EMT). EMT is a highly conserved cellular process that allows polarized, generally immotile epithelial cells to convert to motile mesenchymal-appearing cells. This process was initially recognized during several critical stages of embryonic development and has more recently been implicated in promoting carcinoma invasion and metastasis (2-4). During EMT, three major changes occur: (i) morphological changes from a cobblestone-like monolayer of epithelial cells to dispersed, spindle-shaped mesenchymal cells with migratory protrusions; (ii) changes of differentiation markers from cell-cell junction proteins and cytokeratin intermediate filaments to vimentin filaments and fibronectin; and (iii) acquisition of invasiveness through the extracellular matrix (4). Decreased E-cadherin expression or gain of vimentin expression is closely correlated with various indices of PCa progression, including grade, local invasiveness, dissemination into the blood, and tumor relapse after radiotherapy (5-8).
Two bicyclic compounds containing Arg-Gly-Asp (RGD) motifs (RGDf and RGD) were synthesized by cyc... more Two bicyclic compounds containing Arg-Gly-Asp (RGD) motifs (RGDf and RGD) were synthesized by cyclizing the peptide sequence across the macrocyclic ring of DOTA via two non-adjacent carboxylate pendent arms. The Lu(3+) or Cu(2+) complexes of these compounds, c(DOTA-RGDf) and c(DOTA-RGD), showed a metal dependent affinity towards integrin α(v)β(3)in vitro and the (177)Lu(3+) or (64)Cu(2+) labelled derivatives showed specific tumour uptake in MCF7 and U87MG tumour bearing mice.
Driven by the ever-increasing availability of preclinical and clinical positron emission tomograp... more Driven by the ever-increasing availability of preclinical and clinical positron emission tomography (PET) scanners, the use of non-standard PET nuclides has been growing exponentially in the past decade. Largely complementary to the roles of the four standard PET nuclides ((15)O, (13)N, (11)C, and (18)F) in PET, non-standard PET nuclides enable the novel design and synthesis of a wider range of PET tracers to probe a variety of biological events. However, characterized by emitting high energy positrons and cascade gamma rays, non-standard PET nuclides with half-lives ranging from seconds to days must be judiciously chosen for specific applications. Generally, chemistries with non-standard PET nuclides are more manageable given a wealthy of existing standard operation procedures for the preparation of radiotracers for gamma scintigraphy or single photon emission tomography (SPECT). This review describes most of the non-standard PET nuclides that have recently been reported for basic PET research or clinical studies with focus on the unique features of their productions, radiochemical procedures, and applications. The main drawbacks of each nuclide are also discussed along with special considerations that must be given towards its practice use in PET.
Positron emission tomography (PET), a nuclear imaging technique, has become a standard-of-care to... more Positron emission tomography (PET), a nuclear imaging technique, has become a standard-of-care tool for diagnosis, staging treatment planning, and therapeutic efficacy monitoring of patients with cancer or other diseases. 1À5 In addition to clinical applications, PET is also widely used in laboratory research to study the underlying mechanisms of diseases and to facilitate the discovery of new treatments. 6 Development and application of PET imaging probes from the standard PET radionuclides ( 15 O: t 1/2 = 2.04 min; 13 N: t 1/2 = 9.96 min; 11 C: t 1/2 = 20.4 min; and 18 F: t 1/2 = 110 min) suffers from the short half-lives of the radionuclides, which mandates the presence of a radiochemistry laboratory in close proximity to a cyclotron facility. 7 To date, PET probe development using nonstandard PET radionuclides (e.g., Cu, 68 Ga, 89 Zr, 124 I) has drawn considerable interest given its independence from a cyclotron facility. 8,9 Among the nonstandard PET radionuclides, 68 Ga (t 1/2 = 68 min, 89% β + , E β+max = 1.92 MeV, 11% EC) has the most clinical significance as it can be obtained on as-needed basis from a benchtop 68 Ge/ 68 Ga generator system thereby negating the onsite cyclotron requirement. 10À14 Compared to 18 F, the shorter half-life of 68 Ga is not necessarily a hindrance in preclinical or clinical applications because its well-established coordination chemistry enables rapid radiolabeling with high radiochemical yields, 15,16 which provides an opportunity to develop commercial kits to prepare PET probes onsite for diagnostic and prognostic imaging of diseases.
ABSTRACT Objectives: Gold nanoparticles (AuNPs) have gained significant attention in biomedical a... more ABSTRACT Objectives: Gold nanoparticles (AuNPs) have gained significant attention in biomedical applications due to their ease of synthesis, unique physico-chemical properties, and modifiable surface. Copper-64 is an attractive radioisotope in PET research due to its low positron range, availability, and reasonably long half-life (t1/2 = 12.7 hr). It is principally a suitable candidate for the development of AuNP-based in vivo theranostic agents. Herewith, we investigated a facile synthetic approach to incorporate 64Cu into the core of PEGylated AuNPs by metallic doping technique as against to macrocyclic chelation tactic followed in earlier reports. Methods: Synthetic methodology to prepare radioactive AuNPs was developed and optimized. The in vivo integrity of developed [64Cu]AuNPs was also evaluated by a comparative biodistribution study using both radioactive gamma counting (64Cu) and ICP-MS (Au). Results: Our optimized synthesis methodology produced stable, biocompatible (<1% hemolytic) and nanometric [64Cu]AuNPs (51.45±2.73 nm) within 150 min in high yields (>70%). ICP-MS based Au biodistribution pattern was found to be in agreement with 64Cu gamma counting report inferring retention of radio-chemical integrity following in vivo administration. The retention of radiochemical integrity can be ascribed to the direct integration of 64Cu into the lattice structure of AuNPs during synthesis. Further, CT imaging done at 24 hr p.i. showed enhancement in tumor CT signal from 194.1 HU to 233.2 HU (20% CT contrast enhancement), which can be envisaged to the localization of AuNPs in the tumor mass. Conclusions: This investigation reports effective synthesis of stabile, biocompatibile and nanometric gold nanoparticles with high radiolabelling efficiency. High tumor localization, significantly high tumor CT contrast (p<0.005) as well as retention of radio-chemical integrity under in vivo environment submits the prospective potential of developed nanoparticles for preclinical translational applications in tumor imaging and diagnosis.
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Papers by G. Hao