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1.  Modulation of in Vivo Tumor Radiation Response via Gold Nanoshell-Mediated Vascular-Focused Hyperthermia: Characterizing an Integrated Antihypoxic and Localized Vascular Disrupting Targeting Strategy 
Nano letters  2008;8(5):1492-1500.
We report noninvasive modulation of in vivo tumor radiation response using gold nanoshells. Mild-temperature hyperthermia generated by near-infrared illumination of gold nanoshell-laden tumors, noninvasively quantified by magnetic resonance temperature imaging, causes an early increase in tumor perfusion that reduces the hypoxic fraction of tumors. A subsequent radiation dose induces vascular disruption with extensive tumor necrosis. Gold nanoshells sequestered in the perivascular space mediate these two tumor vasculature-focused effects to improve radiation response of tumors. This novel integrated antihypoxic and localized vascular disrupting therapy can potentially be combined with other conventional antitumor therapies.
doi:10.1021/nl080496z
PMCID: PMC3952070  PMID: 18412402
2.  Ursolic Acid Inhibits Growth and Metastasis of Human Colorectal Cancer in an Orthotopic Nude Mouse Model by Targeting Multiple Cell Signaling Pathways: Chemosensitization with Capecitabine 
Purpose
Development of chemoresistance, poor prognosis, and metastasis often renders the current treatments for colorectal cancer (CRC) ineffective. Whether ursolic acid (UA), a component of numerous medicinal plants, either alone or in combination with capecitabine, can inhibit the growth and metastasis of human CRC was investigated.
Experimental design
The effect of UA on proliferation of colorectal cancer cell lines was examined by mitochondrial dye-uptake assay, apoptosis by esterase staining, NF-κB activation by DNA binding assay and protein expression by western blot. The effect of UA on the growth and chemosensitization was also examined in orthotopically-implanted CRC in nude mice.
Results
We found that UA inhibited the proliferation of different colon cancer cell lines. This is correlated with inhibition of constitutive NF-κB activation and downregulation of cell survival (Bcl-xL, Bcl-2, cFLIP, survivin), proliferative (Cyclin D1), and metastatic (MMP-9, VEGF, ICAM-1) proteins. When examined in an orthotopic nude-mice model, UA significantly inhibited tumor volume, ascites formation and distant organ metastasis, and this effect was enhanced with capecitabine. Immunohistochemistry of tumor tissue indicated that UA downregulated biomarkers of proliferation (Ki-67) and microvessel density (CD31). This effect was accompanied by suppression of NF-κB, STAT3, and β-catenin. In addition, UA suppressed EGFR, and induced p53, and p21 expression. We also observed bioavailability of UA in the serum and tissue of animals.
Conclusion
Overall our results demonstrate that UA can inhibit the growth and metastasis of CRC and further enhance the therapeutic effects of capecitabine through suppression of multiple biomarkers linked to inflammation, proliferation, invasion, angiogenesis, and metastasis.
doi:10.1158/1078-0432.CCR-11-2805
PMCID: PMC3677707  PMID: 22832932
3.  Zyflamend Suppresses Growth and Sensitizes Human Pancreatic Tumors to Gemcitabine in an Orthotopic Mouse Model Through Modulation of Multiple Targets 
Agents that can potentiate the efficacy of standard chemotherapy against pancreatic cancer are of great interest. Because of their low cost and safety, patients commonly use a variety of dietary supplements, although evidence of their efficacy is often lacking. One such commonly used food supplement, Zyflamend, is a polyherbal preparation with potent anti-inflammatory activities, and preclinical efficacy against prostate and oral cancer. Whether Zyflamend has any efficacy against human pancreatic cancer alone or in combination with gemcitibine, a commonly used agent, was examined in cell cultures and in an orthotopic mouse model. In vitro, Zyflamend inhibited the proliferation of pancreatic cancer cell lines regardless of p53 status and also enhanced gemcitabine-induced apoptosis. This finding correlated with inhibition of NF-κB activation by Zyflamend and suppression of cyclin D1, c-myc, COX-2, Bcl-2, IAP, survivin, VEGF, ICAM-1, and CXCR4. In nude mice, oral administration of Zyflamend alone significantly inhibited the growth of orthotopically transplanted human pancreatic tumors, and when combined with gemcitabine, further enhanced the antitumor effects. Immunohistochemical and Western blot analyses of tumor tissue showed that the suppression of pancreatic cancer growth correlated with inhibition of proliferation index marker (Ki-67), COX-2, MMP-9, NF-κB, and VEGF. Overall, these results suggest that the concentrated multiherb product Zyflamend alone can inhibit the growth of human pancreatic tumors and, in addition, can sensitize pancreatic cancers to gemcitabine through the suppression of multiple targets linked to tumorigenesis.
doi:10.1002/ijc.26442
PMCID: PMC3288649  PMID: 21935918
Zyflamend; pancreatic cancer; inflammation
4.  Nanoparticle-mediated hyperthermia in cancer therapy 
Therapeutic delivery  2011;2(8):1001-1014.
A small rise in tumor temperature (hyperthermia) makes cancer cells more susceptible to radiation and chemotherapy. The means of achieving this is not trivial, and traditional methods have certain drawbacks. Loading tumors with systematically asministered energy-transducing nanoparticles can circumvent several of the obstacles to achieve tumor hyperthermia. However, nanoparticles also face unique challenges prior to clinical implementation. This article summarizes the state-of-the-art current technology and discusses the advantages and challenges of the three major nanoparticle formulations in focus: gold nanoshells and nanorods, superparamagnetic iron oxide particles and carbon nanotubes.
PMCID: PMC3323111  PMID: 22506095
5.  Inhibition of radiation-induced DNA repair and pro-survival pathways contribute to vorinostat-mediated radiosensitization of pancreatic cancer cells 
Pancreas  2010;39(8):1277-1283.
Objective:
The intrinsic radioresistance of pancreatic cancer (PaCa) is due to multiple oncogenic signaling pathways. In contrast to combining radiation therapy (RT) with targeted therapeutic agent(s) whose blockade can be circumvented by redundant signaling pathways, we evaluated the combination of RT with a broad-spectrum histone deacetylase inhibitor, vorinostat.
Methods:
Radiosensitization by vorinostat was analyzed using clonogenic survival assays. Apoptosis was evaluated using flow cytometry and immunoblotting. DNA repair was evaluated using immunofluorescence assessment of histone2AX phosphorylation and immunoblotting for DNA repair proteins. Pro-survival pathway proteins were measured by immunoblotting and electrophoretic mobility shift assays.
Results:
Vorinostat significantly sensitized PaCa cells to radiation, but vorinostat-induced apoptosis did not contribute significantly to the observed radiosensitization. However, vorinostat inhibited DNA damage repair by targeting key DNA repair proteins and also abrogated pro-survival pathways responsible for PaCa aggressiveness and radioresistance. Specifically, the constitutively overexpressed epidermal growth factor receptor and nuclear factor kappaB pathways were shown to be induced by radiation and inhibited by vorinostat.
Conclusions:
Vorinostat augments the anti-tumor effects of RT by abrogating radioresistance responses of PaCa cells mediated by pro-survival and DNA repair pathways, and promises to be a clinically relevant adjunct to RT for treatment of PaCa.
doi:10.1097/MPA.0b013e3181dd63e1
PMCID: PMC2955787  PMID: 20531243
Vorinostat; Pancreatic Cancer; Radiation; NF-κB; EGFR; Radiosensitization
6.  γ-Tocotrienol Inhibits Pancreatic Tumors and Sensitizes Them to Gemcitabine Treatment by Modulating the Inflammatory Microenvironment 
Cancer research  2010;70(21):8695-8705.
Pancreatic cancers generally respond poorly to chemotherapy, prompting a need to identify agents that could sensitize tumors to treatment. In this study, we investigated the response of human pancreatic cells to gamma-tocotrienol (γ-T3), a novel, unsaturated form of vitamin E found in palm oil and rice bran oil, to determine whether it could potentiate the effects of gemcitabine, a standard of care in clinical treatment of pancreatic cancer. γ-T3 inhibited the in vitro proliferation of pancreatic cancer cell lines with variable p53 status and potentiated gemcitabine-induced apoptosis. These effects correlated with an inhibition of NF-κB activation by γ-T3 and a suppression of key cellular regulators including cyclin D1, c-Myc, COX-2, Bcl-2, cIAP, survivin, VEGF, ICAM-1, and CXCR4. In an orthotopic nude mouse model of human pancreatic cancer, oral administration of γ-T3 inhibited tumor growth and enhanced the antitumor properties of gemcitabine. Immunohistochemical analysis indicated a correlation between tumor growth inhibition and reduced expression of Ki-67, COX-2, MMP-9, NF-κB p65 and VEGF in the tissue. Combination treatment also downregulated NF-κB activity along with the NF-κB-regulated gene products cyclin D1, c-Myc, VEGF, MMP-9, CXCR4. Consistent with an enhancement of tumor apoptosis caspase activation was observed in tumor tissues. Overall, Our findings suggest that γ-T3 can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing of NF-κB-mediated inflammatory pathways linked to tumorigenesis.
doi:10.1158/0008-5472.CAN-10-2318
PMCID: PMC2970705  PMID: 20864511
tocotrienol; pancreatic cancer; NF-κB; inflammation
7.  Intra-organ Biodistribution of Gold Nanoparticles Using Intrinsic Two-photon Induced Photoluminescence 
Lasers in surgery and medicine  2010;42(7):630-639.
Background and Objectives
Gold nanoparticles (GNPs) such as gold nanoshells (GNSs) and gold nanorods (GNRs) have been explored in a number of in vitro and in vivo studies as imaging contrast and cancer therapy agents due to their highly desirable spectral and molecular properties. While the organ-level biodistribution of these particles has been reported previously, little is known about the cellular level or intra-organ biodistribution. The objective of this study was to demonstrate the use of intrinsic two-photon induced photoluminescence (TPIP) to study the cellular level biodistribution of GNPs.
Study Design/Materials and Methods
Tumor xenografts were created in twenty-seven male nude mice (Swiss nu/nu) using HCT 116 cells (CCL-247, ATCC, human colorectal cancer cell line). GNSs and GNRs were systemically injected 24 hr. prior to tumor harvesting. A skin flap with the tumor was excised and sectioned as 8 μm thick tissues for imaging GNPs under a custom-built multiphoton microscope. For multiplexed imaging, nuclei, cytoplasm, and blood vessels were demonstrated by hematoxylin and eosin (H&E) staining, YOYO-1 iodide staining and CD31-immunofluorescence staining.
Results
Distribution features of GNPs at the tumor site were determined from TPIP images. GNSs and GNRs had a heterogeneous distribution with higher accumulation at the tumor cortex than tumor core. GNPs were also observed in unique patterns surrounding the perivascular region. While most GNSs were confined at the distance of approximately 400 μm inside the tumor edge, GNRs were shown up to 1.5 mm penetration inside the edge.
Conclusions
We have demonstrated the use of TPIP imaging in a multiplexed fashion to image both GNPs and nuclei, cytoplasm, or vasculature simultaneously. We also confirmed that TPIP imaging enabled visualization of GNP distribution patterns within the tumor and other critical organs. These results suggest that direct luminescence-based imaging of metal nanoparticles holds a valuable and promising position in understanding the accumulation kinetics of GNPs. In addition, these techniques will be increasingly important as the use of these particles progress to human clinical trials where standard histopathology techniques are used to analyze their effects.
doi:10.1002/lsm.20935
PMCID: PMC3052865  PMID: 21399728
gold nanoshell; gold nanorod; two-photon induced photoluminescence
8.  Resveratrol, a multitargeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer 
Gemcitabine, while a standard treatment of advanced pancreatic cancer (PaCa), alone is not very effective. New agents that are safe and effective are highly needed. Resveratrol is one such agent which is safe and multitargeted; and has been linked with suppression of survival, proliferation, invasion and angiogenesis of cancer. Whether resveratrol can sensitize PaCa to gemcitabine in vitro and in vivo was investigated. We established PaCa xenografts in nude mice, randomized into 4 groups, and treated with vehicle, gemcitabine, resveratrol and with combination. Modulation of NF-κB and markers of proliferation, angiogenesis and invasion were ascertained using electrophoretic mobility shift assay (EMSA), immunohistochemistry and western blot analysis. Resveratrol inhibited the proliferation of 4 different human PaCa cell lines, synergized the apoptotic effects of gemcitabine, inhibited the constitutive activation of NF-κB and expression of bcl-2, bcl-xL, COX-2, cyclin D1 MMP-9 and VEGF. In an orthotopic model of human PaCa, we found that resveratrol significantly suppressed the growth of the tumor (p < 0.001) and this effect was further enhanced by gemcitabine (p < 0.001). Both the markers of proliferation index Ki-67 and the micro vessel density CD31 were significantly downregulated in tumor tissue by the combination of gemcitabine and resveratrol (p < 0.001 vs. control; p < 0.01 vs. gemcitabine). As compared to vehicle control, resveratrol also suppressed the NF-κB activation and expression of cyclin D1, COX-2, ICAM-1, MMP-9 and survivin. Overall our results demonstrate that resveratrol can potentiate the effects of gemcitabine through suppression of markers of proliferation, invasion, angiogenesis and metastasis.
doi:10.1002/ijc.25041
PMCID: PMC3090706  PMID: 19908231
apoptosis; chemoresistance; chemotherapeutic agents; NF-κB; pancreatic cancer
9.  Gadolinium Chloride Augments Tumor-Specific Imaging of Targeted Quantum Dots in vivo 
ACS nano  2010;4(7):4131-4141.
Non-specific sequestration of nanoparticles by the reticulo-endothelial system (RES) results in the degradation of image quality of nanoparticle-based imaging. We demonstrate that Gadolinium chloride (GdCl3) pretreatment inactivates RES macrophages thereby increasing circulatory time and amplifying tumor-specific signal of conjugated nanoparticles in vivo. The experimental results were validated using compartmental modeling and the rate parameters for the observed kinetics pattern were estimated. This pretreatment strategy could have broad applicability across biomedical applications utilizing theranostic nanoparticles that are sequestered by the RES.
doi:10.1021/nn901919w
PMCID: PMC3090730  PMID: 20586481
Gadolinium chloride; nanoparticle; imaging; Kupffer cell; quantum dots
10.  A novel small molecule inhibitor of protein kinase D blocks pancreatic cancer growth in vitro and in vivo 
Molecular cancer therapeutics  2010;9(5):1136-1146.
Protein kinase D (PKD) family members are increasingly implicated in multiple normal and abnormal biological functions, including signaling pathways that promote mitogenesis in pancreatic cancer (PaCa). However, nothing is known about the effects of targeting PKD in PaCa. Our PKD-inhibitor discovery program identified CRT0066101 as a specific inhibitor of all PKD isoforms. The aim of our study was to determine the effects of CRT0066101 in PaCa. Initially, we showed that autophosphorylated PKD1 and PKD2 (activated PKD1/2) are significantly upregulated in PaCa and that PKD1/2 are expressed in multiple PaCa cell-lines. Using Panc-1 as a model system, we demonstrated that CRT0066101 reduced BrdU incorporation, increased apoptosis, blocked neurotensin (NT)-induced PKD1/2 activation, reduced NT-induced PKD-mediated Hsp27 phosphorylation, attenuated PKD1-mediated NF-κB activation, and abrogated expression of NF-κB-dependent-dependent proliferative and pro-survival proteins. We showed that CRT0066101 given orally (80 mg/kg/day) for 28 days significantly abrogated PaCa growth in Panc-1 subcutaneous xenograft model. Activated PKD1/2 expression in the treated tumor-explants was significantly inhibited with peak tumor concentration (12 µM) of CRT0066101 achieved within 2 h after oral administration. Further, we showed that CRT0066101 given orally (80 mg/kg/day) for 21 days in Panc-1 orthotopic model potently blocked tumor growth in vivo. CRT0066101 significantly reduced Ki-67+ proliferation index (p< 0.01), increased TUNEL+ apoptotic cells (p<0.05), and abrogated expression of NF-κB-dependent proteins including cyclin D1, survivin, and cIAP-1. Our results demonstrate for the first time that a PKD-specific small molecule inhibitor CRT0066101 blocks PaCa growth in vivo and show that PKD is a novel therapeutic target in PaCa.
doi:10.1158/1535-7163.MCT-09-1145
PMCID: PMC2905628  PMID: 20442301
protein kinase D; small molecule inhibitor; pancreatic cancer; tumor xenografts
11.  Nanoparticle-mediated thermal therapy: Evolving strategies for prostate cancer therapy 
Purpose
Recent advances in nanotechnology have resulted in the manufacture of a plethora of nanoparticles with different sizes, shapes, core physicochemical properties and surface modifications that are being investigated for potential medical applications, particularly for the treatment of cancer. This review focuses on the therapeutic use of customized gold nanoparticles, magnetic nanoparticles and carbon nanotubes that efficiently generate heat upon electromagnetic (light and magnetic fields) stimulation after direct injection into tumors or preferential accumulation in tumors following systemic administration. This review will also focus on the evolving strategies to improve the therapeutic index of prostate cancer treatment using nanoparticle-mediated hyperthermia.
Conclusions
Nanoparticle-mediated thermal therapy is a new and minimally invasive tool in the armamentarium for the treatment of cancers. Unique challenges posed by this form of hyperthermia include the non-target biodistribution of nanoparticles in the reticuloendothelial system when administered systemically, the inability to visualize or quantify the global concentration and spatial distribution of these particles within tumors, the lack of standardized thermal modeling and dosimetry algorithms, and the concerns regarding their biocompatibility. Nevertheless, novel particle compositions, geometries, activation strategies, targeting techniques, payload delivery strategies, and radiation dose enhancement concepts are unique attributes of this form of hyperthermia that warrant further exploration. Capitalizing on these opportunities and overcoming these challenges offers the possibility of seamless and logical translation of this nanoparticle-mediated hyperthermia paradigm from the bench to the bedside.
doi:10.3109/02656736.2010.485593
PMCID: PMC3071560  PMID: 20858069
Nanoparticles; magnetic; optical; activatable; hyperthermia; prostate cancer
12.  Integrin αvβ3-targeted gold nanoshells augment tumor vasculature-specific imaging and therapy 
Purpose
Gold nanoshells (NSs) have already shown great promise as photothermal actuators for cancer therapy. Integrin αvβ3 is a marker that is specifically and preferentially overexpressed on multiple tumor types and on angiogenic tumor neovasculature. Active targeting of NSs to integrin αvβ3 offers the potential to increase accumulation preferentially in tumors and thereby enhance therapy efficacy.
Methods
Enzyme-linked immunosorbent assay (ELISA) and cell binding assay were used to study the in vitro binding affinities of the targeted nanoconjugate NS–RGDfK. In vivo biodistribution and tumor specificity were analyzed using 64Cu-radiolabeled untargeted and targeted NSs in live nude rats bearing head and neck squamous cell carcinoma (HNSCC) xenografts. The potential thermal therapy applications of NS–RGDfK were evaluated by subablative thermal therapy of tumor xenografts using untargeted and targeted NSs.
Results
ELISA and cell binding assay confirmed the binding affinity of NS–RGDfK to integrin αvβ3. Positron emission tomography/computed tomography imaging suggested that tumor targeting is improved by conjugation of NSs to cyclo(RGDfK) and peaks at ~20 hours postinjection. In the subablative thermal therapy study, greater biological effectiveness of targeted NSs was implied by the greater degree of tumor necrosis.
Conclusion
The results presented in this paper set the stage for the advancement of integrin αvβ3-targeted NSs as therapeutic nanoconstructs for effective cancer therapy.
doi:10.2147/IJN.S15479
PMCID: PMC3058535  PMID: 21423588
nanoparticle; cyclo(RGDfK); cancer; thermal ablation
13.  Near-infrared narrow-band imaging of gold/silica nanoshells in tumors 
Journal of biomedical optics  2009;14(2):024044.
Gold nanoshells (GNS) are a new class of nanoparticles that can be optically tuned to scatter or absorb light from the near-ultraviolet to near-infrared (NIR) region by varying the core (dielectric silica)/shell (gold) ratio. In addition to spectral tunability, GNS are inert and bioconjugatable, making them potential labels for in vivo imaging and therapy of tumors. We report the use of GNS as exogenous contrast agents for enhanced visualization of tumors using narrow-band imaging (NBI). NBI takes advantage of the strong NIR absorption of GNS to distinguish between blood and nanoshells in the tumor by imaging in narrow wavelength bands in the visible and NIR, respectively. Using tissue-simulating phantoms, we determined the optimum wavelengths to enhance contrast between blood and GNS. We then used the optimum wavelengths for ex vivo imaging of tumors extracted from human colon cancer xenograft bearing mice injected with GNS. Systemically delivered GNS accumulated passively in tumor xenografts by the enhanced permeability and retention (EPR) effect. Ex vivo NBI of tumor xenografts demonstrated heterogeneous distribution of GNS with a clear distinction from the tumor vasculature. The results of this study demonstrate the feasibility of using GNS as contrast agents to visualize tumors using NBI.
doi:10.1117/1.3120494
PMCID: PMC2810638  PMID: 19405772
gold nanoshells; narrow-band imaging; cancer
14.  Neutrophil Gelatinase-Associated Lipocalin: A Novel Suppressor of Invasion and Angiogenesis in Pancreatic Cancer 
Cancer research  2008;68(15):6100-6108.
Neutrophil gelatinase associated lipocalin (NGAL) is a 25 kDa secreted acute phase protein, which is also upregulated in multiple cancers, including breast, lung, and pancreas. Recently, NGAL has been proposed as an early biomarker in pancreatic cancer (PaCa). However, its biological role in PaCa is unknown. In this study, we examined in vitro and in vivo functional role of NGAL in PaCa. Well to moderately differentiated PaCa cells (AsPC-1, BxPC-3, and Capan-2) expressed high levels of NGAL but moderate to poorly differentiated PaCa cells (PANC-1 and MIAPaCa-2) expressed undetectable NGAL levels. Immunohistochemistry of untreated tissue microarray showed specific NGAL staining in resected PaCa specimens (p=0.0167). Stable NGAL overexpression (MIAPaCa-2 and PANC-1) significantly blocked PaCa cells adhesion and invasion in vitro and vice versa with stable NGAL-shRNA PaCa clones (BxPC-3 and AsPC-1). Moreover, NGAL overexpression reduced focal adhesion kinase (FAK) tyrosine-397 phosphorylation in PaCa cells. Further, NGAL overexpression potently decreased angiogenesis in vitro partly through reduced VEGF production and vice versa. Stable NGAL over- or underexpression had no effects on PaCa cell survival, viability, and response to chemotherapeutic drugs. Finally, MIAPaCa-2 cells overexpressing NGAL reduced tumor volume (p=0.012), local and distant metastasis (p=0.002), and angiogenesis (p=0.05) with no effect on K-67 proliferation index (p>0.1) in an orthotopic nude mouse PaCa model. Collectively, our results suggest that NGAL reduces adhesion/invasion partly by suppressing FAK activation and inhibits angiogenesis partly by blocking VEGF production in PaCa cells. Thus, NGAL is a potential suppressor of invasion and angiogenesis in advanced PaCa.
doi:10.1158/0008-5472.CAN-08-0540
PMCID: PMC2714276  PMID: 18676832
NGAL; lipocalin 2; invasion; angiogenesis; pancreatic cancer

Results 1-14 (14)