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1.  Non-invasive, Multimodal Functional Imaging of the Intestine with Frozen Micellar Naphthalocyanines 
Nature nanotechnology  2014;9(8):631-638.
There is a need for safer and improved methods for non-invasive imaging of the gastrointestinal tract. Modalities based on X-ray radiation, magnetic resonance and ultrasound suffer from limitations with respect to safety, accessibility or lack of adequate contrast. Functional intestinal imaging of dynamic gut processes has not been practical using existing approaches. Here, we report the development of a family of nanoparticles that can withstand the harsh conditions of the stomach and intestine, avoid systemic absorption, and give rise to good optical contrast for photoacoustic imaging. The hydrophobicity of naphthalocyanine dyes was exploited to generate purified ~20 nm frozen micelles, which we call nanonaps, with tunable and large near-infrared absorption values (>1000). Unlike conventional chromophores, nanonaps exhibited non-shifting spectra at ultrahigh optical densities and, following oral administration in mice, passed safely through the gastrointestinal tract. Non-invasive, non-ionizing photoacoustic techniques were used to visualize nanonap intestinal distribution with low background and remarkable resolution with 0.5 cm depth, and enabled real-time intestinal functional imaging with ultrasound co-registration. Positron emission tomography following seamless nanonap radiolabelling allowed complementary whole body imaging.
PMCID: PMC4130353  PMID: 24997526
2.  52Mn Production for PET/MRI Tracking Of Human Stem Cells Expressing Divalent Metal Transporter 1 (DMT1) 
Theranostics  2015;5(3):227-239.
There is a growing demand for long-term in vivo stem cell imaging for assessing cell therapy techniques and guiding therapeutic decisions. This work develops the production of 52Mn and establishes proof of concept for the use of divalent metal transporter 1 (DMT1) as a positron emission tomography (PET) and magnetic resonance imaging (MRI) reporter gene for stem cell tracking in the rat brain. 52Mn was produced via proton irradiation of a natural chromium target. In a comparison of two 52Mn separation methods, solvent-solvent extraction was preferred over ion exchange chromatography because of reduced chromium impurities and higher 52Mn recovery. In vitro uptake of Mn-based PET and MRI contrast agents (52Mn2+ and Mn2+, respectively) was enhanced in DMT1 over-expressing human neural progenitor cells (hNPC-DMT1) compared to wild-type control cells (hNPC-WT). After cell transplantation in the rat striatum, increased uptake of Mn-based contrast agents in grafted hNPC-DMT1 was detected in in vivo manganese-enhanced MRI (MEMRI) and ex vivo PET and autoradiography. These initial studies indicate that this approach holds promise for dual-modality PET/MR tracking of transplanted stem cells in the central nervous system and prompt further investigation into the clinical applicability of this technique.
PMCID: PMC4279187  PMID: 25553111
Positron emission tomography (PET); manganese-enhanced magnetic resonance imaging (MEMRI); multimodality imaging; manganese-52 (52Mn); cell tracking; reporter gene.
3.  Chelator-Free Synthesis of a Dual-Modality PET/MRI Agent 
Angewandte Chemie (International ed. in English)  2013;52(50):10.1002/anie.201306306.
PMCID: PMC3855680  PMID: 24166933
radioarsenic; SPION; PET; MRI; lymph node mapping; multimodality imaging
4.  Quantum Dot-Based Nanoprobes for In Vivo Targeted Imaging 
Current molecular medicine  2013;13(10):1549-1567.
Fluorescent semiconductor quantum dots (QDs) have attracted tremendous attention over the last decade. The superior optical properties of QDs over conventional organic dyes make them attractive labels for a wide variety of biomedical applications, whereas their potential toxicity and instability in biological environment has puzzled scientific researchers. Much research effort has been devoted to surface modification and functionalization of QDs to make them versatile probes for biomedical applications, and significant progress has been made over the last several years. This review article aims to describe the current state-of-the-art of the synthesis, modification, bioconjugation, and applications of QDs for in vivo targeted imaging. In addition, QD-based multifunctional nanoprobes are also summarized.
PMCID: PMC3838460  PMID: 24206136
quantum dots (QDs); nanoparticles (NPs); molecular imaging; cancer nanotechnology; multimodality imaging; near-infrared fluorescence (NIRF)
5.  Multimodality Imaging of CXCR4 in Cancer: Current Status towards Clinical Translation 
Current molecular medicine  2013;13(10):1538-1548.
CXCR4 has gained tremendous attention over the last decade, since it was found to be up-regulated in a wide variety of cancer types, in addition to its role in human immunodeficiency virus infection. Molecular imaging of CXCR4 with small molecules, peptides, and antibodies has been a vibrant research area over the last several years. In this review article, we will summarize the current status of imaging CXCR4 with fluorescence, bioluminescence, positron emission tomography, and single-photon emission computed tomography techniques. Since each molecular imaging modality has its own strengths and weaknesses, dual-modality probes that can be detected by more than one imaging techniques have also been investigated. Non-invasive visualization of CXCR4 expression has potential clinical applications in multiple facets of patient management. While big strides have been made over the last several years in the development of CXCR4-targeted imaging probes, clinical translation and investigation of these agents in cancer patients are eagerly awaited. Since CXCR4 is also involved in many other diseases beyond cancer, these clinically translatable probes can also play multiple roles in other pathological disorders such as myocardial infarction and several immunodeficiency disorders.
PMCID: PMC3838476  PMID: 24206137
CXCR4; molecular imaging; positron emission tomography (PET); metastasis; chemokine receptor; chemokine; cancer
6.  Biomedical Applications of Zinc Oxide Nanomaterials 
Current molecular medicine  2013;13(10):1633-1645.
Nanotechnology has witnessed tremendous advancement over the last several decades. Zinc oxide (ZnO), which can exhibit a wide variety of nanostructures, possesses unique semiconducting, optical, and piezoelectric properties hence has been investigated for a wide variety of applications. One of the most important features of ZnO nanomaterials is low toxicity and biodegradability. Zn2+ is an indispensable trace element for adults (~10 mg of Zn2+ per day is recommended) and it is involved in various aspects of metabolism. Chemically, the surface of ZnO is rich in -OH groups, which can be readily functionalized by various surface decorating molecules. In this review article, we summarized the current status of the use of ZnO nanomaterials for biomedical applications, such as biomedical imaging (which includes fluorescence, magnetic resonance, positron emission tomography, as well as dual-modality imaging), drug delivery, gene delivery, and biosensing of a wide array of molecules of interest. Research in biomedical applications of ZnO nanomaterials will continue to flourish over the next decade, and much research effort will be needed to develop biocompatible/biodegradable ZnO nanoplatforms for potential clinical translation.
PMCID: PMC3838497  PMID: 24206130
Zinc oxide; molecular imaging; cancer; nanosensor; drug delivery; gene delivery; personalized medicine
7.  Biomedical Applications of Functionalized Hollow Mesoporous Silica Nanoparticles: Focusing on Molecular Imaging 
Nanomedicine (London, England)  2013;8(12):10.2217/nnm.13.177.
Hollow mesoporous silica nanoparticles (HMSNs), with a large cavity inside each original mesoporous silica nanoparticle (MSN), have recently gained increasing interest due to their tremendous potential for cancer imaging and therapy. The last several years have witnessed a rapid development in engineering of functionalized HMSNs (i.e. f-HMSNs) with various types of inorganic functional nanocrystals integrated into the system for imaging and therapeutic applications. In this review article, we summarize the recent progress in the design and biological applications of f-HMSNs, with a special emphasis on molecular imaging. Commonly used synthetic strategies for the generation of high quality HMSNs will be discussed in detail, followed by a systematic review of engineered f-HMSNs for optical, positron emission tomography, magnetic resonance, and ultrasound imaging in preclinical studies. Lastly, we also discuss the challenges and future research directions regarding the use of f-HMSNs for cancer imaging and therapy.
PMCID: PMC3844935  PMID: 24279491
Hollow mesoporous silica nanoparticles (HMSNs); molecular imaging; nanomedicine; theranostics; cancer; optical imaging; positron emission tomography (PET)
8.  Functionalized Upconversion Nanoparticles: Versatile Nanoplatforms for Translational Research 
Current molecular medicine  2013;13(10):1613-1632.
The design, application, and translation of targeted multimodality molecular imaging probes based on nanotechnology has attracted increasing attentions during the last decade and will continue to play vital roles in cancer diagnosis and personalized medicine. With the growing awareness of drawbacks of traditional organic dyes and quantum dots, biocompatible lanthanide ion doped upconversion nanoparticles have emerged as promising candidates for clinically translatable imaging probes, owing to their unique features that are suitable for future targeted multimodal imaging in living subjects. In this review, we summarized the recent advances in the field of functionalized upconversion nanoparticles (f-UCNP) for biological imaging and therapy in vivo, and discussed the future research directions, obstacles ahead, and the potential use of f-UCNP in translational research.
PMCID: PMC3845686  PMID: 24206131
Molecular Imaging; Multimodality Probe; Personalized Therapy; Translational Research; Upconversion Nanoparticle (UCNP)
9.  Antibody-Based Imaging of HER-2: Moving into the Clinic 
Current molecular medicine  2013;13(10):1523-1537.
Human epidermal growth factor receptor-2 (HER-2) mediates a number of important cellular activities, and is up-regulated in a diverse set of cancer cell lines, especially breast cancer. Accordingly, HER-2 has been regarded as a common drug target in cancer therapy. Antibodies can serve as ideal candidates for targeted tumor imaging and drug delivery, due to their inherent affinity and specificity. Advanced by the development of a wide variety of imaging techniques, antibody-based imaging of HER-2 can allow for early detection and localization of tumors, as well as monitoring of drug delivery and tissue’s response to drug treatment. In this review article, antibody-based imaging of HER-2 are summarized and discussed, with an emphasis on the involved imaging methods.
PMCID: PMC3852915  PMID: 24206138
Antibody; Drug delivery; Radioimmunoscintigraphy (RIS); Positron emission tomography (PET); Single-photon emission computed tomography (SPECT); Magnetic resonance imaging (MRI); Near-infrared fluorescence (NIRF) imaging; Photoacoustic tomography (PAT)
10.  Preparation and functionalization of graphene nanocomposites for biomedical applications 
Nature protocols  2013;8(12):10.1038/nprot.2013.146.
Functionalized nano-graphene– and graphene-based nanocomposites have gained tremendous attention in the area of biomedicine in recent years owing to their biocompatibility, the ease with which they can be functionalized and their properties such as thermal and electrical conductivity. potential applications for functionalized nanoparticles range from drug delivery and multimodal imaging to exploitation of the electrical properties of graphene toward the preparation of biosensing devices. this protocol covers the preparation, functionalization and bioconjugation of various graphene derivatives and nanocomposites. starting from graphite, the preparations of graphene oxide (GO), reduced GO (RGO) and magnetic GO–based nanocomposite, as well as how to functionalize them with biocompatible polymers such as polyethylene glycol (PEG), are described in detail. We also provide procedures for 125I radiolabeling of PEGylated GO and the preparation of GO-based gene carriers; other bioconjugation approaches including drug loading, antibody conjugation and fluorescent labeling are similar to those described previously and used for bioconjugation of PEGylated carbon nanotubes. We hope this article will help researchers in this field to fabricate graphene-based bioconjugates with high reproducibility for various applications in biomedicine. the sample preparation procedures take various times ranging from 1 to 2 d.
PMCID: PMC3878091  PMID: 24202553
11.  Image-guided and tumor-targeted drug delivery with radiolabeled unimolecular micelles 
Biomaterials  2013;34(33):8323-8332.
Unimolecular micelles formed by dendritic amphiphilic block copolymers poly(amidoamine)–poly(l-lactide)-b-poly(ethylene glycol) conjugated with anti-CD105 monoclonal antibody (TRC105) and 1,4,7-triazacyclononane-N, N’, N-triacetic acid (NOTA, a macrocyclic chelator for 64Cu) (abbreviated as PAMAM–PLA-b-PEG–TRC105) were synthesized and characterized. Doxorubicin (DOX), a model anti-cancer drug, was loaded into the hydrophobic core of the unimolecular micelles formed by PAMAM and PLA via physical encapsulation. The unimolecular micelles exhibited a uniform size distribution and pH-sensitive drug release behavior. TRC105-conjugated unimolecular micelles showed a CD105-associated cellular uptake in human umbilical vein endothelial cells (HUVEC) compared with non-targeted unimolecular micelles, which was further validated by cellular uptake in CD105-negative MCF-7 cells. In 4T1 murine breast tumor-bearing mice, 64Cu-labeled targeted micelles exhibited a much higher level of tumor accumulation than 64Cu-labeled non-targeted micelles, measured by serial non-invasive positron emission tomography (PET) imaging and confirmed by biodistribution studies. These unimolecular micelles formed by dendritic amphiphilic block copolymers that synergistically integrate passive and active tumor-targeting abilities with pH-controlled drug release and PET imaging capabilities provide the basis for future cancer theranostics.
PMCID: PMC3785312  PMID: 23932288
Unimolecular micelles; Dendritic amphiphilic block copolymer; Nanocarriers; CD105 (endoglin); Molecular imaging; Positron emission tomography (PET)
12.  In Vivo Tumor Targeting and Image-Guided Drug Delivery with Antibody-Conjugated, Radiolabeled Mesoporous Silica Nanoparticles 
ACS nano  2013;7(10):10.1021/nn403617j.
Since the first use of biocompatible mesoporous silica (mSiO2) nanoparticles as drug delivery vehicles, in vivo tumor targeted imaging and enhanced anti-cancer drug delivery has remained a major challenge. In this work, we describe the development of functionalized mSiO2 nanoparticles for actively targeted positron emission tomography (PET) imaging and drug delivery in 4T1 murine breast tumor-bearing mice. Our structural design involves the synthesis, surface functionalization with thiol groups, PEGylation, TRC105 antibody (specific for CD105/endoglin) conjugation, and 64Cu-labeling of uniform 80 nm sized mSiO2 nanoparticles. Systematic in vivo tumor targeting studies clearly demonstrated that 64Cu-NOTA-mSiO2-PEG-TRC105 could accumulate prominently at the 4T1 tumor site via both the enhanced permeability and retention effect and TRC105-mediated binding to tumor vasculature CD105. As a proof-of-concept, we also demonstrated successful enhanced tumor targeted delivery of doxorubicin (DOX) in 4T1 tumor-bearing mice after intravenous injection of DOX-loaded NOTA-mSiO2-PEG-TRC105, which holds great potential for future image-guided drug delivery and targeted cancer therapy.
PMCID: PMC3834886  PMID: 24083623
Mesoporous silica (mSiO2) nanoparticles; tumor angiogenesis; in vivo tumor targeting; positron emission tomography (PET); drug delivery; theranostics
13.  microPET of Tumor Integrin αvβ3 Expression Using 18F-Labeled PEGylated Tetrameric RGD Peptide (18F-FPRGD4) 
In vivo imaging of αvβ3 expression has important diagnostic and therapeutic applications. Multimeric cyclic RGD peptides are capable of improving the integrin αvβ3–binding affinity due to the polyvalency effect. Here we report an example of 18F-labeled tetrameric RGD peptide for PET of αvβ3 expression in both xenograft and spontaneous tumor models.
The tetrameric RGD peptide E{E[c(RGDyK)]2}2 was derived with amino-3,6,9-trioxaundecanoic acid (mini-PEG; PEG is poly(ethylene glycol)) linker through the glutamate α-amino group. NH2-mini-PEG-E{E[c(RGDyK)]2}2 (PRGD4) was labeled with 18F via the N-succinimidyl-4-18F-fluorobenzoate (18F-SFB) prosthetic group. The receptor-binding characteristics of the tetrameric RGD peptide tracer 18F-FPRGD4 were evaluated in vitro by a cell-binding assay and in vivo by quantitative microPET imaging studies.
The decay-corrected radiochemical yield for 18F-FPRGD4 was about 15%, with a total reaction time of 180 min starting from 18F-F−. The PEGylation had minimal effect on integrin-binding affinity of the RGD peptide. 18F-FPRGD4 has significantly higher tumor uptake compared with monomeric and dimeric RGD peptide tracer analogs. The receptor specificity of 18F-FPRGD4 in vivo was confirmed by effective blocking of the uptake in both tumors and normal organs or tissues with excess c(RGDyK).
The tetrameric RGD peptide tracer 18F-FPRGD4 possessing high integrin-binding affinity and favorable biokinetics is a promising tracer for PET of integrin αvβ3 expression in cancer and other angiogenesis related diseases.
PMCID: PMC4183663  PMID: 17704249
microPET; integrin αvβ3; tetrameric RGD peptide; PEGylation; 18F
14.  Pharmacokinetic Issues of Imaging with Nanoparticles: Focusing on Carbon Nanotubes and Quantum Dots 
With many desirable properties, nanoparticles hold tremendous potential for non-invasive molecular imaging and improving the efficacy of small molecule drugs. The pharmacokinetics (PK) and tissue distribution of nanoparticles largely define their in vivo performance and potential toxicity, which are fundamental issues that need to be elucidated. In this review article, we summarized how molecular imaging techniques (e.g. positron emission tomography, fluorescence imaging, etc.) can facilitate the investigation of PK profiles of nanoparticles, using carbon nanotubes (CNTs) and quantum dots (QDs) as representative examples. Different imaging techniques can provide useful insights in monitoring the in vivo behavior and tissue distribution of these nanoparticles, and a number of strategies were employed to improve the PK profiles of CNTs and QDs. Based on the available literature reports, it can be concluded that chemical and physical properties of the nanoparticles (e.g. surface functionalization, hydrodynamic size, shape, surface charge, etc.), along with the administration routes/doses, can play important roles in determining the PK and biodistribution pattern of nanoparticles. Robust chemistry for surface modification of nanoparticles is the key to success in future biomedical and clinical applications.
PMCID: PMC3773279  PMID: 23715931
Pharmacokinetics (PK); molecular imaging; nanoparticles; carbon nanotube (CNT); quantum dot (QD); cancer; angiogenesis; positron emission tomography (PET); fluorescence
15.  Imaging Gene Expression in Live Cells and Tissues 
Cold Spring Harbor protocols  2011;2011(4):pdb.top103.
Monitoring gene expression is crucial for studying the responses of gene therapy and clarifying the function of certain genes in various environments. Molecular imaging is a powerful tool for noninvasive visualization of gene expression. This chapter will summarize the current status of fluorescence and bioluminescence imaging (BLI) of gene expression in live cells and tissues, and the emphasis will be mainly on the early studies that pioneered the field. First, we will describe fluorescence imaging of gene expression with a wide variety of fluorescent proteins. Next, we will discuss the strategies for BLI of gene expression. Besides incorporating the reporter gene into the host DNA, mRNA-based BLI of gene expression will also be briefly mentioned. Lastly, the construction of dual and triple fusion reporter genes will be presented. Since no single imaging modality is perfect and sufficient to obtain all of the necessary information for a given question, a combination of multiple molecular imaging modalities can offer synergistic advantages over any modality alone. Noninvasive optical imaging of gene expression has revolutionized biomedical research and the progress made over the last decade should allow molecular imaging to play a major role in the field of gene therapy. For basic and preclinical research, optical imaging is certainly indispensable for imaging gene expression. However, for clinical imaging of gene expression, positron emission tomography (PET) holds the greatest promise.
PMCID: PMC4175735  PMID: 21460057
16.  18F-labeled mini-PEG spacered RGD dimer (18F-FPRGD2): synthesis and microPET imaging of αvβ3 integrin expression 
We have previously reported that 18F-FB-E[c(RGDyK)]2 (18F-FRGD2) allows quantitative PET imaging of integrin αvβ3 expression. However, the potential clinical translation was hampered by the relatively low radiochemical yield. The goal of this study was to improve the radiolabeling yield, without compromising the tumor targeting efficiency and in vivo kinetics, by incorporating a hydrophilic bifunctional mini-PEG spacer.
18F-FB-mini-PEG-E[c(RGDyK)]2 (18F-FPRGD2) was synthesized by coupling N-succinimidyl-4-18F-fluorobenzoate (18F-SFB) with NH2-mini-PEG-E[c(RGDyK)]2 (denoted as PRGD2). In vitro receptor binding affinity, metabolic stability, and integrin αvβ3 specificity of the new tracer 18F-FPRGD2 were assessed. The diagnostic value of 18F-FPRGD2 was evaluated in subcutaneous U87MG glioblastoma xenografted mice and in c-neu transgenic mice by quantitative microPET imaging studies.
The decay-corrected radiochemical yield based on 18F-SFB was more than 60% with radiochemical purity of >99%. 18F-FPRGD2 had high receptor binding affinity, metabolic stability, and integrin αvβ3-specific tumor uptake in the U87MG glioma xenograft model comparable to those of 18F-FRGD2. The kidney uptake was appreciably lower for 18F-FPRGD2 compared with 18F-FRGD2 [2.0±0.2%ID/ g for 18F-FPRGD2 vs 3.0±0.2%ID/g for 18F-FRGD2 at 1 h post injection (p.i.)]. The uptake in all the other organs except the urinary bladder was at background level. 18F-FPRGD2 also exhibited excellent tumor uptake in c-neu oncomice (3.6±0.1%ID/g at 30 min p.i.).
Incorporation of a mini-PEG spacer significantly improved the overall radiolabeling yield of 18F-FPRGD2. 18F-FPRGD2 also had reduced renal uptake and similar tumor targeting efficacy as compared with 18F-FRGD2. Further testing and clinical translation of 18F-FRGD2 are warranted.
PMCID: PMC4167588  PMID: 17492285
Integrin αvβ3; Dimeric RGD peptide; Mini-PEG spacer; MicroPET; Fluorine-18
17.  Photoacoustic Imaging 
Cold Spring Harbor protocols  2011;2011(9):10.1101/pdb.top065508 pdb.top065508.
Photoacoustic imaging, based on the photoacoustic effect, has come a long way over the last decade. Possessing many attractive characteristics such as the use of non-ionizing electromagnetic waves, good resolution/contrast, portable instrumention, as well as the ability to quantitate the signal to a certain extent, photoacoustic techniques have been applied for the imaging of cancer, wound healing, disorders in the brain, gene expression, among others. As a promising structural, functional and molecular imaging modality for a wide range of biomedical applications, photoacoustic imaging systems can be briefly categorized into two types: photoacoustic tomography (PAT, the focus of this chapter) and photoacoustic microscopy (PAM). We will first briefly describe the endogenous (e.g. hemoglobin and melanin) and exogenous contrast agents (e.g. indocyanine green, various gold nanoparticles, single-walled carbon nanotubes, quantum dots, and fluorescent proteins) for photoacoustic imaging. Next, we will discuss in detail the applications of non-targeted photoacoustic imaging. Recently, molecular photoacoustic (MPA) imaging has gained significant interest and a few proof-of-principle studies have been reported. We will summarize the current state-of-the-art of MPA imaging, including the imaging of gene expression and combination of photoacoustic imaging with other imaging modalities. Lastly, we will point out the obstacles facing photoacoustic imaging. Although photoacoustic imaging will likely continue to be a highly vibrant research field for the years to come, the key question of whether MPA imaging could provide significant advantages over non-targeted photoacoustic imaging remains to be demonstrated in the future.
PMCID: PMC4167744  PMID: 21880823
18.  In Vivo Bioluminescence Tumor Imaging of RGD Peptide-modified Adenoviral Vector Encoding Firefly Luciferase Reporter Gene 
The goal of this study is to demonstrate the feasibility of chemically modified human adenovirus (Ad) vectors for tumor retargeting.
E1- and E3-deleted Ad vectors carrying firefly luciferase reporter gene under cytomegalovirus promoter (AdLuc) was surface-modified with cyclic arginine–glycine–aspartic acid (RGD) peptides through a bifunctional poly(ethyleneglycol) linker (RGD-PEG-AdLuc) for integrin αvβ3 specific delivery. The Coxsackie and adenovirus viral receptor (CAR) and integrin αvβ3 expression in various tumor cell lines was determined by reverse transcriptase PCR and fluorescence-activated cell sorting. Bioluminescence imaging was performed in vitro and in vivo to evaluate RGD-modified AdLuc infectivity.
RGD-PEG-AdLuc abrogated the native CAR tropism and exhibited significantly enhanced transduction efficiency of integrin-positive tumors than AdLuc through intravenous administration.
This approach provides a robust platform for site-specific gene delivery and noninvasive monitoring of the transgene delivery efficacy and homing.
PMCID: PMC4165526  PMID: 17297551
Adenovirus; Firefly luciferase; Reporter gene; Integrin αvβ3; RGD; Bioluminescence imaging
19.  Quantitative PET Imaging of Tumor Integrin αvβ3 Expression with 18F-FRGD2 
The development of noninvasive methods to visualize and quantify integrin αvβ3 expression in vivo appears to be crucial for the success of antiangiogenic therapy based on integrin antagonism. Precise documentation of integrin receptor levels will allow appropriate selection of patients who will most likely benefit from an antiintegrin treatment regimen. Imaging can also be used to provide an optimal dosage and time course for treatment based on receptor occupancy studies. In addition, imaging integrin expression will be important to evaluate antiintegrin treatment efficacy and to develop new therapeutic drugs with favorable tumor targeting and in vivo kinetics. We labeled the dimeric RGD peptide E[c(RGDyK)]2 with 18F and evaluated its tumor-targeting efficacy and pharmacokinetics of 18F-FB–E[c(RGDyK)]2 (18F-FRGD2).
E[c(RGDyK)]2 was labeled with 18F by conjugation coupling with N-succinimidyl-4-18F-fluorobenzoate (18F-SFB) under a slightly basic condition. The in vivo metabolic stability of 18F-FRGD2 was determined. The diagnostic value after injection of 18F-FRGD2 was evaluated in various xenograft models by dynamic microPET followed by ex vivo quantification of tumor integrin level.
Starting with 18F− Kryptofix 2.2.2./K2CO3 solution, the total reaction time for 18F-FRGD2, including final high-performance liquid chromatography purification, is about 200 ± 20 min. Typical decay-corrected radiochemical yield is 23% ± 2% (n = 20). 18F-FRGD2 is metabolically stable. The binding potential extrapolated from graphical analysis of PET data and Logan plot correlates well with the receptor density measured by sodium dodecyl sulfate polyacrylamide electrophoresis and autoradiography in various xenograft models. The tumor-to-background ratio at 1 h after injection of 18F-FRGD2 also gives a good linear relationship with the tumor tissue integrin level.
The dimeric RGD peptide tracer 18F-FRGD2, with high integrin specificity and favorable excretion profile, may be translated into the clinic for imaging integrin αvβ3 expression. The binding potential calculated from simplified tracer kinetic modeling such as the Logan plot appears to be an excellent indicator of tumor integrin density.
PMCID: PMC4160026  PMID: 16391195
molecular imaging; integrin αvβ3; dimeric RGD peptide; dynamic microPET; Logan plot
20.  Monitoring of the Biological Response to Murine Hindlimb Ischemia With 64Cu-Labeled Vascular Endothelial Growth Factor-121 Positron Emission Tomography 
Circulation  2008;117(7):915-922.
Vascular endothelial growth factor-121 (VEGF121), an angiogenic protein secreted in response to hypoxic stress, binds to VEGF receptors (VEGFRs) overexpressed on vessels of ischemic tissue. The purpose of this study was to evaluate 64Cu-VEGF121 positron emission tomography for noninvasive spatial, temporal, and quantitative monitoring of VEGFR2 expression in a murine model of hindlimb ischemia with and without treadmill exercise training.
Methods and Results
64Cu-labeled VEGF121 and a VEGF mutant were tested for VEGFR2 binding specificity in cell culture. Mice (n=58) underwent unilateral ligation of the femoral artery, and postoperative tissue ischemia was assessed with laser Doppler imaging. Longitudinal VEGFR2 expression in exercised and nonexercised mice was quantified with 64Cu-VEGF121 positron emission tomography at postoperative day 8, 15, 22, and 29 and correlated with postmortem γ-counting. Hindlimbs were excised for immunohistochemistry, Western blotting, and microvessel density measurements. Compared with the VEGF mutant, VEGF121 showed specific binding to VEGFR2. Perfusion in ischemic hindlimbs fell to 9% of contralateral hindlimb on postoperative day 1 and recovered to 82% on day 29. 64Cu-VEGF121 uptake in ischemic hindlimbs increased significantly (P<0.001) from a control level of 0.61 ±0.17% ID/g (percentage of injected dose per gram) to 1.62±0.35% ID/g at postoperative day 8, gradually decreased over the following 3 weeks (0.59±0.14% ID/g at day 29), and correlated with γ-counting (R2=0.99). Compared with nonexercised mice, 64Cu-VEGF121 uptake was increased significantly (P≤0.0001) in exercised mice (at day 15, 22, and 29) and correlated with VEGFR2 levels as obtained by Western blotting (R2=0.76). Ischemic hindlimb tissue stained positively for VEGFR2. In exercised mice, microvessel density was increased significantly (P<0.001) compared with nonexercised mice.
64Cu-VEGF121 positron emission tomography allows longitudinal spatial and quantitative monitoring of VEGFR2 expression in murine hindlimb ischemia and indirectly visualizes enhanced angiogenesis stimulated by treadmill exercise training.
PMCID: PMC4157592  PMID: 18250264
imaging; arteriosclerosis; exercise; angiogenesis; tomography; peripheral vascular disease; growth substances
21.  CARM1 Methylates Chromatin Remodeling Factor BAF155 to Enhance Tumor Progression and Metastasis 
Cancer cell  2014;25(1):21-36.
Coactivator-associated arginine methyltransferase 1 (CARM1), a coactivator for various cancer-relevant transcription factors, is overexpressed in breast cancer. To elucidate the functions of CARM1 in tumorigenesis, we knocked out CARM1 from several breast cancer cell lines using Zinc-Finger Nuclease technology, which resulted in drastic phenotypic and biochemical changes. The CARM1 KO cell lines enabled identification of CARM1 substrates, notably the SWI/SNF core subunit BAF155. Methylation of BAF155 at R1064 was found to be an independent prognostic biomarker for cancer recurrence and to regulate breast cancer cell migration and metastasis. Furthermore, CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation.
PMCID: PMC4004525  PMID: 24434208
22.  Imaging tumor angiogenesis in breast cancer experimental lung metastasis with positron emission tomography, near-infrared fluorescence, and bioluminescence 
Angiogenesis  2013;16(3):663-674.
The goal of this study was to develop a molecular imaging agent that can allow for both positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging of CD105 expression in metastatic breast cancer. TRC105, a chimeric anti-CD105 monoclonal antibody, was labeled with both a NIRF dye (i.e., IRDye 800CW) and 64Cu to yield 64Cu-NOTA-TRC105-800CW. Flow cytometry analysis revealed no difference in CD105 binding affinity/specificity between TRC105 and NOTA-TRC105-800CW. Serial bioluminescence imaging (BLI) was carried out to non-invasively monitor the lung tumor burden in BALB/c mice, after intravenous injection of firefly luciferase-transfected 4T1 (i.e., fLuc-4T1) murine breast cancer cells to establish the experimental lung metastasis model. Serial PET imaging revealed that fLuc-4T1 lung tumor uptake of 64Cu-NOTA-TRC105-800CW was 11.9 ± 1.2, 13.9 ± 3.9, and 13.4 ± 2.1 %ID/g at 4, 24, and 48 h post-injection respectively (n = 3). Biodistribution studies, blocking fLuc-4T1 lung tumor uptake with excess TRC105, control experiments with 64Cu-NOTA-cetuximab-800CW (which served as an isotype-matched control), ex vivo BLI/PET/NIRF imaging, autoradiography, and histology all confirmed CD105 specificity of 64Cu-NOTA-TRC105-800CW. Successful PET/NIRF imaging of tumor angiogenesis (i.e., CD105 expression) in the breast cancer experimental lung metastasis model warrants further investigation and clinical translation of dual-labeled TRC105-based agents, which can potentially enable early detection of small metastases and image-guided surgery for tumor removal.
PMCID: PMC3706271  PMID: 23471463
Breast cancer; Tumor angiogenesis; Lung metastasis; Positron emission tomography (PET); Near-infrared fluorescence (NIRF); CD105/endoglin; ImmunoPET; Image-guided surgery
23.  Positron Emission Tomography Imaging of Angiogenesis in a Murine Hindlimb Ischemia Model with 64Cu-Labeled TRC105 
Molecular pharmaceutics  2013;10(7):2749-2756.
The goal of this study was to assess ischemia-induced angiogenesis with 64Cu-NOTA-TRC105 positron emission tomography (PET) in a murine hindlimb ischemia model of peripheral artery disease (PAD). CD105 binding affinity/specificity of NOTA-conjugated TRC105 (an anti-CD105 antibody) was evaluated by flow cytometry, which exhibited no difference from unconjugated TRC105. BALB/c mice were anesthetized and the right femoral artery was ligated to induce hindlimb ischemia, with the left hindlimb serving as an internal control. Laser Doppler imaging showed that perfusion in the ischemic hindlimb plummeted to ~20% of the normal level after surgery, and gradually recovered to near normal level on day 24. Ischemia-induced angiogenesis was non-invasively monitored and quantified with 64Cu-NOTA-TRC105 PET on postoperative days 1, 3, 10, 17, & 24. 64Cu-NOTA-TRC105 uptake in the ischemic hindlimb increased significantly from the control level of 1.6±0.2 %ID/g to 14.1±1.9 %ID/g at day 3 (n=3), and gradually decreased with time (3.4±1.9 %ID/g at day 24), which correlated well with biodistribution studies performed on days 3 & 24. Blocking studies confirmed the CD105 specificity of tracer uptake in the ischemic hindlimb. Increased CD105 expression on days 3 and 10 following ischemia was confirmed by histology and RT-PCR. This is the first report of PET imaging of CD105 expression during ischemia-induced angiogenesis. 64Cu-NOTA-TRC105 PET may play multiple roles in future PAD-related research and improve PAD patient management by identifying the optimal timing of treatment and monitoring the efficacy of therapy.
PMCID: PMC3836864  PMID: 23738915
angiogenesis; ischemia; positron emission tomography (PET); peripheral artery disease (PAD); imaging; CD105 (endoglin)
24.  Plumbagin, a medicinal plant (Plumbago zeylanica) - derived 1,4-naphthoquinone, inhibits growth and metastasis of human prostate cancer PC-3M-luciferase cells in an orthotopic xenograft mouse model 
Molecular oncology  2012;7(3):428-439.
We present here first time that Plumbagin (PL), a medicinal plant-derived 1,4-naphthoquinone, inhibits the growth and metastasis of prostate cancer (PCa) in an orthotopic xenograft mouse model. In this study, human PCa PC-3M-luciferase cells (2X106) were injected into the prostate of athymic nude mice. Three days post cell implantation, mice were treated with PL (2 mg/kg body wt. i.p five days in a week) for 8 weeks. Growth and metastasis of PC-3M-luciferase cells was examined weekly by bioluminescence imaging of live mice. PL-treatment significantly (p=0.0008) inhibited the growth of orthotopic xenograft tumors. PCa metastasis into the liver, lungs and lymph nodes was determined by bioluminescence imaging and histopathology. Results demonstrated a significant inhibition of metastasis into liver (p=0.037), but inhibition of metastasis into the lungs (p=0.60) and liver (p=0.27) was not observed to be significant. These results were further confirmed by histopathology of these organs. Results of histopathology demonstrated a significant inhibition of metastasis into lymph nodes (p=0.034) and lungs (p=0.028), and a trend to significance in liver (p=0.075). None of the mice in the PL-treatment group showed PCa metastasis into the liver, but these mice had small metastasis foci into the lymph nodes and lungs. However, control mice had large metastatic foci into the lymph nodes, lungs, and liver. PL-caused inhibition of the growth and metastasis of PC-3M cells accompanies inhibition of the expression of: 1) PKCε, pStat3Tyr705, and pStat3Ser727, 2) Stat3 downstream target genes (survivin and BclxL), 3) proliferative markers Ki-67 and PCNA, 4) metastatic marker MMP9, MMP2, and uPA, and 5) angiogenesis markers CD31 and VEGF. Taken together, these results suggest that PL inhibits tumor growth and metastasis of human PCa PC3-M-luciferase cells, which could be used as a therapeutic agent for the prevention and treatment of human PCa. PL: Plumbagin, PCa: Prostate cancer.
PMCID: PMC3625495  PMID: 23273564
Plumbagin; prostate cancer; and orthotopic xenograft model
25.  Engineering of Hollow Mesoporous Silica Nanoparticles for Remarkably Enhanced Tumor Active Targeting Efficacy 
Scientific Reports  2014;4:5080.
Hollow mesoporous silica nanoparticle (HMSN) has recently gained increasing interests due to their tremendous potential as an attractive nano-platform for cancer imaging and therapy. However, possibly due to the lack of efficient in vivo targeting strategy and well-developed surface engineering techniques, engineering of HMSN for in vivo active tumor targeting, quantitative tumor uptake assessment, multimodality imaging, biodistribution and enhanced drug delivery have not been achieved to date. Here, we report the in vivo tumor targeted positron emission tomography (PET)/near-infrared fluorescence (NIRF) dual-modality imaging and enhanced drug delivery of HMSN using a generally applicable surface engineering technique. Systematic in vitro and in vivo studies have been performed to investigate the stability, tumor targeting efficacy and specificity, biodistribution and drug delivery capability of well-functionalized HMSN nano-conjugates. The highest uptake of TRC105 (which binds to CD105 on tumor neovasculature) conjugated HMSN in the 4T1 murine breast cancer model was ~10%ID/g, 3 times higher than that of the non-targeted group, making surface engineered HMSN a highly attractive drug delivery nano-platform for future cancer theranostics.
PMCID: PMC4038837  PMID: 24875656

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