Search tips
Search criteria

Results 1-25 (151)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
more »
author:("choke, Peter")
1.  Activatable Organic Near-Infrared Fluorescent Probes Based on a Bacteriochlorin Platform: Synthesis and Multicolor in Vivo Imaging with a Single Excitation 
Bioconjugate Chemistry  2014;25(2):362-369.
Near infrared (NIR) fluorescent probes are ideal for in vivo imaging because they offer deeper tissue penetration and lower background autofluorescence. Although most fluorophores in this range are cyanine-based dyes, several new classes of fluorescent NIR probes have been developed. In this study, we developed organic bacteriochlorin derivatives, NMP4 and NMP5, which are excited with a single green light and emit different narrow, well-resolved bands in the NIR (peak of 739 and 770 nm for NMP4 and NMP5, respectively). When conjugated to galactosyl-human serum albumin (hGSA) or glucosyl-human serum albumin (glu-HSA), both targeting H-type lectins, including the β-d-galactose receptor expressing on ovarian cancer, these agents become targeted, activatable, single excitation, multicolor NIR fluorescence probes. After conjugation to either glu-HSA or hGSA, substantial quenching of fluorescence occurs that is reversed after cell binding and internalization. In vitro studies showed higher cancer cell uptake with NMP4 or NMP5 conjugated to hGSA compared to the same conjugates with glu-HSA. In vivo single excitation two-color imaging was performed after intraperitoneal injection of these agents into mice with disseminated ovarian cancer. Excited with a single green light, distinct NIR emission spectra from each fluorophore were detected and could be distinguished with spectral unmixing. In vivo results using a red fluorescence protein (RFP) labeled tumor model of disseminated ovarian cancer demonstrated high sensitivity and specificity for all probes. The success of single excitation, 2-color NIR fluorescence imaging with a new class of bacteriochlorin-based activatable fluorophores, NMP4 and NMP5, paves the way for further exploration of noncyanine dye-based NIR fluorophores.
PMCID: PMC3983136  PMID: 24450401
2.  Imaging and pathology findings after an initial negative MRI-US fusion-guided and 12-core extended sextant prostate biopsy session 
A magnetic resonance imaging-ultrasonography (MRI-US) fusion-guided prostate biopsy increases detection rates compared to an extended sextant biopsy. The imaging characteristics and pathology outcomes of subsequent biopsies in patients with initially negative MRI-US fusion biopsies are described in this study.
We reviewed 855 biopsy sessions of 751 patients (June 2007 to March 2013). The fusion biopsy consisted of two cores per lesion identified on multiparametric MRI (mpMRI) and a 12-core extended sextant transrectal US (TRUS) biopsy. Inclusion criteria were at least two fusion biopsy sessions, with a negative first biopsy and mpMRI before each.
The detection rate on the initial fusion biopsy was 55.3%; 336 patients had negative findings. Forty-one patients had follow-up fusion biopsies, but only 34 of these were preceded by a repeat mpMRI. The median interval between biopsies was 15 months. Fourteen patients (41%) were positive for cancer on the repeat MRI-US fusion biopsy. Age, prostate- specific antigen (PSA), prostate volume, PSA density, digital rectal exam findings, lesion diameter, and changes on imaging were comparable between patients with negative and positive rebiopsies. Of the patients with positive rebiopsies, 79% had a positive TRUS biopsy before referral (P = 0.004). Ten patients had Gleason 3+3 disease, three had 3+4 disease, and one had 4+4 disease.
In patients with a negative MRI-US fusion prostate biopsy and indications for repeat biopsy, the detection rate of the follow-up sessions was lower than the initial detection rate. Of the prostate cancers subsequently found, 93% were low grade (≤3+4). In this low risk group of patients, increasing the follow-up time interval should be considered in the appropriate clinical setting.
PMCID: PMC4289157  PMID: 24509182
3.  Computer Aided-Diagnosis of Prostate Cancer on Multiparametric MRI: A Technical Review of Current Research 
BioMed Research International  2014;2014:789561.
Prostate cancer (PCa) is the most commonly diagnosed cancer among men in the United States. In this paper, we survey computer aided-diagnosis (CADx) systems that use multiparametric magnetic resonance imaging (MP-MRI) for detection and diagnosis of prostate cancer. We review and list mainstream techniques that are commonly utilized in image segmentation, registration, feature extraction, and classification. The performances of 15 state-of-the-art prostate CADx systems are compared through the area under their receiver operating characteristic curves (AUC). Challenges and potential directions to further the research of prostate CADx are discussed in this paper. Further improvements should be investigated to make prostate CADx systems useful in clinical practice.
PMCID: PMC4267002  PMID: 25525604
4.  The Role of MRI in Prostate Cancer Active Surveillance 
BioMed Research International  2014;2014:203906.
Prostate cancer is the most common cancer diagnosis in American men, excluding skin cancer. The clinical behavior of prostate cancer varies from low-grade, slow growing tumors to high-grade aggressive tumors that may ultimately progress to metastases and cause death. Given the high incidence of men diagnosed with prostate cancer, conservative treatment strategies such as active surveillance are critical in the management of prostate cancer to reduce therapeutic complications of radiation therapy or radical prostatectomy. In this review, we will review the role of multiparametric MRI in the selection and follow-up of patients on active surveillance.
PMCID: PMC4266760  PMID: 25525592
5.  Photoimmunotherapy of Gastric Cancer Peritoneal Carcinomatosis in a Mouse Model 
PLoS ONE  2014;9(11):e113276.
Photoimmunotherapy (PIT) is a new cancer treatment that combines the specificity of antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to near infrared (NIR) light. We performed PIT in a model of disseminated gastric cancer peritoneal carcinomatosis and monitored efficacy with in vivo GFP fluorescence imaging. In vitro and in vivo experiments were conducted with a HER2-expressing, GFP-expressing, gastric cancer cell line (N87-GFP). A conjugate comprised of a photosensitizer, IR-700, conjugated to trastuzumab (tra-IR700), followed by NIR light was used for PIT. In vitro PIT was evaluated by measuring cytotoxicity with dead staining and a decrease in GFP fluorescence. In vivo PIT was evaluated in a disseminated peritoneal carcinomatosis model and a flank xenograft using tumor volume measurements and GFP fluorescence intensity. In vivo anti-tumor effects of PIT were confirmed by significant reductions in tumor volume (at day 15, p<0.0001 vs. control) and GFP fluorescence intensity (flank model: at day 3, PIT treated vs. control p<0.01 and peritoneal disseminated model: at day 3 PIT treated vs. control, p<0.05). Cytotoxic effects in vitro were shown to be dependent on the light dose and caused necrotic cell rupture leading to GFP release and a decrease in fluorescence intensity in vitro. Thus, loss of GFP fluorescence served as a useful biomarker of cell necrosis after PIT.
PMCID: PMC4234664  PMID: 25401794
6.  Unsupervised Deconvolution of Dynamic Imaging Reveals Intratumor Vascular Heterogeneity and Repopulation Dynamics 
PLoS ONE  2014;9(11):e112143.
With the existence of biologically distinctive malignant cells originated within the same tumor, intratumor functional heterogeneity is present in many cancers and is often manifested by the intermingled vascular compartments with distinct pharmacokinetics. However, intratumor vascular heterogeneity cannot be resolved directly by most in vivo dynamic imaging. We developed multi-tissue compartment modeling (MTCM), a completely unsupervised method of deconvoluting dynamic imaging series from heterogeneous tumors that can improve vascular characterization in many biological contexts. Applying MTCM to dynamic contrast-enhanced magnetic resonance imaging of breast cancers revealed characteristic intratumor vascular heterogeneity and therapeutic responses that were otherwise undetectable. MTCM is readily applicable to other dynamic imaging modalities for studying intratumor functional and phenotypic heterogeneity, together with a variety of foreseeable applications in the clinic.
PMCID: PMC4224420  PMID: 25379705
7.  Whole Prostate Volume and Shape Changes with the Use of an Inflatable and Flexible Endorectal Coil 
Purpose. To determine to what extent an inflatable endorectal coil (ERC) affects whole prostate (WP) volume and shape during prostate MRI. Materials and Methods. 79 consecutive patients underwent T2W MRI at 3T first with a 6-channel surface coil and then with the combination of a 16-channel surface coil and ERC in the same imaging session. WP volume was assessed by manually contouring the prostate in each T2W axial slice. PSA density was also calculated. The maximum anterior-posterior (AP), left-right (LR), and craniocaudal (CC) prostate dimensions were measured. Changes in WP prostate volume, PSA density, and prostate dimensions were then evaluated. Results. In 79 patients, use of an ERC yielded no significant change in whole prostate volume (0.6 ± 5.7%, P = 0.270) and PSA density (−0.2 ± 5.6%, P = 0.768). However, use of an ERC significantly decreased the AP dimension of the prostate by −8.6 ± 7.8% (P < 0.001), increased LR dimension by 4.5 ± 5.8% (P < 0.001), and increased the CC dimension by 8.8 ± 6.9% (P < 0.001). Conclusion. Use of an ERC in prostate MRI results in the shape deformation of the prostate gland with no significant change in the volume of the prostate measured on T2W MRI. Therefore, WP volumes calculated on ERC MRI can be reliably used in clinical workflow.
PMCID: PMC4211158  PMID: 25374680
8.  Characteristics of Congenital Hepatic Fibrosis in a Large Cohort of Patients With Autosomal Recessive Polycystic Kidney Disease 
Gastroenterology  2012;144(1):112-121.e2.
Autosomal recessive polycystic kidney disease (ARPKD), the most common ciliopathy of childhood, is characterized by congenital hepatic fibrosis and progressive cystic degeneration of kidneys. We aimed to describe congenital hepatic fibrosis in patients with ARPKD, confirmed by detection of mutations in PKHD1.
Patients with ARPKD and congenital hepatic fibrosis were evaluated at the National Institutes of Health from 2003 to 2009. We analyzed clinical, molecular, and imaging data from 73 patients (age, 1–56 years; average, 12.7 ± 13.1 years) with kidney and liver involvement (based on clinical, imaging, or biopsy analyses) and mutations in PKHD1.
Initial symptoms were liver related in 26% of patients, and others presented with kidney disease. One patient underwent liver and kidney transplantation, and 10 others received kidney transplants. Four presented with cholangitis and one with variceal bleeding. Sixty-nine percent of patients had enlarged left lobes on magnetic resonance imaging, 92% had increased liver echogenicity on ultrasonography, and 65% had splenomegaly. Splenomegaly started early in life; 60% of children younger than 5 years had enlarged spleens. Spleen volume had an inverse correlation with platelet count and prothrombin time but not with serum albumin level. Platelet count was the best predictor of spleen volume (area under the curve of 0.88905), and spleen length corrected for patient’s height correlated inversely with platelet count (R2 = 0.42, P < .0001). Spleen volume did not correlate with renal function or type of PKHD1 mutation. Twenty-two of 31 patients who underwent endoscopy were found to have varices. Five had variceal bleeding, and 2 had portosystemic shunts. Forty-percent had Caroli syndrome, and 30% had an isolated dilated common bile duct.
Platelet count is the best predictor of the severity of portal hypertension, which has early onset but is underdiagnosed in patients with ARPKD. Seventy percent of patients with ARPKD have biliary abnormalities. Kidney and liver disease are independent, and variability in severity is not explainable by type of PKHD1 mutation;
PMCID: PMC4162098  PMID: 23041322
Ductal Plate Malformation; Noncirrhotic Portal Hypertension; Genetics; Hepatorenal Fibrocystic Disease
9.  Editorial Comments 
The Journal of urology  2012;189(1):92.
PMCID: PMC4136648  PMID: 23158414
The Journal of urology  2002;167(1):10-15.
Thermal tissue ablation with radio frequency energy is an experimental treatment of renal tumor. We report early results of an ongoing trial of percutaneous radio frequency ablation for small renal tumors.
Materials and Methods
Patients with percutaneously accessible renal tumors were evaluated for radio frequency ablation. Tumors were solid on computerized tomography (CT), 3 cm. or less in diameter and enlarging during at least 1 year. Ablation was performed at the Interventional Radiology suite under ultrasound and/or CT guidance. A 50 W., 460 kHz. electrosurgical generator delivered radio frequency energy via a percutaneously placed 15 gauge coaxial probe. At least 2, 10 to 12-minute ablation cycles were applied to each lesion. Patients were observed overnight before discharge from hospital and reevaluated 2 months later.
A total of 24 ablations were performed in 21 patients with renal tumor, including solid von Hippel-Lindau clear cell tumor in 19 and hereditary papillary renal cancer 2. Most (22 of 24) procedures were performed with patients under conscious sedation. At 2 months postoperatively mean tumor diameter plus or minus standard deviation decreased from 2.4 ± 0.4 to 2.0 ± 0.5 cm. (p = 0.001), and a majority of tumors (19 of 24, 79%) ceased to be enhanced on contrast CT. Mean serum creatinine plus or minus standard deviation was unchanged during this interval (1.0 ± 0.2 mg./dl.). No major and 4 minor complications were encountered, including 2 episodes each of transient psoas pain and flank skin numbness.
Percutaneous radio frequency ablation of small renal tumor is well tolerated and minimally invasive. It will remain experimental until procedural and imaging parameters that correlate with tumor destruction are validated.
PMCID: PMC4136670  PMID: 11743264
kidney neoplasms; carcinoma; renal cell; surgical procedures; minimally invasive
11.  Magnetic resonance imaging (MRI)-guided transurethral ultrasound therapy of the prostate: a preclinical study with radiological and pathological correlation using customised MRI-based moulds 
BJU international  2013;112(4):10.1111/bju.12126.
To characterise the feasibility and safety of a novel transurethral ultrasound (US)-therapy device combined with real-time multi-plane magnetic resonance imaging (MRI)-based temperature monitoring and temperature feedback control, to enable spatiotemporally precise regional ablation of simulated prostate gland lesions in a preclinical canine model.
To correlate ablation volumes measured with intra-procedural cumulative thermal damage estimates, post-procedural MRI, and histopathology.
Materials and methods
Three dogs were treated with three targeted ablations each, using a prototype MRI-guided transurethral US-therapy system (Philips Healthcare, Vantaa, Finland).
MRI provided images for treatment planning, guidance, real-time multi-planar thermometry, as well as post-treatment evaluation of efficacy.
After treatment, specimens underwent histopathological analysis to determine the extent of necrosis and cell viability.
Statistical analyses (Pearson’s correlation, Student’s t-test) were used to evaluate the correlation between ablation volumes measured with intra-procedural cumulative thermal damage estimates, post-procedural MRI, and histopathology.
MRI combined with a transurethral US-therapy device enabled multi-planar temperature monitoring at the target as well as in surrounding tissues, allowing for safe, targeted, and controlled ablations of prescribed lesions.
Ablated volumes measured by cumulative thermal dose positively correlated with volumes determined by histopathological analysis (r2 0.83, P < 0.001).
Post-procedural contrast-enhanced and diffusion-weighted MRI showed a positive correlation with non-viable areas on histopathological analysis (r2 0.89, P < 0.001, and r20.91, P = 0.003, respectively).
Additionally, there was a positive correlation between ablated volumes according to cumulative thermal dose and volumes identified on post-procedural contrast-enhanced MRI (r2 0.77, P < 0.01).
There was no difference in mean ablation volumes assessed with the various analysis methods (P > 0.05, Student’s t-test).
MRI-guided transurethral US therapy enabled safe and targeted ablations of prescribed lesions in a preclinical canine prostate model.
Ablation volumes were reliably predicted by intra- and post-procedural imaging.
Clinical studies are needed to confirm the feasibility, safety, oncological control, and functional outcomes of this therapy in patients in whom focal therapy is indicated.
PMCID: PMC3816743  PMID: 23746198
thermal ablation; therapeutic ultrasound; thermotherapy; minimally invasive therapy; magnetic resonance imaging; image-guided therapy
12.  Functional MRI in Prostate Cancer Detection 
BioMed Research International  2014;2014:590638.
Multiparametric magnetic resonance imaging (MP-MRI) has emerged as a promising method for the detection of prostate cancer. The functional MRI components of the MP-MRI consist of the diffusion weighted MRI, dynamic contrast enhanced MRI, and magnetic resonance spectroscopic imaging. The purpose of this paper is to review the existing literature about the use of functional MRI in prostate cancer detection.
PMCID: PMC4158139  PMID: 25215284
13.  Polychromatic in vivo imaging of multiple targets using visible and near infrared light 
Advanced drug delivery reviews  2012;65(8):1112-1119.
Conventional diagnostic imaging methods such as X-ray CT, MRI, and nuclear medicine are inherently monochromatic meaning that they can depict only one molecular target at a time. Optical imaging has the unique ability to be polychromatic and therefore multi-color imaging employing targeted agents conjugated to fluorophores of varying wavelength enables multiple simultaneous readouts thus providing greater multiplexed information. Numerous successful multicolor imaging techniques have recently been reported using optical imaging in vivo animal disease models, thus adding to a growing body of research supporting the clinical viability and applicability of these technologies. Herein, we review multicolor optical imaging from the basic chemistry and physics perspective and then extend this to biological and medical applications.
PMCID: PMC3672391  PMID: 23220327
Molecular imaging; Fluorescence; Multi-color; Cancer; Surgery; Endoscope; Fluorescence-guidance
14.  Cediranib for Metastatic Alveolar Soft Part Sarcoma 
Journal of Clinical Oncology  2013;31(18):2296-2302.
Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor, for which no effective standard systemic treatment exists for patients with unresectable disease. Cediranib is a potent, oral small-molecule inhibitor of all three vascular endothelial growth factor receptors (VEGFRs).
Patients and Methods
We conducted a phase II trial of once-daily cediranib (30 mg) given in 28-day cycles for patients with metastatic, unresectable ASPS to determine the objective response rate (ORR). We also compared gene expression profiles in pre- and post-treatment tumor biopsies and evaluated the effect of cediranib on tumor proliferation and angiogenesis using positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging.
Of 46 patients enrolled, 43 were evaluable for response at the time of analysis. The ORR was 35%, with 15 of 43 patients achieving a partial response. Twenty-six patients (60%) had stable disease as the best response, with a disease control rate (partial response + stable disease) at 24 weeks of 84%. Microarray analysis with validation by quantitative real-time polymerase chain reaction on paired tumor biopsies from eight patients demonstrated downregulation of genes related to vasculogenesis.
In this largest prospective trial to date of systemic therapy for metastatic ASPS, we observed that cediranib has substantial single-agent activity, producing an ORR of 35% and a disease control rate of 84% at 24 weeks. On the basis of these results, an open-label, multicenter, randomized phase II registration trial is currently being conducted for patients with metastatic ASPS comparing cediranib with another VEGFR inhibitor, sunitinib.
PMCID: PMC3677840  PMID: 23630200
15.  Activatable fluorescent cys-diabody conjugated with indocyanine green derivative: consideration of fluorescent catabolite kinetics on molecular imaging 
Journal of Biomedical Optics  2013;18(10):101304.
Antibody fragments including diabodies have more desirable pharmacokinetic characteristics than whole antibodies. An activatable optical imaging probe based on a cys-diabody targeting prostate-specific membrane antigen conjugated with the near-infrared fluorophore, indocyanine green (ICG), was designed such that it can only be activated when bound to the tumor, leading to high signal-to-background ratios. We employed short polyethylene glycol (PEG) linkers between the ICG and the reactive functional group (Sulfo-OSu group), resulting in covalent conjugation of ICG to the cys-diabody, which led to lower dissociation of ICG from cys-diabody early after injection, reducing hepatic uptake. However, unexpectedly, high and long-term fluorescence was observed in the kidneys, liver, and blood pool more than 1 h after injection of the cys-diabody PEG-ICG conjugate. A biodistribution study using I125-labeled cys-diabody-ICG showed immediate uptake in the kidneys followed by a rapid decrease, while gastric activity increased due to released radioiodine during rapid cys-diabody-ICG catabolism in the kidneys. To avoid this catabolic pathway, it would be preferable to use antibody fragments large enough not to be filtered through glomerulus or to conjugate the fragments with fluorescent dyes that are readily excreted into urine when cleaved from the cys-diabody to achieve high tumor-specific detection.
PMCID: PMC3677842  PMID: 23752742
optical probe; activatable imaging; diabody; indocyanine green; polyethylene glycol linker; catabolism
16.  Phase II clinical trial of cediranib in patients with metastatic castration-resistant prostate cancer 
BJU international  2013;111(8):1269-1280.
To assess the efficacy and toxicity of cediranib, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, in patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel-based therapy.
Patients and Methods
The study used a Simon two-stage trial design, which required at least two of 12 patients in the first cohort to be progression-free at 6 months.
We enrolled a total of 35 evaluable patients who all received cediranib 20 mg orally daily.
In a second cohort, 23 additional patients received prednisone 10 mg daily with cediranib.
Endpoints included tumour response, progression-free survival (PFS), overall survival (OS), vascular permeability via dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and toxicity.
A total of 59 patients were enrolled, of whom 67% had received two or more previous chemotherapy regimens.
Six of 39 patients with measurable disease had confirmed partial responses and one had an unconfirmed partial response.
At 6 months, 43.9% of patients were progression-free; the median PFS and OS periods for all patients were 3.7 months and 10.1 months, respectively.
We found that the DCE-MRI variables baseline transport constant (Ktrans) and rate constant at day 28 were significantly associated with PFS in univariate analyses, but only baseline Ktrans remained significant when considered jointly.
The most frequent toxicities were hypertension, fatigue, anorexia and weight loss; the addition of prednisone reduced the incidence of constitutional toxicities.
This study demonstrated that cediranib was generally well tolerated with some anti-tumour activity in highly pretreated patients with metastatic CRPC who had progressive disease after docetaxel-based therapy.
PMCID: PMC3660464  PMID: 23419134
castration-resistant prostate cancer; angiogenesis inhibitors; cediranib; AZD2171
17.  The effects of conjugate and light dose on photo-immunotherapy induced cytotoxicity 
BMC Cancer  2014;14:389.
Photoimmunotherapy (PIT) is a highly cell-selective cancer therapy, which employs monoclonal antibodies conjugated to a potent photosensitizer (mAb-IR700). Once the conjugate has bound to the target cell, exposure to near infrared (NIR) light induces necrosis only in targeted cells with minimal damage to adjacent normal cells in vivo. Herein, we report on the effect of altering mAb-IR700 and light power and dose on effectiveness of PIT.
For evaluating cytotoxicity, we employed ATP-dependent bioluminescence imaging using a luciferase-transfected MDA-MB-468luc cell line, which expresses EGFR and luciferase. In in vitro experiments, panitumumab-IR700 (Pan-IR700) concentration was varied in combination with varying NIR light doses administered by an LED at one of three power settings, 100 mA and 400 mA continuous wave and 1733 mA intermittent wave. For in vivo experiments, the MDA-MB-468luc orthotopic breast cancer was treated with varying doses of Pan-IR700 and light.
The in vitro cell study demonstrated that PIT induced cytotoxicity depended on light dose, when the conjugate concentration was kept constant. Increasing the dose of Pan-IR700 allowed lowering of the light dose to achieve equal effects thus indicating that for a given level of efficacy, the conjugate concentration multiplied by the light dose was a constant. A similar relationship between conjugate and light dose was observed in vivo.
The efficacy of PIT is defined by the product of the number of bound antibody conjugates and the dose of NIR light and can be achieve equally with continuous and pulse wave LED light using different power densities.
PMCID: PMC4055275  PMID: 24885589
Photoimmunotherapy; Near infrared light; Light dose; Necrosis; Cytotoxicity
18.  Short PEG-Linkers Improve the Performance of Targeted, Activatable Monoclonal Antibody-Indocyanine Green Optical Imaging Probes 
Bioconjugate chemistry  2013;24(5):811-816.
The ability to switch optical imaging probes from the quenched (off) to the active state (on) has greatly improved target to background ratios. The optimal activation efficiency of an optical probe depends on complete quenching before activation and complete de-quenching after activation. For instance, monoclonal antibody-indocyanine green (mAb-ICG) conjugates, which are promising agents for clinical translation, are normally quenched but can be activated, when bound to a cell surface receptor and internalized. However, the small fraction of commonly used ICG derivative (ICG-Sulfo-OSu) can bind noncovalently to its mAb and is thus, gradually released from the mAb leading to relatively high background signal especially in the liver and the abdomen. In this study, we re-engineered a mAb-ICG conjugate, (Panitumumab-ICG) using bifunctional ICG derivatives (ICG-PEG4-Sulfo-OSu and ICG-PEG8-Sulfo-OSu) with short polyethylene glycol (PEG) linkers. Higher covalent binding (70–86%) was observed using the bifunctional ICG with short PEG linkers resulting in less in vivo non-covalent dissociation. Panitumumab-ICG conjugates with short PEG linkers were able to detect human epidermal growth factor receptor 1 (EGFR)-positive tumors with high tumor-to-background ratios (15.8 and 6.9 for EGFR positive tumor-to-negative tumor and tumor-to-liver ratios, respectively, at 3 d postinjection).
PMCID: PMC3674550  PMID: 23600922
indocyanine green; PEG linker; fluorescence imaging; activatable; monoclonal antibody
19.  Immuno-PET imaging of the hepatocyte growth factor receptor Met using the one-armed antibody Onartuzumab (MetMAb) 
The over-expression and -activation of hepatocyte growth factor receptor (Met) in various cancers has been linked to increased proliferation, progression to metastatic disease, and drug resistance. Developing a PET imaging agent to assess Met expression would aid in diagnosis and monitoring responses to Met-targeted therapies. In these studies Onartuzumab (MetMAb), the experimental therapeutic one-armed monoclonal antibody, was radiolabeled with 76Br or 89Zr and evaluated as an imaging agent in Met expressing cell lines and mouse xenografts.
89Zr-df-Onartuzumab was synthesized using a desferrioxamine-Onartuzumab conjugate (df-Onartuzumab); 76Br-Onartuzumab was labeled directly. Met binding studies were performed using the human tumor-derived cell lines MKN-45, SNU-16 and U87-MG, which have relatively high, moderate and low levels of Met, respectively. Biodistribution and microPET imaging studies were performed in MKN-45 and U87-MG xenografts.
76Br-Onartuzumab and 89Zr-df-Onartuzumab exhibited specific, high affinity Met binding (nM) that was concordant with established Met expression levels. In MKN-45 (gastric carcinoma) xenografts, both tracers cleared slowly from non-target tissues with the highest uptakes in tumor, blood, kidney, and lung. 76Br-Onartuzumab MKN-45 tumor uptakes remained relatively constant from 18 h (5%ID/g) to 48 h (3%ID/g) and exhibited tumor:muscle ratios ranging from 4:1 to 6:1. In contrast, 89Zr-df-Onartuzumab MKN-45 tumor uptake continued to accumulate from 18 h (10%ID/g) to 120 h (23%ID/g), attaining tumor:muscle ratios ranging from 20:1 to 27:1. MKN-45 tumors were easily visualized in imaging studies with both tracers at 18 h but after 48 h 89Zr-df-Onartuzumab image quality improved with at least 2 fold greater tumor uptakes compared to non-target tissues. MKN-45 tumor uptakes for both tracers correlated significantly with tumor mass and Met expression, and were not affected by the presence of plasma shed Met.
89Zr-df-Onartuzumab and 76Br-Onartuzumab specifically targeted Met in vitro and in vivo; 89Zr-df-Onartuzumab achieved higher tumor uptakes and tumor:muscle ratios than 76Br-Onartuzumab at later times suggesting that 89Zr-df-Onartuzumab would be better suited to image Met for diagnostic and prognostic purposes.
PMCID: PMC3982858  PMID: 22917884
Immuno-PET imaging; Met receptor; Onartuzumab; MetMAb
20.  Performance Characteristics of a Positron Projection Imager For Mouse Whole-body Imaging 
Nuclear medicine and biology  2013;40(3):321-330.
We describe a prototype positron projection imager (PPI) for visualizing the whole-body biodistribution of positron-emitting compounds in mouse-size animals. The final version of the PPI will be integrated into the MONICA portable dual-gamma camera system to allow the user to interchangeably image either single photon or positron-emitting compounds in a shared software and hardware environment.
A mouse is placed in the mid-plane between two identical, opposed, pixelated LYSO arrays separated by 21.8-cm and in time coincidence. An image of the distribution of positron decays in the animal is formed on this mid-plane by coincidence events that fall within a small cone angle to the perpendicular to the two detectors and within a user-specified energy window. We measured the imaging performance of this device with phantoms and in tests performed in mice injected with various compounds labeled with positron-emitting isotopes.
Representative performance measurements yielded the following results (energy window 250–650 keV, cone angle 3.5-degrees): resolution in the image mid-plane, 1.66-mm (FWHM), resolution ±1.5-cm above and below the image plane, 2.2-mm (FWHM), sensitivity: 0.237-cps/kBq (8.76-cps/μCi) 18F (0.024% absolute). Energy resolution was 15.9% with a linear-count-rate operating range of 0–14.8 MBq (0–400 μCi) and a corrected sensitivity variation across the field-of-view of <3%. Whole-body distributions of [18F] FDG and [18F] fluoride were well visualized in mice of typical size.
Performance measurements and field studies indicate that the PPI is well suited to whole-body positron projection imaging of mice. When integrated into the MONICA gamma camera system, the PPI may be particularly useful early in the drug development cycle where, like MONICA, basic whole-body biodistribution data can direct future development of the agent under study and where logistical factors (e.g., available imaging space, non-portability, and cost) may be limitations.
PMCID: PMC3596450  PMID: 23402672
Pre-clinical imaging; cancer drug development; mouse whole-body imaging; positron projection imaging
21.  Tracking the Luminal Exposure and Lymphatic Drainage Pathways of Intravaginal and Intrarectal Inocula Used in Nonhuman Primate Models of HIV Transmission 
PLoS ONE  2014;9(3):e92830.
Over 80% of sexual HIV-1 transmissions originate from a single viral variant, but the underlying basis for this transmission bottleneck remains to be elucidated. Nonhuman primate models of mucosal virus transmission allow opportunities to gain insight into the basis of this mucosal bottleneck. We used simulated inocula consisting of either non-infectious vital dye or contrast dye with non-invasive magnetic resonance imaging (MRI) to visualize mucosal exposure and passive lymphatic drainage patterns following vaginal and rectal exposures in Indian origin rhesus macaques. Results revealed a limited overall distance of dye coverage from the anal verge following 1 ml (n  = 8) intrarectally administered, which greatly increased with a 3 ml (n = 8) volume. Intravaginal dye exposure using 2 ml revealed complete coverage of the mucosa of the vagina and ectocervix, however dye was not detectable in the endocervix, uterus, fallopian tubes or ovaries in nuliparous sexually mature rhesus macaques (n = 9). In addition, following submucosal and intranodal injections of vital dye or MRI contrast dye in the rectum (n = 9), or distal and proximal vagina (n = 4), the lymphatic drainage pathways were identified as first the internal then common iliac chain followed by para-aortic lymph nodes. Drainage from the distal descending colon (n = 8) was via the para-colonic lymph nodes followed by the inferior mesenteric and para-aortic lymph nodes. Analysis after vaginal challenge with infectious SIVmac239 followed by euthanasia at day 3 revealed a pattern of viral dissemination consistent with the imaging results. These results provide insights into potential patterns of viral dissemination that can help guide efforts to better elucidate the earliest events of virus transmission and potential intervention strategies.
PMCID: PMC3965472  PMID: 24667371
22.  18F-Fluorodeoxyglucose positron emission tomography in the management of patients with thymic epithelial tumors 
There is limited data regarding the role of 18F-Fluorodeoxyglucose positron emission tomography ([18F]-FDG PET) imaging in management of patients with thymic epithelial tumors (TET). The primary objective of this study was to assess the usefulness of early [18F]-FDG PET to monitor treatment efficacy and its correlation with Response Evaluation Criteria in Solid Tumors (RECIST) in patients with TETs.
Experimental Design
[18F]-FDG PET/CT scans were performed at baseline and after six weeks of treatment in patients enrolled in two phase II and one phase I/II clinical trials. Based on data from other solid tumors, metabolic response was defined as a reduction of [18F]-FDG uptake by more than 30% as assessed by average standardized uptake values (SUV) of up to five most metabolically active lesions.
Fifty six patients with unresectable Masaoka stage III or IV TETs were included. There was a close correlation between early metabolic response and subsequent best response using RECIST (P <0.0001 to 0.0003): sensitivity and specificity for prediction of best response were 95% and 100% respectively. Metabolic responders had significantly longer progression-free survival (median 11.5 vs. 4.6 months, P = 0.044) and a trend towards longer overall survival (median 31.8 vs. 18.4 months, P = 0.14) than non-responders. [18F]-FDG uptake was significantly higher in thymic carcinoma compared with thymoma (P= 0.0004 to 0.0010).
In patients with advanced TETs, early metabolic response closely correlates with outcome of therapy. [18F]-FDG PET may be used to monitor treatment efficacy and assess histological differences in patients with advanced TETs.
PMCID: PMC3602145  PMID: 23382114
thymoma; thymic carcinoma; 18F-Fluorodeoxyglucose positron emission tomography; Response Evaluation Criteria in Solid Tumors; Metabolic response
23.  Gaussian Process Inference for Estimating Pharmacokinetic Parameters of Dynamic Contrast-Enhanced MR Images 
In this paper, we propose a new pharmacokinetic model for parameter estimation of dynamic contrast-enhanced (DCE) MRI by using Gaussian process inference. Our model is based on the Tofts dual-compartment model for the description of tracer kinetics and the observed time series from DCE-MRI is treated as a Gaussian stochastic process. The parameter estimation is done through a maximum likelihood approach and we propose a variant of the coordinate descent method to solve this likelihood maximization problem. The new model was shown to outperform a baseline method on simulated data. Parametric maps generated on prostate DCE data with the new model also provided better enhancement of tumors, lower intensity on false positives, and better boundary delineation when compared with the baseline method. New statistical parameter maps from the process model were also found to be informative, particularly when paired with the PK parameter maps.
PMCID: PMC3936338  PMID: 23286178
DCE-MRI; Gaussian Stochastic Process; Pharmacokinetic Model; Bayesian Inference; Coordinate Descent Optimization
25.  Markedly Enhanced Permeability and Retention Effects Induced by Photo-Immunotherapy of Tumors 
ACS nano  2012;7(1):717-724.
A major barrier to cancer treatment is the inability to deliver sufficient concentrations of drug to the tumor without incurring systemic toxicities. Nanomaterials are appealing because they can carry a large drug payload, however, tumor delivery is limited by modest leakage and retention in most tumors. We observed that after photoimmunotherapy (PIT), which is a light mediated treatment based on an antibody-photosensitizer conjugate, there was surprisingly high leakage of nanosized (10–200 nm) agents into the tumor bed. PIT rapidly induced death in perivascular cancer cells leading to immediate and dramatic increases in vascular permeability resulting in up to 24-fold greater accumulation of nanonanomaterials within the PIT-treated tumor compared with controls, an effect termed “super-enhanced permeability and retention” (SUPR). In a treatment study, PIT followed by liposome-containing daunorubicin, DaunoXome (diameter 50 nm), resulted in greater survival in tumor-bearing mice than either PIT or DaunoXome alone. Thus, PIT greatly enhances delivery of nanosized reagents and thus holds promise to improve therapeutic responses.
PMCID: PMC3586604  PMID: 23214407
drug delivery; super-enhanced permeability and retention effect; photoimmunotherapy; nanomaterials; cancer imaging; cancer therapy

Results 1-25 (151)