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1.  Active Targeting Using HER-2-affibody-conjugated Nanoparticles Enabled Sensitive and Specific Imaging of Orthotopic HER-2 Positive Ovarian Tumors 
Despite advances in cancer diagnosis and treatment, ovarian cancer remains one of the most fatal cancer types. The development of targeted nanoparticle imaging probes and therapeutics offers promising approaches for early detection and effective treatment of ovarian cancer. In this study, we have developed HER-2 targeted magnetic iron oxide nanoparticles (IONPs) by conjugating a high affinity and small size HER-2 affibody that is labeled with a unique near infrared dye (NIR-830) to the nanoparticles. Using a clinically relevant orthotopic human ovarian tumor xenograft model, we have shown that HER-2 targeted IONPs are selectively delivered into both primary and disseminated ovarian tumors, enabling non-invasive optical and MR imaging of the tumors as small as 1 mm in the peritoneal cavity. We have determined that HER-2 targeted delivery of the IONPs is essential for specific and sensitive imaging of the HER-2 positive tumor since we are unable to detect the imaging signal in the tumors following systemic delivery of non-targeted IONPs into the mice bearing HER-2 positive SKOV3 tumors. Furthermore, imaging signals and the IONPs are not detected in HER-2 low expressing OVCAR3 tumors after systemic delivery of HER-2 targeted-IONPs. Since HER-2 is expressed in a high percentage of ovarian cancers, the HER-2 targeted dual imaging modality IONPs have potential for the development of novel targeted imaging and therapeutic nanoparticles for ovarian cancer detection, targeted drug delivery, and image-guided therapy and surgery.
doi:10.1002/smll.201301593
PMCID: PMC3946402  PMID: 24038985
HER-2 targeted nanoparticles; HER-2 affibody; NIR-830 dye; orthotopic human ovarian tumor xenograft model
2.  Facile non-hydrothermal synthesis of oligosaccharides coated sub-5 nm magnetic iron oxide nanoparticles with dual MRI contrast enhancement effect 
Ultrafine sub-5 nm magnetic iron oxide nanoparticles coated with oligosaccharides (SIO) with dual T1-T2 weighted contrast enhancing effect and fast clearance has been developed as magnetic resonance imaging (MRI) contrast agent. Excellent water solubility, biocompatibility and high stability of such sub-5 nm SIO nanoparticles were achieved by using the “in-situ polymerization” coating method, which enables glucose forming oligosaccharides directly on the surface of hydrophobic iron oxide nanocrystals. Reported ultrafine SIO nanoparticles exhibit a longitudinal relaxivity (r1) of 4.1 mM−1s−1 and a r1/r2 ratio of 0.25 at 3 T (clinical field strength), rendering improved T1 or “brighter” contrast enhancement in T1-weighted MRI in addition to typical T2 or “darkening” contrast of conventional iron oxide nanoparticles. Such dual contrast effect can be demonstrated in liver imaging with T2 “darkening” contrast in the liver parenchyma but T1 “bright” contrast in the hepatic vasculature. More importantly, this new class of ultrafine sub-5 nm iron oxide nanoparticles showed much faster body clearance than those with larger sizes, promising better safety for clinical applications.
doi:10.1039/C4TB00811A
PMCID: PMC4147377  PMID: 25181490
3.  Theranostic Nanoparticles Carrying Doxorubicin Attenuate Targeting Ligand Specific Antibody Responses Following Systemic Delivery 
Theranostics  2015;5(1):43-61.
Understanding the effects of immune responses on targeted delivery of nanoparticles is important for clinical translations of new cancer imaging and therapeutic nanoparticles. In this study, we found that repeated administrations of magnetic iron oxide nanoparticles (IONPs) conjugated with mouse or human derived targeting ligands induced high levels of ligand specific antibody responses in normal and tumor bearing mice while injections of unconjugated mouse ligands were weakly immunogenic and induced a very low level of antibody response in mice. Mice that received intravenous injections of targeted and polyethylene glycol (PEG)-coated IONPs further increased the ligand specific antibody production due to differential uptake of PEG-coated nanoparticles by macrophages and dendritic cells. However, the production of ligand specific antibodies was markedly inhibited following systemic delivery of theranostic nanoparticles carrying a chemotherapy drug, doxorubicin. Targeted imaging and histological analysis revealed that lack of the ligand specific antibodies led to an increase in intratumoral delivery of targeted nanoparticles. Results of this study support the potential of further development of targeted theranostic nanoparticles for the treatment of human cancers.
doi:10.7150/thno.10350
PMCID: PMC4265747  PMID: 25553097
Targeting ligands; nanoparticles; antibody; immune response; tumor imaging; nanoparticle delivery.
4.  Correlation between epidermal growth factor receptor and tumor stem cell markers CD44/CD24 and their relationship with prognosis in breast invasive ductal carcinoma 
We studied the correlation between epidermal growth factor receptor (EGFR) and the tumor stem cell markers CD44/CD24 in breast invasive ductal carcinoma (BIDC) and their relationship with prognosis. We analyzed the clinical data of 139 BIDC cases retrospectively, detecting EGFR, CD44, and CD24 expressions in tumor tissue using immunohistochemistry. The proportion of EGFR-, CD44-, and CD24-positive cases was 59.0, 62.3, and 30.9 %, respectively. The proportion of CD44-positive [76.9 % (p < 0.05)] and EGFR-positive [67.2 % (p = 0.108)] cases in the triple-negative breast cancer (TNBC) group was higher than that of the non-TNBC group. In the non-TNBC group, 36.5 % was CD24-positive, higher than that in the TNBC group but not statistically significant. The proportion of CD44-positive cases was significantly higher in the EGFR-positive group than in the EGFR-negative group (p = 0.017). EGFR-positive cases were significantly correlated with premenopausal status (p = 0.036), distant metastasis (p = 0.018), and estrogen receptor-negative status (p = 0.020). CD44-positive status was significantly correlated with human epidermal growth receptor 2 (HER2)-negative (p = 0.023), estrogen receptor-negative (p = 0.021), and progesterone receptor-negative status (p = 0.004). CD24-positive status was significantly correlated with HER2-positive status (p = 0.001). Kaplan–Meier survival analysis showed that TNBC patients had shorter survival. EGFR-positive and CD44-positive status were both correlated with shorter survival in the lymph node- and HR-negative groups, while CD24 positive was significantly correlated with poor survival in lymph node-negative and HR-positive patients. EGFR and CD44 expressions have a significantly positive correlation (p = 0.017) in BIDC. Patients both EGFR and CD44 positive had the worst outcome.
doi:10.1007/s12032-014-0275-2
PMCID: PMC4246130  PMID: 25429827
Breast infiltrating ductal carcinoma; EGFR; CD44; CD24; Prognosis
5.  Nanoparticles for cancer imaging: The good, the bad, and the promise 
Nano today  2013;8(5):454-460.
Summary
Recent advances in molecular imaging and nanotechnology are providing new opportunities for biomedical imaging with great promise for the development of novel imaging agents. The unique optical, magnetic, and chemical properties of materials at the scale of nanometers allow the creation of imaging probes with better contrast enhancement, increased sensitivity, controlled biodistribution, better spatial and temporal information, multi-functionality and multi-modal imaging across MRI, PET, SPECT, and ultrasound. These features could ultimately translate to clinical advantages such as earlier detection, real time assessment of disease progression and personalized medicine. However, several years of investigation into the application of these materials to cancer research has revealed challenges that have delayed the successful application of these agents to the field of biomedical imaging. Understanding these challenges is critical to take full advantage of the benefits offered by nano-sized imaging agents. Therefore, this article presents the lessons learned and challenges encountered by a group of leading researchers in this field, and suggests ways forward to develop nanoparticle probes for cancer imaging. Published by Elsevier Ltd.
doi:10.1016/j.nantod.2013.06.001
PMCID: PMC4240321  PMID: 25419228
Nanomedicine; Cancer; Imaging; Detection; Screening
6.  Detection of insulinoma using 68Gallium-DOTATATE PET/CT: a case report 
Gland Surgery  2014;3(4):E1-E5.
Insulinomas are the most common cause of endogenous hyperinsulinemic hypoglycemia in non-diabetic adults. They are most often benign, small and difficult to localize with current imaging techniques. This is of high importance, as complete surgical resection is the only curative treatment. Anatomic imaging, 111In-pentetreotide scan and 68Gallium-DOTATATE positron emission tomography/computed tomography (PET/CT) were compared in a patient with insulinoma. 68Gallium-DOTATATE PET/CT and selective arterial calcium stimulation localized the insulinoma. At surgery, a tumor in the anterior aspect of the pancreatic body was found which confirmed the preoperative localization, and a 2.1 cm tumor was enucleated, World Health Organization (WHO) grade I insulinoma. The patient remains euglycemic and free of symptoms at last follow up. In conclusion, 68Gallium-DOTATATE PET/CT imaging may be a useful adjunct localizing study for insulinomas. It is a non-invasive preoperative localization study that could guide surgical exploration for successful therapy.
doi:10.3978/j.issn.2227-684X.2014.10.02
PMCID: PMC4244512  PMID: 25493261
Insulinoma; 68Gallium-DOTATATE; neuroendocrine tumor (NET); positron emission tomography (PET)
7.  Development of Receptor Targeted Magnetic Iron Oxide Nanoparticles for Efficient Drug Delivery and Tumor Imaging 
The development of multifunctional nanoparticles that have dual capabilities of tumor imaging and delivering therapeutic agents into tumor cells holds great promises for novel approaches for tumor imaging and therapy. We have engineered urokinase plasminogen activator receptor (uPAR) targeted biodegradable nanoparticles using a size uniform and amphiphilic polymer-coated magnetic iron oxide (IO) nanoparticle conjugated with the amino-terminal fragment (ATF) of urokinase plasminogen activator (uPA), which is a high affinity natural ligand for uPAR. We further developed methods to encapsulate hydrophobic chemotherapeutic drugs into the polymer layer on the IO nanoparticles, making these targeted magnetic resonance imaging (MRI) sensitive nanoparticles drug delivery vehicles. Using a fluorescent drug doxorubicin (Dox) as a model system, we showed that this hydrophobic drug can be efficiently encapsulated into the uPAR-targeted IO nanoparticles. This class of Dox-loaded nanoparticles has a compact size and is stable in pH 7.4 buffer. However, encapsulated Doxcan be released from the nanoparticles at pH 4.0 to 5.0 within 2 hrs. In comparison with the effect of equivalent dosage of free drug or non-targeted IO-Dox nanoparticles, uPAR-targeted IO-Dox nanoparticles deliver higher levels of Dox into breast cancer cells and produce a stronger inhibitory effect on tumor cell growth. Importantly, Dox-loaded IO nanoparticles maintain their T2 MRI contrast effect after being internalized into the tumor cells due to their significant susceptibility effect in the cells, indicating that this drug delivery nanoparticle has the potential to be used as targeted therapeutic imaging probes for monitoring the drug delivery using MRI.
doi:10.1166/jbn.2008.007
PMCID: PMC4139059  PMID: 25152701
Magnetic Iron Oxide Nanoparticles; uPAR; Targeted Nanoparticle; Breast Cancer; Drug Delivery Nanoparticle; Doxorubicin
8.  Casein-coated Iron Oxide Nanoparticles for High MRI Contrast Enhancement and Efficient Cell Targeting 
ACS applied materials & interfaces  2013;5(11):4632-4639.
Surface properties, as well as inherent physicochemical properties, of the engineered nanomaterials play important roles in their interactions with the biological systems, which eventually affect their efficiency in diagnostic and therapeutic applications. Here we report a new class MRI contrast agent based on milk casein protein coated iron oxide nanoparticles (CNIOs) with a core size of 15 nm and hydrodynamic diameter ~30 nm. These CNIOs exhibited excellent water-solubility, colloidal stability, and biocompatibility. Importantly, CNIOs exhibited prominent T2 enhancing capability with a transverse relaxivity r2 of 273 mM−1s−1 at 3 Tesla. The transverse relaxivity is ~2.5-fold higher than that of iron oxide nanoparticles with the same core but an amphiphilic polymer coating. CNIOs showed pH-responsive properties, formed loose and soluble aggregates near the pI (pH~4.0). The aggregates could be dissociated reversibly when the solution pH was adjusted away from the pI. The transverse relaxation property and MRI contrast enhancing effect of CNIOs remained unchanged in the pH range of 2.0 to 8.0. Further functionalization of CNIOs can be achieved via surface modification of the protein coating. Bio-affinitive ligands, such as a single chain fragment from the antibody of epidermal growth factor receptor (ScFvEGFR), could be readily conjugated onto the protein coating, enabling specific targeting to MDA-MB-231 breast cancer cells over-expressing EGFR. T2-weighted MRI of mice intravenously administered with CNIOs demonstrated strong contrast enhancement in the liver and spleen. These favorable properties suggest CNIOs as a class of biomarker targeted magnetic nanoparticles for MRI contrast enhancement and related biomedical applications.
doi:10.1021/am400713j
PMCID: PMC3699787  PMID: 23633522
iron; oxide; nanoparticles; magnetic resonance; imaging; casein; contrast agent; targeting
9.  Theranostic Nanoparticles with Controlled Release of Gemcitabine for Targeted Therapy and MRI of Pancreatic Cancer 
ACS nano  2013;7(3):2078-2089.
The tumor stroma in human cancers significantly limits the delivery of therapeutic agents into cancer cells. To develop an effective therapeutic approach overcoming the physical barrier of the stroma, we engineered urokinase plasminogen activator receptor (uPAR)-targeted magnetic iron oxide nanoparticles (IONPs) carrying gemcitabine (Gem) as a chemotherapy drug for targeted delivery into uPAR-expressing tumor and stromal cells. The uPAR-targeted nanoparticle construct, ATF-IONP-Gem, was prepared by conjugating IONPs with the amino-terminal fragment (ATF) peptide of the receptor-binding domain of uPA, a natural ligand of uPAR, and Gem via a lysosomally cleavable tetrapeptide linker. These theranostic nanoparticles enable intracellular release of Gem following receptor-mediated endocytosis of ATF-IONP-Gem into tumor cells, and also allow in vivo magnetic resonance imaging (MRI) of tumors. Our results demonstrated the pH- and lysosomal enzyme-dependent release of gemcitabine, preventing the drug from enzymatic degradation. Systemic administrations of ATF-IONP-Gem significantly inhibited the growth of orthotopic human pancreatic cancer xenografts in nude mice. With MRI contrast enhancement by IONPs, we detected the presence of IONPs in the residual tumor lesions following the treatment, suggesting the possibility of monitoring drug delivery and assessing drug resistant tumors by MRI. The theranostic ATF-IONP-Gem nanoparticle has great potential for the development of targeted therapeutic and imaging approaches that are capable of overcoming the tumor stromal barrier, thus enhancing the therapeutic effect of nanoparticle drugs on pancreatic cancers.
doi:10.1021/nn3043463
PMCID: PMC3609912  PMID: 23402593
targeted cancer therapy; theranostic nanoparticle; uPAR; pancreatic cancer; gemcitabine; controlled drug release; magnetic resonance imaging; drug delivery
10.  DOT corrected fluorescence molecular tomography using targeted contrast agents for small animal tumor imaging 
PURPOSE
To demonstrate diffuse optical tomography (DOT) corrected fluorescence molecular tomography (FMT) for quantitatively imaging tumor-targeted contrast agents in a 4T1 mouse mammary tumor model.
PROCEDURES
In the first set of experiments, we validated our DOT corrected FMT method using subcutaneously injected 4T1 cells pre-labeled with a near-infrared (NIR) Cy 5.5 dye labeled recombinant amino-terminal fragment (ATF) of the receptor binding domain of urokinase plasminogen activator (uPA), which binds to uPA receptor (uPAR) that is highly expressed in breast cancer tissues. Next, we apply the DOT corrected FMT method to quantitatively evaluate the ability of sensitive tumor imaging after systemic delivery of new uPAR-targeted optical imaging probes in the mice bearing 4T1 mammary tumors. These uPAR-targeted optical imaging probes are ATF peptides labeled with a newly developed NIR-830 dye being conjugated to magnetic iron oxide nanoparticles (IONPs).
RESULTS
Our results have shown that DOT corrected FMT can accurately quantify and localize the injected imaging probe labeled 4T1 cells. Following systemic delivery of the targeted imaging nanoprobes into the mice bearing orthotopic mammary tumors, specific accumulation of the imaging probes in the orthotopic mammary tumors was detected in the mice that received uPAR targeted NIR-830-ATF-IONP probes but not in the mice injected with non-targeted NIR-830-mouse serum albumin (MSA)-IONPs. Additionally, DOT corrected FMT also enables the detection of both locally recurrent tumor and lung metastasis in the mammary tumor model 72 hrs after systemic administration of the uPAR-targeted NIR-830-labeled ATF peptide imaging probes.
CONCLUSIONS
DOT corrected FMT and uPAR-targeted optical imaging probes have great potential for detection of breast cancer, recurrent tumor and metastasis in small animals.
doi:10.3233/XST-130365
PMCID: PMC3785613  PMID: 23507851
DOT fluorescence tomography targeted contrast agents
11.  uPAR-targeted Optical Imaging Contrasts as Theranostic Agents for Tumor Margin Detection 
Theranostics  2013;4(1):106-118.
Complete removal of tumors by surgery is the most important prognostic factor for cancer patients with the early stage cancers. The ability to identify invasive tumor edges of the primary tumor, locally invaded small tumor lesions, and drug resistant residual tumors following neoadjuvant therapy during surgery should significantly reduce the incidence of local tumor recurrence and improve survival of cancer patients. In this study, we report that urokinase plasminogen activator (uPA) and its receptor (uPAR) are the ligand/cell surface target pair for the development of targeted optical imaging probes for enhancing imaging contrasts in the tumor border. Recombinant peptides of the amino terminal fragment (ATF) of the receptor binding domain of uPA were labeled with near infrared fluorescence (NIR) dye molecules either as peptide-imaging or peptide-conjugated nanoparticle imaging probes. Systemic delivery of the uPAR-targeted imaging probes in mice bearing orthotopic human breast or pancreatic tumor xenografts or mouse mammary tumors led to the accumulation of the probes in the tumor and stromal cells, resulting in strong signals for optical imaging of tumors and identification of tumor margins. Histological analysis showed that a high level of uPAR-targeted nanoparticles was present in the tumor edge or active tumor stroma immediately adjacent to the tumor cells. Furthermore, following targeted therapy using uPAR-targeted theranostic nanoparticles, residual tumors were detectable by optical imaging through the imaging contrasts produced by NIR-dye-labeled theranostic nanoparticles in drug resistant tumor cells. Therefore, results of our study support the potential of the development of uPAR-targeted imaging and theranostic agents for image-guided surgery.
doi:10.7150/thno.7409
PMCID: PMC3881230  PMID: 24396518
uPAR; optical imaging; theranostic nanoparticles; tumor margin; and image-guided surgery
12.  Anti-HER2 antibody and ScFvEGFR-conjugated antifouling magnetic iron oxide nanoparticles for targeting and magnetic resonance imaging of breast cancer 
Antifouling magnetic iron oxide nanoparticles (IONPs) coated with block copolymer poly(ethylene oxide)-block-poly(γ-methacryloxypropyltrimethoxysilane) (PEO-b-PγMPS) were investigated for improving cell targeting by reducing nonspecific uptake. Conjugation of a HER2 antibody, Herceptin®, or a single chain fragment (ScFv) of antibody against epidermal growth factor receptor (ScFvEGFR) to PEO-b-PγMPS-coated IONPs resulted in HER2-targeted or EGFR-targeted IONPs (anti-HER2-IONPs or ScFvEGFR-IONPs). The anti-HER2-IONPs bound specifically to SK-BR-3, a HER2-overexpressing breast cancer cell line, but not to MDA-MB-231, a HER2-underexpressing cell line. On the other hand, the ScFvEGFR-IONPs showed strong reactivity with MDA-MB-231, an EGFR-positive human breast cancer cell line, but not with MDA-MB-453, an EGFR-negative human breast cancer cell line. Transmission electron microscopy revealed internalization of the receptor-targeted nanoparticles by the targeted cancer cells. In addition, both antibody-conjugated and non-antibody-conjugated IONPs showed reduced nonspecific uptake by RAW264.7 mouse macrophages in vitro. The developed IONPs showed a long blood circulation time (serum half-life 11.6 hours) in mice and low accumulation in both the liver and spleen. At 24 hours after systemic administration of ScFvEGFR-IONPs into mice bearing EGFR-positive breast cancer 4T1 mouse mammary tumors, magnetic resonance imaging revealed signal reduction in the tumor as a result of the accumulation of the targeted IONPs.
doi:10.2147/IJN.S49069
PMCID: PMC3794963  PMID: 24124366
magnetic nanoparticles; active targeting; antifouling; breast cancer; magnetic resonance imaging
13.  T1-Weighted Ultrashort Echo Time Method for Positive Contrast Imaging of Magnetic Nanoparticles and Cancer Cells Bound With the Targeted Nanoparticles 
Purpose
To obtain positive contrast based on T1 weighting from magnetic iron oxide nanoparticle (IONP) using ultrashort echo time (UTE) imaging and investigate quantitative relationship between positive contrast and the core size and concentration of IONPs.
Materials and Methods
Solutions of IONPs with different core sizes and concentrations were prepared. T1 and T2 relaxation times of IONPs were measured using the inversion recovery turbo spin echo (TSE) and multi-echo spin echo sequences at 3 Tesla. T1-weighted UTE gradient echo and T2-weighted TSE sequences were used to image IONP samples. U87MG glioblastoma cells bound with arginine-glycine-aspartic acid (RGD) peptide and IONP conjugates were scanned using UTE, T1 and T2-weighted sequences.
Results
Positive contrast was obtained by UTE imaging from IONPs with different core sizes and concentrations. The relative-contrast-to-water ratio of UTE images was three to four times higher than those of T2-weighted TSE images. The signal intensity increases as the function of the core size and concentration. Positive contrast was also evident in cell samples bound with RGD-IONPs.
Conclusion
UTE imaging allows for imaging of IONPs and IONP bound tumor cells with positive contrast and provides contrast enhancement and potential quantification of IONPs in molecular imaging applications.
doi:10.1002/jmri.22412
PMCID: PMC3785614  PMID: 21182139
magnetic nanoparticle; magnetic resonance imaging; iron oxide; ultrashort TE; molecular Imaging
14.  Microelectromechanical systems scanning-mirror-based handheld probe for fluorescence molecular tomography 
Applied optics  2012;51(20):4678-4683.
A novel handheld probe based on a microelectromechanical systems (MEMS) scanning mirror for three-dimensional (3D) fluorescence molecular tomography (FMT) is described. The miniaturized probe consists of a MEMS mirror for delivering an excitation light beam to multiple preselected points at the tissue surface and an optical fiber array for collecting the fluorescent emission light from the tissue. Several phantom experiments based on indocyanine green, an FDA approved near-infrared (NIR) fluorescent dye, were conducted to assess the imaging ability of this device. Tumor-bearing mice with systematically injected tumor-targeted NIR fluorescent probes were scanned to further demonstrate the ability of this MEMS-based FMT for imaging small animals.
PMCID: PMC3725146  PMID: 22781242
15.  In vivo magnetic enrichment and multiplex photoacoustic detection of circulating tumour cells 
Nature nanotechnology  2009;4(12):855-860.
The spread of cancer cells between organs, a process known as metastasis, is the cause of most cancer deaths1,2. Detecting circulating tumour cells—a common marker for the development of metastasis3,4—is difficult because ex vivo methods are not sensitive enough owing to limited blood sample volume and in vivo diagnosis is time-consuming as large volumes of blood must be analysed5–7. Here, we show a way to magnetically capture circulating tumour cells in the bloodstream of mice followed by rapid photoacoustic detection. Magnetic nanoparticles, which were functionalized to target a receptor commonly found in breast cancer cells, bound and captured circulating tumour cells under a magnet. To improve detection sensitivity and specificity, gold-plated carbon nanotubes conjugated with folic acid were used as a second contrast agent for photoacoustic imaging. By integrating in vivo multiplex targeting, magnetic enrichment, signal amplification and multicolour recognition, our approach allows circulating tumour cells to be concentrated from a large volume of blood in the vessels of tumour-bearing mice, and this could have potential for the early diagnosis of cancer and the prevention of metastasis in humans.
doi:10.1038/nnano.2009.333
PMCID: PMC3663137  PMID: 19915570
16.  Molecular Imaging of Pancreatic Cancer in an Animal Model Using Targeted Multifunctional Nanoparticles 
Gastroenterology  2009;136(5):1514-25.e2.
Background & Aims
Identification of a ligand/receptor system that enables functionalized nanoparticles to efficiently target pancreatic cancer holds great promise for the development of novel approaches for the detection and treatment of pancreatic cancer. Urokinase plasminogen activator receptor (uPAR), a cellular receptor that is highly expressed in pancreatic cancer and tumor stromal cells, is an excellent surface molecule for receptor-targeted imaging of pancreatic cancer using multifunctional nanoparticles.
Methods
The uPAR-targeted dual-modality molecular imaging nanoparticle probe is designed and prepared by conjugating a near-infrared dye-labeled amino-terminal fragment of the receptor binding domain of urokinase plasminogen activator to the surface of functionalized magnetic iron oxide nanoparticles.
Results
We have shown that the systemic delivery of uPAR-targeted nanoparticles leads to their selective accumulation within tumors of orthotopically xenografted human pancreatic cancer in nude mice. The uPAR-targeted nanoparticle probe binds to and is subsequently internalized by uPAR-expressing tumor cells and tumor-associated stromal cells, which facilitates the intratumoral distribution of the nanoparticles and increases the amount and retention of the nanoparticles in a tumor mass. Imaging properties of the nanoparticles enable in vivo optical and magnetic resonance imaging of uPAR-elevated pancreatic cancer lesions.
Conclusions
Targeting uPAR using biodegradable multifunctional nanoparticles allows for the selective delivery of the nanoparticles into primary and metastatic pancreatic cancer lesions. This novel receptor-targeted nanoparticle is a potential molecular imaging agent for the detection of pancreatic cancer.
doi:10.1053/j.gastro.2009.01.006
PMCID: PMC3651919  PMID: 19208341
17.  Single Chain Epidermal Growth Factor Receptor Antibody Conjugated Nanoparticles for in vivo Tumor Targeting and Imaging 
Epidermal growth factor receptor (EGFR) targeted nanoparticle are developed by conjugating a single-chain anti-EGFR antibody (ScFvEGFR) to surface functionalized quantum dots (QDs) or magnetic iron oxide (IO) nanoparticles. The results show that ScFvEGFR can be successfully conjugated to the nanoparticles, resulting in compact ScFvEGFR nanoparticles that specifically bind to and are internalized by EGFR-expressing cancer cells, thereby producing a fluorescent signal or magnetic resonance imaging (MRI) contrast. In vivo tumor targeting and uptake of the nanoparticles in human cancer cells is demonstrated after systemic delivery of ScFvEGFR-QDs or ScFvEGFR-IO nanoparticles into an orthotopic pancreatic cancer model. Therefore, ScFvEGFR nanoparticles have potential to be used as a molecular-targeted in vivo tumor imaging agent. Efficient internalization of ScFvEGFR nanoparticles into tumor cells after systemic delivery suggests that the EGFR-targeted nanoparticles can also be used for the targeted delivery of therapeutic agents.
doi:10.1002/smll.200800714
PMCID: PMC3626261  PMID: 19089838
antibodies; drug delivery; nanoparticles; proteins; quantum dots
18.  Multiplexed Fluorescence Imaging of Tumor Biomarkers in Gene Expression and Protein Levels for Personalized and Predictive Medicine 
Current molecular medicine  2009;9(8):1017-1023.
Combining ground breaking research and developments in cancer biomarkers, nanotechnology and molecular targeted medicine, a new realm of therapy is possible: personalized and predictive medicine. Developing a method to detect the overexpression of several tumor marker genes simultaneously, knowing that a single cell generally expresses more than one altered gene, should have a high predictive value for identifying cancer cells amidst the normal cellular background. Theoretically, a cancer’s unique molecular profile can be used to predict its invasive and metastatic potential, its ability to evade immune surveillance, and its potential response to treatment. Fluorescent probes have been developed to detect the levels of expression of various biomarkers in tumor cells and tissues. Expression of biomarker messenger RNAs (mRNAs) or the presence of a specific mutation in an oncogene in cancer cells can be detected using molecular beacons (MBs) that only emit fluorescent signals after binding to its specific target mRNAs. Antibodies or ligands labeled with fluorophores or fluorescent quantum dots (QDs) have been successfully used to identify specific proteins expressed in cells. Furthermore, multiplex imaging using both MBs and antibodies labeled with a fluorescent probe on the same sample may provide important information correlating the level of mRNA expression and the subsequent level of protein production for a given biomarker. This technology will be useful in research investigating cancer biology, molecular imaging and molecular profiling. With the identification of biomarkers that are related to aggressive tumor types, we may be able to predict within certain patient populations who will develop invasive cancers, and what their prognosis will be given different treatment modalities, ultimately delivering medical care and treatment strategies that are specifically tailored to each individual patient, making personalized and predictive medicine a reality.
PMCID: PMC3594694  PMID: 19747113
Biomarkers; molecular beacons; molecular profiling; multiplexed imaging; nanotechnology; personalized medicine; predictive medicine; quantum dots
19.  Handheld miniature probe integrating diffuse optical tomography with photoacoustic imaging through a MEMS scanning mirror 
Biomedical Optics Express  2013;4(3):427-432.
We describe a novel dual-modality imaging approach that integrates diffuse optical tomography (DOT) and photoacoustic imaging (PAI) through a miniaturized handheld probe based on microelectromechanical systems (MEMS) scanning mirror. We validate this dual-modal DOT/PAI approach using extensive phantom experiments, and demonstrate its application for tumor imaging using tumor-bearing mice systematically injected with targeted contrast agents.
doi:10.1364/BOE.4.000427
PMCID: PMC3595086  PMID: 23504287
(110.6960) Tomography; (170.0110) Imaging systems; (170.5120) Photoacoustic imaging
20.  Antibody Conjugated Magnetic Iron Oxide Nanoparticles for Cancer Cell Separation in Fresh Whole Blood 
Biomaterials  2011;32(36):9758-9765.
A highly efficient process using iron oxide magnetic nanoparticles (IO)-based immunomagnetic separation of tumor cells from fresh whole blood has been developed. The process involved polymer coated 30 nm IO that was modified with antibodies (Ab) against human epithelial growth factor receptor 2 (anti-HER2 or anti-HER2/neu) forming IO-Ab. HER2 is a cell membrane protein that is over expressed in several types of human cancer cells. Using a HER2/neu over expressing human breast cancer cell line, SK-BR3, as a model cell, the IO-Ab was used to separate 73.6 % (with a maximum capture of 84%) of SK-BR3 cells that were spiked in 1 mL of fresh human whole blood. The IO-Ab preferentially bound to SK-BR3 cells over normal cells found in blood due to the high level of HER2/neu receptor on the cancer cells unlike the normal cell surfaces. The results showed that the nanosized magnetic nanoparticles exhibited an enrichment factor (cancer cells over normal cells) of 1:10,000,000 in a magnetic field (with gradient of 100 T/m) through the binding of IO-Ab on the cell surface that resulted in the preferential capture of the cancer cells. This research holds promise for efficient separation of circulating cancer cells in fresh whole blood.
doi:10.1016/j.biomaterials.2011.08.076
PMCID: PMC3220927  PMID: 21920599
magnetic nanoparticles; iron oxide; cancer cells; cell sorting; immunomagnetic separation
21.  Designing Caspase-3 Sensors for Imaging of Apoptosis in Living Cells 
doi:10.1002/chem.200901439
PMCID: PMC3480176  PMID: 19655355
apoptosis; caspase-3; enhanced green fluorescent proteins; protease sensors; ratiometric measurements
22.  Survivin upregulation, dependent on leptin-EGFR-Notch1 axis, is essential for leptin induced migration of breast carcinoma cells 
Endocrine-Related Cancer  2011;18(4):413-428.
Obese breast cancer patients exhibit a higher risk for larger tumor burden and increased metastasis. Molecular effects of obesity on carcinogenesis are mediated by autocrine and paracrine effects of adipocytokine leptin. Leptin participates in tumor progression and metastasis of human breast. We show that leptin induces clonogenicity and migration potential of breast cancer cells. We found that survivin expression is induced in response to leptin. In this study, we examine the role and leptin-mediated regulation of survivin. Leptin treatment leads to survivin upregulation, due in part to the activation of Notch1 and release of transcriptionally active Notch1-intracellular-domain (NICD). ChIP analysis show that NICD gets recruited to survivin promoter at CSL-binding-site in response to leptin treatment. Inhibition of Notch1 activity inhibits leptin-induced survivin upregulation. Leptin-induced transactivation of EGFR is involved in leptin-mediated Notch1 and survivin upregulation showing a novel upstream role of leptin-EGFR-Notch1 axis. We further show that leptin-induced migration of breast cancer cells requires survivin, as overexpression of survivin further increases, whereas silencing survivin abrogates leptin-induced migration. Using a pharmacological approach to inhibit survivin, we show that 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase inhibitors (HRIs), lovastatin, can effectively inhibit leptin-induced survivin expression and migration. Importantly, leptin increased breast tumor growth in nude mice. These data show a novel role for survivin in leptin-induced migration and put forth pharmacological survivin inhibition as a potential novel therapeutic target. This conclusion is supported by in vivo data showing overexpression of leptin and survivin in epithelial cells of high grade ductal carcinoma in situ and high grade invasive carcinoma.
doi:10.1530/ERC-11-0075
PMCID: PMC3361735  PMID: 21555376
Breast Cancer cell migration; Leptin; Notch; EGFR; Survivin
23.  Current and Future Clinical Applications for Optical Imaging of Cancer: From Intraoperative Surgical Guidance to Cancer Screening 
Seminars in oncology  2011;38(1):109-118.
Optical imaging is an inexpensive, fast, and sensitive imaging approach for the non-invasive detection of human cancers in locations that are accessible by an optical imaging device. Light is used to probe cellular and molecular function in the context of cancer in the living body. Recent advances in the development of optical instrumentation make it possible to detect optical signals produced at a tissue depth of several centimeters. The optical signals can be endogenous contrasts that capture the heterogeneity and biological status of different tissues including tumors, or extrinsic optical contrasts that selectively accumulate in tumors to be imaged after local or systemic delivery. The use of optical imaging is now being applied in the clinic and operating room for the localization and resection of malignant tumors in addition to screening for cancer.
doi:10.1053/j.seminoncol.2010.11.008
PMCID: PMC3061227  PMID: 21362519
Optical Imaging; Cancer; Glioblastoma; Breast Cancer; Bladder Cancer; Near Infrared; Nanoparticles
24.  Improving the Magnetic Resonance Imaging Contrast and Detection Methods with Engineered Magnetic Nanoparticles 
Theranostics  2012;2(1):86-102.
Engineering and functionalizing magnetic nanoparticles have been an area of the extensive research and development in the biomedical and nanomedicine fields. Because their biocompatibility and toxicity are well investigated and better understood, magnetic nanoparticles, especially iron oxide nanoparticles, are better suited materials as contrast agents for magnetic resonance imaging (MRI) and for image-directed delivery of therapeutics. Given tunable magnetic properties and various surface chemistries from the coating materials, most applications of engineered magnetic nanoparticles take advantages of their superb MRI contrast enhancing capability as well as surface functionalities. It has been found that MRI contrast enhancement by magnetic nanoparticles is highly dependent on the composition, size and surface properties as well as the degree of aggregation of the nanoparticles. Therefore, understanding the relationships between these intrinsic parameters and the relaxivities that contribute to MRI contrast can lead to establishing essential guidance that may direct the design of engineered magnetic nanoparticles for theranostics applications. On the other hand, new contrast mechanism and imaging strategy can be developed based on the novel properties of engineered magnetic nanoparticles. This review will focus on discussing the recent findings on some chemical and physical properties of engineered magnetic nanoparticles affecting the relaxivities as well as the impact on MRI contrast. Furthermore, MRI methods for imaging magnetic nanoparticles including several newly developed MRI approaches aiming at improving the detection and quantification of the engineered magnetic nanoparticles are described.
doi:10.7150/thno.4006
PMCID: PMC3263519  PMID: 22272222
magnetic nanoparticles; engineering; functionalizing; magnetic resonance imaging
25.  Molecular Beacon Imaging of Tumor Marker Gene Expression in Pancreatic Cancer Cells 
Cancer biology & therapy  2005;4(5):561-570.
We have developed a fluorescence imaging-based approach to detect expression of tumor marker genes in pancreatic cancer cells using molecular beacons (MBs). MBs are short hairpin oligonucleotide probes that bind to specific oligonucleotide sequences and produce fluorescent signals. MBs targeting transcripts of two tumor marker genes, mutant K-ras and survivin, were synthesized and their specificity in detection of the expression of those genes in pancreatic cancer cells was examined. We found that K-ras MBs differentially bind to mutant K-ras mRNAs, resulting in strong fluorescent signals in pancreatic cancer cells with specific mutant K-ras genes but not in normal cells or cancer cells expressing either wild type or a different mutation of the K-ras gene. Additionally, MBs targeting survivin mRNA produced a bright fluorescent signal specifically in pancreatic cancer cells. We also demonstrated that MBs labeled with different fluorophores could detect survivin and mutant K-ras mRNAs simultaneously in single cancer cells. Furthermore, we showed that survivin and K-ras MBs have a high specificity in identifying cancer cells on frozen sections of pancreatic cancer tissues. In conclusion, molecular beacon-based imaging of expression of tumor marker genes has potential for the development of novel approaches for the detection of pancreatic cancer cells.
PMCID: PMC3163158  PMID: 15917666
molecular imaging; molecular beacon; K-ras mutation; survivin; in situ gene expression detection and pancreatic cancer cells

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