Imaging Tiny Hepatic Tumor Xenografts via Endoglin-Targeted Paramagnetic/Optical Nanoprobe.

PubMed

Yan, Huihui; Gao, Xihui; Zhang, Yunfei; Chang, Wenju; Li, Jianhui; Li, Xinwei; Du, Qin; Li, Cong

2018-05-23

Surgery is the mainstay for treating hepatocellular carcinoma (HCC). However, it is a great challenge for surgeons to identify HCC in its early developmental stage. The diagnostic sensitivity for a tiny HCC with a diameter less than 1.0 cm is usually as low as 10-33% for computed tomography (CT) and 29-43% for magnetic resonance imaging (MRI). Although MRI is the preferred imaging modality for detecting HCC, with its unparalleled spatial resolution for soft tissue, the commercially available contrast agent, such as Gd 3+ -DTPA, cannot accurately define HCC because of its short circulation lifetime and lack of tumor-targeting specificity. Endoglin (CD105), a type I membrane glycoprotein, is highly expressed both in HCC cells and in the endothelial cells of neovasculature, which are abundant at the tumor periphery. In this work, a novel single-stranded DNA oligonucleotide-based aptamer was screened by systematic evolution of ligands in an exponential enrichment assay and showed a high binding affinity ( K D = 98 pmol/L) to endoglin. Conjugating the aptamers and imaging reporters on a G5 dendrimer created an HCC-targeting nanoprobe that allowed the successful visualization of orthotopic HCC xenografts with diameters as small as 1-4 mm. Significantly, the invasive tumor margin was clearly delineated, with a tumor to normal ratio of 2.7 by near-infrared (NIR) fluorescence imaging and 2.1 by T 1 -weighted MRI. This multimodal nanoprobe holds promise not only for noninvasively defining tiny HCC by preoperative MRI but also for guiding tumor excision via intraoperative NIR fluorescence imaging, which will probably gain benefit for the patient's therapeutic response and improve the survival rate.

In vivo targeting and imaging of tumor vasculature with radiolabeled, antibody-conjugated nanographene.

PubMed

Hong, Hao; Yang, Kai; Zhang, Yin; Engle, Jonathan W; Feng, Liangzhu; Yang, Yunan; Nayak, Tapas R; Goel, Shreya; Bean, Jero; Theuer, Charles P; Barnhart, Todd E; Liu, Zhuang; Cai, Weibo

2012-03-27

Herein we demonstrate that nanographene can be specifically directed to the tumor neovasculature in vivo through targeting of CD105 (i.e., endoglin), a vascular marker for tumor angiogenesis. The covalently functionalized nanographene oxide (GO) exhibited excellent stability and target specificity. Pharmacokinetics and tumor targeting efficacy of the GO conjugates were investigated with serial noninvasive positron emission tomography imaging and biodistribution studies, which were validated by in vitro, in vivo, and ex vivo experiments. The incorporation of an active targeting ligand (TRC105, a monoclonal antibody that binds to CD105) led to significantly improved tumor uptake of functionalized GO, which was specific for the neovasculature with little extravasation, warranting future investigation of these GO conjugates for cancer-targeted drug delivery and/or photothermal therapy to enhance therapeutic efficacy. Since poor extravasation is a major hurdle for nanomaterial-based tumor targeting in vivo, this study also establishes CD105 as a promising vascular target for future cancer nanomedicine. © 2012 American Chemical Society

Improved decision making for prioritizing tumor targeting antibodies in human xenografts: Utility of fluorescence imaging to verify tumor target expression, antibody binding and optimization of dosage and application schedule.

PubMed

Dobosz, Michael; Haupt, Ute; Scheuer, Werner

2017-01-01

Preclinical efficacy studies of antibodies targeting a tumor-associated antigen are only justified when the expression of the relevant antigen has been demonstrated. Conventionally, antigen expression level is examined by immunohistochemistry of formalin-fixed paraffin-embedded tumor tissue section. This method represents the diagnostic "gold standard" for tumor target evaluation, but is affected by a number of factors, such as epitope masking and insufficient antigen retrieval. As a consequence, variances and discrepancies in histological staining results can occur, which may influence decision-making and therapeutic outcome. To overcome these problems, we have used different fluorescence-labeled therapeutic antibodies targeting human epidermal growth factor receptor (HER) family members and insulin-like growth factor-1 receptor (IGF1R) in combination with fluorescence imaging modalities to determine tumor antigen expression, drug-target interaction, and biodistribution and tumor saturation kinetics in non-small cell lung cancer xenografts. For this, whole-body fluorescence intensities of labeled antibodies, applied as a single compound or antibody mixture, were measured in Calu-1 and Calu-3 tumor-bearing mice, then ex vivo multispectral tumor tissue analysis at microscopic resolution was performed. With the aid of this simple and fast imaging method, we were able to analyze the tumor cell receptor status of HER1-3 and IGF1R, monitor the antibody-target interaction and evaluate the receptor binding sites of anti-HER2-targeting antibodies. Based on this, the most suitable tumor model, best therapeutic antibody, and optimal treatment dosage and application schedule was selected. Predictions drawn from obtained imaging data were in excellent concordance with outcome of conducted preclinical efficacy studies. Our results clearly demonstrate the great potential of combined in vivo and ex vivo fluorescence imaging for the preclinical development and characterization of

Tumor-targeting peptides from combinatorial libraries*

PubMed Central

Liu, Ruiwu; Li, Xiaocen; Xiao, Wenwu; Lam, Kit S.

2018-01-01

Cancer is one of the major and leading causes of death worldwide. Two of the greatest challenges infighting cancer are early detection and effective treatments with no or minimum side effects. Widespread use of targeted therapies and molecular imaging in clinics requires high affinity, tumor-specific agents as effective targeting vehicles to deliver therapeutics and imaging probes to the primary or metastatic tumor sites. Combinatorial libraries such as phage-display and one-bead one-compound (OBOC) peptide libraries are powerful approaches in discovering tumor-targeting peptides. This review gives an overview of different combinatorial library technologies that have been used for the discovery of tumor-targeting peptides. Examples of tumor-targeting peptides identified from each combinatorial library method will be discussed. Published tumor-targeting peptide ligands and their applications will also be summarized by the combinatorial library methods and their corresponding binding receptors. PMID:27210583

In Vivo Tumor Targeting and Image-Guided Drug Delivery with Antibody-Conjugated, Radiolabeled Mesoporous Silica Nanoparticles

PubMed Central

Chen, Feng; Hong, Hao; Zhang, Yin; Valdovinos, Hector F.; Shi, Sixiang; Kwon, Glen S.; Theuer, Charles P.; Barnhart, Todd E.; Cai, Weibo

2013-01-01

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. PMID:24083623

Deep, noninvasive imaging and surgical guidance of submillimeter tumors using targeted M13-stabilized single-walled carbon nanotubes

PubMed Central

Ghosh, Debadyuti; Bagley, Alexander F.; Na, Young Jeong; Birrer, Michael J.; Bhatia, Sangeeta N.; Belcher, Angela M.

2014-01-01

Highly sensitive detection of small, deep tumors for early diagnosis and surgical interventions remains a challenge for conventional imaging modalities. Second-window near-infrared light (NIR2, 950–1,400 nm) is promising for in vivo fluorescence imaging due to deep tissue penetration and low tissue autofluorescence. With their intrinsic fluorescence in the NIR2 regime and lack of photobleaching, single-walled carbon nanotubes (SWNTs) are potentially attractive contrast agents to detect tumors. Here, targeted M13 virus-stabilized SWNTs are used to visualize deep, disseminated tumors in vivo. This targeted nanoprobe, which uses M13 to stably display both tumor-targeting peptides and an SWNT imaging probe, demonstrates excellent tumor-to-background uptake and exhibits higher signal-to-noise performance compared with visible and near-infrared (NIR1) dyes for delineating tumor nodules. Detection and excision of tumors by a gynecological surgeon improved with SWNT image guidance and led to the identification of submillimeter tumors. Collectively, these findings demonstrate the promise of targeted SWNT nanoprobes for noninvasive disease monitoring and guided surgery. PMID:25214538

Deep, noninvasive imaging and surgical guidance of submillimeter tumors using targeted M13-stabilized single-walled carbon nanotubes.

PubMed

Ghosh, Debadyuti; Bagley, Alexander F; Na, Young Jeong; Birrer, Michael J; Bhatia, Sangeeta N; Belcher, Angela M

2014-09-23

Highly sensitive detection of small, deep tumors for early diagnosis and surgical interventions remains a challenge for conventional imaging modalities. Second-window near-infrared light (NIR2, 950-1,400 nm) is promising for in vivo fluorescence imaging due to deep tissue penetration and low tissue autofluorescence. With their intrinsic fluorescence in the NIR2 regime and lack of photobleaching, single-walled carbon nanotubes (SWNTs) are potentially attractive contrast agents to detect tumors. Here, targeted M13 virus-stabilized SWNTs are used to visualize deep, disseminated tumors in vivo. This targeted nanoprobe, which uses M13 to stably display both tumor-targeting peptides and an SWNT imaging probe, demonstrates excellent tumor-to-background uptake and exhibits higher signal-to-noise performance compared with visible and near-infrared (NIR1) dyes for delineating tumor nodules. Detection and excision of tumors by a gynecological surgeon improved with SWNT image guidance and led to the identification of submillimeter tumors. Collectively, these findings demonstrate the promise of targeted SWNT nanoprobes for noninvasive disease monitoring and guided surgery.

Tumor-targeting peptides from combinatorial libraries.

PubMed

Liu, Ruiwu; Li, Xiaocen; Xiao, Wenwu; Lam, Kit S

2017-02-01

Cancer is one of the major and leading causes of death worldwide. Two of the greatest challenges in fighting cancer are early detection and effective treatments with no or minimum side effects. Widespread use of targeted therapies and molecular imaging in clinics requires high affinity, tumor-specific agents as effective targeting vehicles to deliver therapeutics and imaging probes to the primary or metastatic tumor sites. Combinatorial libraries such as phage-display and one-bead one-compound (OBOC) peptide libraries are powerful approaches in discovering tumor-targeting peptides. This review gives an overview of different combinatorial library technologies that have been used for the discovery of tumor-targeting peptides. Examples of tumor-targeting peptides identified from each combinatorial library method will be discussed. Published tumor-targeting peptide ligands and their applications will also be summarized by the combinatorial library methods and their corresponding binding receptors. Copyright © 2017. Published by Elsevier B.V.

Paramagnetic and fluorescent liposomes for target-specific imaging and therapy of tumor angiogenesis

PubMed Central

Kluza, Ewelina; Van Tilborg, Geralda A. F.; van der Schaft, Daisy W. J.; Griffioen, Arjan W.; Mulder, Willem J. M.; Nicolay, Klaas

2010-01-01

Angiogenesis is essential for tumor growth and metastatic potential and for that reason considered an important target for tumor treatment. Noninvasive imaging technologies, capable of visualizing tumor angiogenesis and evaluating the efficacy of angiostatic therapies, are therefore becoming increasingly important. Among the various imaging modalities, magnetic resonance imaging (MRI) is characterized by a superb spatial resolution and anatomical soft-tissue contrast. Revolutionary advances in contrast agent chemistry have delivered versatile angiogenesis-specific molecular MRI contrast agents. In this paper, we review recent advances in the preclinical application of paramagnetic and fluorescent liposomes for noninvasive visualization of the molecular processes involved in tumor angiogenesis. This liposomal contrast agent platform can be prepared with a high payload of contrast generating material, thereby facilitating its detection, and is equipped with one or more types of targeting ligands for binding to specific molecules expressed at the angiogenic site. Multimodal liposomes endowed with contrast material for complementary imaging technologies, e.g., MRI and optical, can be exploited to gain important preclinical insights into the mechanisms of binding and accumulation at angiogenic vascular endothelium and to corroborate the in vivo findings. Interestingly, liposomes can be designed to contain angiostatic therapeutics, allowing for image-supervised drug delivery and subsequent monitoring of therapeutic efficacy. PMID:20390447

Polydopamine-based functional composite particles for tumor cell targeting and dual-mode cellular imaging.

PubMed

Zhou, Yalei; Zhou, Jie; Wang, Feng; Yang, Haifeng

2018-05-01

Particles which bear tumor cell targeting and multimode imaging capabilities are promising in tumor diagnosis and cancer therapy. A simple and versatile method to fabricate gold/polydopamine-Methylene Blue@Bovine Serum Albumin-glutaraldehyde-Transferrin composite particles (Au/PDA-MB@BSA-GA-Tf NPs) for tumor cell targeting and fluorescence (FL) / surface-enhanced Raman scattering (SERS) dual-modal imaging were reported in this work. Polydopamine (PDA) spheres played an important role in gold ion reduction, gold nanoparticle (Au NPs) binding and methylene blue (MB) adsorption, MB were employed as both fluorescence label and Raman reporter. In addition, glutaraldehyde (GA) crosslinked bovine serum albumin (BSA) in the outer layer of Au/PDA-MB nanoparticles can prevent MB from dissociation and leakage. The composite nanoparticles were further conjugated with transferrin (Tf) to target transferrin receptor (TfR)-overexpressed cancer cells. The targeting ability as well as the intracellular location of the probe was investigated through SERS mapping and fluorescence imaging. Their excellent biocompatibility was demonstrated by low cytotoxicity against breast cancer cell (4T1 cell). Copyright © 2018 Elsevier B.V. All rights reserved.

Nanobubble-Affibody: Novel ultrasound contrast agents for targeted molecular ultrasound imaging of tumor.

PubMed

Yang, Hengli; Cai, Wenbin; Xu, Lei; Lv, Xiuhua; Qiao, Youbei; Li, Pan; Wu, Hong; Yang, Yilin; Zhang, Li; Duan, Yunyou

2015-01-01

Nanobubbles (NBs), as novel ultrasound contrast agents (UCAs), have attracted increasing attention in the field of molecular ultrasound imaging for tumors. However, the preparation of uniform-sized NBs is considered to be controversial, and poor tumor selectivity in in vivo imaging has been reported. In this study, we fabricated uniform nano-sized NBs (478.2 ± 29.7 nm with polydispersity index of 0.164 ± 0.044, n = 3) using a thin-film hydration method by controlling the thickness of phospholipid films; we then conjugated the NBs with Affibody molecules to produce nano-sized UCAs referred to as NB-Affibody with specific affinity to human epidermal growth factor receptor type 2 (HER2)-overexpressing tumors. NB-Affibody presented good ultrasound enhancement, demonstrating a peak intensity of 104.5 ± 2.1 dB under ultrasound contrast scanning. Ex vivo experiments further confirmed that the NB-Affibody conjugates were capable of targeting HER2-expressing tumor cells in vivo with high affinity. The newly prepared nano-sized NB-Affibody conjugates were observed to be novel targeted UCAs for efficient and safe specific molecular imaging and may have potential applications in early cancer quantitative diagnosis and targeted therapy in the future. Copyright © 2014 Elsevier Ltd. All rights reserved.

In vivo NIRF imaging-guided delivery of a novel NGR-VEGI fusion protein for targeting tumor vasculature.

PubMed

Ma, Wenhui; Li, Guoquan; Wang, Jing; Yang, Weidong; Zhang, Yingqi; Conti, Peter S; Chen, Kai

2014-12-01

Pathological angiogenesis is crucial in tumor growth, invasion and metastasis. Previous studies demonstrated that the vascular endothelial growth inhibitor (VEGI), a member of the tumor necrosis factor superfamily, can be used as a potent endogenous inhibitor of tumor angiogenesis. Molecular probes containing the asparagine-glycine-arginine (NGR) sequence can specifically bind to CD13 receptor which is overexpressed on neovasculature and several tumor cells. Near-infrared fluorescence (NIRF) optical imaging for targeting tumor vasculature offers a noninvasive method for early detection of tumor angiogenesis and efficient monitoring of response to anti-tumor vasculature therapy. The aim of this study was to develop a new NIRF imaging probe on the basis of an NGR-VEGI protein for the visualization of tumor vasculature. The NGR-VEGI fusion protein was prepared from prokaryotic expression, and its function was characterized in vitro. The NGR-VEGI protein was then labeled with a Cy5.5 fluorophore to afford Cy5.5-NGR-VEGI probe. Using the NIRF imaging technique, we visualized and quantified the specific delivery of Cy5.5-NGR-VEGI protein to subcutaneous HT-1080 fibrosarcoma tumors in mouse xenografts. The Cy5.5-NGR-VEGI probe exhibited rapid HT-1080 tumor targeting, and highest tumor-to-background contrast at 8 h post-injection (pi). Tumor specificity of Cy5.5-NGR-VEGI was confirmed by effective blocking of tumor uptake in the presence of unlabeled NGR-VEGI (20 mg/kg). Ex vivo NIRF imaging further confirmed in vivo imaging findings, demonstrating that Cy5.5-NGR-VEGI displayed an excellent tumor-to-muscle ratio (18.93 ± 2.88) at 8 h pi for the non-blocking group and significantly reduced ratio (4.92 ± 0.75) for the blocking group. In conclusion, Cy5.5-NGR-VEGI provided highly sensitive, target-specific, and longitudinal imaging of HT-1080 tumors. As a novel theranostic protein, Cy5.5-NGR-VEGI has the potential to improve cancer treatment by targeting tumor vasculature.

Tumor acidity-activatable TAT targeted nanomedicine for enlarged fluorescence/magnetic resonance imaging-guided photodynamic therapy.

PubMed

Gao, Meng; Fan, Feng; Li, Dongdong; Yu, Yue; Mao, Kuirong; Sun, Tianmeng; Qian, Haisheng; Tao, Wei; Yang, Xianzhu

2017-07-01

Nanoparticles simultaneously integrated the photosensitizers and diagnostic agents represent an emerging approach for imaging-guided photodynamic therapy (PDT). However, the diagnostic sensitivity and therapeutic efficacy of nanoparticles as well as the heterogeneity of tumors pose tremendous challenges for clinical imaging-guided PDT treatment. Herein, a polymeric nanoparticle with tumor acidity (pH e )-activatable TAT targeting ligand that encapsulates the photosensitizer chlorin e6 (Ce6) and chelates contrast agent Gd 3+ is successfully developed for fluorescence/magnetic resonance (MR) dual-model imaging-guided precision PDT. We show clear evidence that the resulting nanoparticle DA TAT-NP [its TAT lysine residues' amines was modified by 2,3-dimethylmaleic anhydride (DA)] efficiently avoids the rapid clearance by reticuloendothelial system (RES) by masking of the TAT peptide, resulting in the significantly prolonged circulation time in the blood. Once accumulating in the tumor tissues, DA TAT-NP is reactivated by tumor acidity to promote cellular uptake, resulting in enlarged fluorescence/MR imaging signal intensity and elevated in vivo PDT therapeutic effect. This concept provides new avenues to design tumor acidity-activatable targeted nanoparticles for imaging-guided cancer therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Optical imaging of tumor microenvironment

PubMed Central

Wu, Yihan; Zhang, Wenjie; Li, Jinbo; Zhang, Yan

2013-01-01

Tumor microenvironment plays important roles in tumor development and metastasis. Features of the tumor microenvironment that are significantly different from normal tissues include acidity, hypoxia, overexpressed proteases and so on. Therefore, these features can serve as not only biomarkers for tumor diagnosis but also theraputic targets for tumor treatment. Imaging modalities such as optical, positron emission tomography (PET) and magnetic resonance imaging (MRI) have been intensively applied to investigate tumor microenvironment. Various imaging probes targeting pH, hypoxia and proteases in tumor microenvironment were thus well developed. In this review, we will focus on recent examples on fluorescent probes for optical imaging of tumor microenvironment. Construction of these fluorescent probes were based on characteristic feature of pH, hypoxia and proteases in tumor microenvironment. Strategies for development of these fluorescent probes and applications of these probes in optical imaging of tumor cells or tissues will be discussed in this review paper. PMID:23342297

An off-on fluorescence probe targeting mitochondria based on oxidation-reduction response for tumor cell and tissue imaging

NASA Astrophysics Data System (ADS)

Yao, Hanchun; Cao, Li; Zhao, Weiwei; Zhang, Suge; Zeng, Man; Du, Bin

2017-10-01

In this study, a tumor-targeting poly( d, l-lactic-co-glycolic acid) (PLGA) loaded "off-on" fluorescent probe nanoparticle (PFN) delivery system was developed to evaluate the region of tumor by off-on fluorescence. The biodegradability of the nanosize PFN delivery system readily released the probe under tumor acidic conditions. The probe with good biocompatibility was used to monitor the intracellular glutathione (GSH) of cancer cells and selectively localize to mitochondria for tumor imaging. The incorporated tumor-targeting probe was based on the molecular photoinduced electron transfer (PET) mechanism preventing fluorescence ("off" state) and could be easily released under tumor acidic conditions. However, the released tumor-targeting fluorescence probe molecule was selective towards GSH with high selectivity and an ultra-sensitivity for the mitochondria of cancer cells and tissues significantly increasing the probe molecule fluorescence signal ("on" state). The tumor-targeting fluorescence probe showed sensitivity to GSH avoiding interference from cysteine and homocysteine. The PFNs could enable fluorescence-guided cancer imaging during cancer therapy. This work may expand the biological applications of PFNs as a diagnostic reagent, which will be beneficial for fundamental research in tumor imaging. [Figure not available: see fulltext.

In vivo type 2 cannabinoid receptor-targeted tumor optical imaging using a near infrared fluorescent probe.

PubMed

Zhang, Shaojuan; Shao, Pin; Bai, Mingfeng

2013-11-20

The type 2 cannabinoid receptor (CB2R) plays a vital role in carcinogenesis and progression and is emerging as a therapeutic target for cancers. However, the exact role of CB2R in cancer progression and therapy remains unclear. This has driven the increasing efforts to study CB2R and cancers using molecular imaging tools. In addition, many types of cancers overexpress CB2R, and the expression levels of CB2R appear to be associated with tumor aggressiveness. Such upregulation of the receptor in cancer cells provides opportunities for CB2R-targeted imaging with high contrast and for therapy with low side effects. In the present study, we report the first in vivo tumor-targeted optical imaging using a novel CB2R-targeted near-infrared probe. In vitro cell fluorescent imaging and a competitive binding assay indicated specific binding of NIR760-mbc94 to CB2R in CB2-mid delayed brain tumor (DBT) cells. NIR760-mbc94 also preferentially labeled CB2-mid DBT tumors in vivo, with a 3.7-fold tumor-to-normal contrast enhancement at 72 h postinjection, whereas the fluorescence signal from the tumors of the mice treated with NIR760 free dye was nearly at the background level at the same time point. SR144528, a CB2R competitor, significantly inhibited tumor uptake of NIR760-mbc94, indicating that NIR760-mbc94 binds to CB2R specifically. In summary, NIR760-mbc94 specifically binds to CB2R in vitro and in vivo and appears to be a promising molecular tool that may have great potential for use in diagnostic imaging of CB2R-positive cancers and therapeutic monitoring as well as in elucidating the role of CB2R in cancer progression and therapy.

SU-E-I-81: Targeting of HER2-Expressing Tumors with Dual PET-MR Imaging Probes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, P; Peng, Y; Sun, M

2015-06-15

Purpose: The detection of human epidermal growth factor receptor type 2 (HER2) expression in malignant tumors provides important information influencing patient management. Radionuclide in vivo imaging of HER2 may permit the detection of HER2 in both primary tumors and metastases by a single noninvasive procedure. Trastuzumab, effective in about 15 % of women with breast cancer, downregulates signalling through the Akt/PI3K and MAPK pathways.These pathways modulate metabolism which can be monitored by positron emission tomography (PET) and magnetic resonance imaging (MRI). Methods: The relationship between response of HER2 overexpressing tumours and changes in imaging PET or SPECT and MRI willmore » be examined by a integrated bimodal imaging probe.Small (7 kDa) high-affinity anti-HER2 Affibody molecules and KCCYSL targeting peptide may be suitable tracers for visualization of HER2-expressing tumors. Peptide-conjugated iron oxide nanoparticles (Fe3O4 NPs) as MRI imaging and CB-TE2A as PET imaging are integrated into a single synthetic molecule in the HER2 positive cancer. Results: One of targeted contrast bimodal imaging probe agents was synthesized and evaluated to target HER2-expressing tumors in a HER2 positive rat model. We will report the newest results regarding the development of bimodal imaging probes. Conclusion: The preliminary results of the bimodal imaging probe presents high correlation of MRI signal and PET imaging intensity in vivo. This unique feature can hardly be obtained by single model contrast agents. It is envisioned that this bimodal agents can hold great potential for accurate detection of HER2-expressing tumors which are critical for clinical management of the disease.« less

Methotrexate-loaded PLGA nanobubbles for ultrasound imaging and Synergistic Targeted therapy of residual tumor during HIFU ablation.

PubMed

Zhang, Xuemei; Zheng, Yuanyi; Wang, Zhigang; Huang, Shuai; Chen, Yu; Jiang, Wei; Zhang, Hua; Ding, Mingxia; Li, Qingshu; Xiao, Xiaoqiu; Luo, Xin; Wang, Zhibiao; Qi, Hongbo

2014-06-01

High intensity focused ultrasound (HIFU) has attracted the great attention in tumor ablation due to its non-invasive, efficient and economic features. However, HIFU ablation has its intrinsic limitations for removing the residual tumor cells, thus the tumor recurrence and metastasis cannot be avoided in this case. Herein, we developed a multifunctional targeted poly(lactic-co-glycolic acid) (PLGA) nanobubbles (NBs), which not only function as an efficient ultrasound contrast agent for tumor imaging, but also a targeted anticancer drug carrier and excellent synergistic agent for enhancing the therapeutic efficiency of HIFU ablation. Methotrexate (MTX)-loaded NBs were synthesized and filled with perfluorocarbon gas subsequently using a facile but general double emulsion evaporation method. The active tumor-targeting monoclonal anti-HLA-G antibodies (mAbHLA-G) were further conjugated onto the surface of nanobubbles. The mAbHLA-G/MTX/PLGA NBs could enhance the ultrasound imaging both in vitro and in vivo, and the targeting efficiency to HLA-G overexpressing JEG-3 cells has been demonstrated. The elaborately designed mAbHLA-G/MTX/PLGA NBs can specifically target to the tumor cells both in vitro and in vivo, and their blood circulation time in vivo was much longer than non-targeted MTX/PLGA NBs. Further therapeutic evaluations showed that the targeted NBs as a synergistic agent can significantly improve the efficiency of HIFU ablation by changing the acoustic environment, and the focused ultrasound can promote the on-demand MTX release both in vitro and in vivo. The in vivo histopathology test and immunohistochemical analysis showed that the mAbHLA-G/MTX/PLGA NBs plus HIFU group presented most serious coagulative necrosis, the lowest proliferation index and the highest apoptotic index. Therefore, the successful introduction of targeted mAbHLA-G/MTX/PLGA NBs provides an excellent platform for the highly efficient, imaging-guided and non-invasive HIFU synergistic therapy

A fast tumor-targeting near-infrared fluorescent probe based on bombesin analog for in vivo tumor imaging.

PubMed

Chen, Haiyan; Wan, Shunan; Zhu, Fenxia; Wang, Chuan; Cui, Sisi; Du, Changli; Ma, Yuxiang; Gu, Yueqing

2014-01-01

Bombesin (BBN), an analog of gastrin-releasing peptide (GRP), of which the receptors are over-expressed on various tumor cells, is able to bind to GRP receptor specifically. In this study, a near-infrared fluorescent dye (MPA) and polyethylene glycol (PEG) were conjugated to BBN analog to form BBN[7-14]-MPA and BBN[7-14]-SA-PEG-MPA. The successful synthesis of the two probes was proved by the characterization via sodium dodecylsulfate-polyacrylamide gel electrophoresis, infrared and optical spectra. Cellular uptakes studies indicated that BBN-based probes were mediated by gastrin-releasing peptide receptors (GRPR) on tumor cells and the PEG modified probe had higher affinity. The dynamic distribution and clearance investigations showed that the BBN-based probes were eliminated by the liver-kidney pathway. Furthermore, both of the BBN-based probes displayed tumor-targeting ability in GRPR over-expressed tumor-bearing mice. The PEG modified probe exhibited faster and higher tumor targeting capability than BBN[7-14]-MPA. The results implied that BBN[7-14]-SA-PEG-MPA could act as an effective fluorescence probe for tumor imaging. Copyright © 2014 John Wiley & Sons, Ltd.

Targeted delivery of antibody-based therapeutic and imaging agents to CNS tumors: Crossing the blood-brain-barrier divide

PubMed Central

Chacko, Ann-Marie; Li, Chunsheng; Pryma, Daniel A.; Brem, Steven; Coukos, George; Muzykantov, Vladimir R.

2014-01-01

Introduction Brain tumors are inherently difficult to treat in large part due to the cellular blood-brain barriers (BBB) that limit the delivery of therapeutics to the tumor tissue from the systemic circulation. Virtually no large-molecules, including antibody-based proteins, can penetrate the BBB. With antibodies fast becoming attractive ligands for highly specific molecular targeting to tumor antigens, a variety of methods are being investigated to enhance the access of these agents to intracranial tumors for imaging or therapeutic applications. Areas covered This review describes the characteristics of the BBB and the vasculature in brain tumors, described as the blood-brain tumor barrier (BBTB). Antibodies targeted to molecular markers of CNS tumors will be highlighted, and current strategies for enhancing the delivery of antibodies across these cellular barriers into the brain parenchyma to the tumor will be discussed. Non-invasive imaging approaches to assess BBB/BBTB permeability and/or antibody targeting will be presented as a means of guiding the optimal delivery of targeted agents to brain tumors. Expert Opinion Pre-clinical and clinical studies highlight the potential of several approaches in increasing brain tumor delivery across the blood-brain barrier divide. However, each carries its own risks and challenges. There is tremendous potential in using neuroimaging strategies to assist in understanding and defining the challenges to translating and optimizing molecularly-targeted antibody delivery to CNS tumors to improve clinical outcomes. PMID:23751126

Nuclear and Fluorescent Labeled PD-1-Liposome-DOX-64Cu/IRDye800CW Allows Improved Breast Tumor Targeted Imaging and Therapy.

PubMed

Du, Yang; Liang, Xiaolong; Li, Yuan; Sun, Ting; Jin, Zhengyu; Xue, Huadan; Tian, Jie

2017-11-06

The overexpression of programmed cell death-1 (PD-1) in tumors as breast cancer makes it a possible target for cancer imaging and therapy. Advances in molecular imaging, including radionuclide imaging and near-infrared fluorescence (NIRF) imaging, enable the detection of tumors with high sensitivity. In this study, we aim to develop a novel PD-1 antibody targeted positron emission tomography (PET) and NIRF labeled liposome loaded with doxorubicin (DOX) and evaluate its application for in vivo cancer imaging and therapy. IRDye800CW and 64 Cu were conjugated to liposomes with PD-1 antibody labeling, and DOX was inside the liposomes to form theranostic nanoparticles. The 4T1 tumors were successfully visualized with PD-1-Liposome-DOX- 64 Cu/IRDye800CW using NIRF/PET imaging. The bioluminescent imaging (BLI) results showed that tumor growth was significantly inhibited in the PD-1-Liposome-DOX-treated group than the IgG control. Our results highlight the potential of using dual-labeled theranostic PD-1 mAb-targeted Liposome-DOX- 64 Cu/IRDye800CW for the management of breast tumor.

Tumor targeting efficiency of bare nanoparticles does not mean the efficacy of loaded anticancer drugs: importance of radionuclide imaging for optimization of highly selective tumor targeting polymeric nanoparticles with or without drug.

PubMed

Lee, Beom Suk; Park, Kyeongsoon; Park, Sangjin; Kim, Gui Chul; Kim, Hyo Jung; Lee, Sangjoo; Kil, Heeseup; Oh, Seung Jun; Chi, Daeyoon; Kim, Kwangmeyung; Choi, Kuiwon; Kwon, Ick Chan; Kim, Sang Yoon

2010-10-15

The better understanding of polymeric nanoparticles as a drug delivery carrier is a decisive factor to get more efficient therapeutic response in vivo. Here, we report the non-invasive imaging of bare polymeric nanoparticles and drug-loaded polymeric nanoparticles to evaluate biodistribution in tumor bearing mice. To make nano-sized drug delivery carrier, glycol chitosan was modified with different degrees of hydrophobic N-acetyl histidine (NAcHis-GC-1, -2, and -3). The biodistribution of polymeric nanoparticles and drug was confirmed by using gamma camera with (131)I-labeled NAcHis-GC and (131)I-labeled doxorubicin (DOX) and by using in vivo live animal imaging with near-infrared fluorescence Cy5.5-labeled NAcHis-GC. Among bare nanoparticles, NAcHis-GC3 (7.8% NAcHis content) showed much higher tumor targeting efficiency than NAcHis-GC1 (3.3% NAcHis content) and NAcHis-GC2 (6.8% NAcHis content). In contrast, for drug-loaded nanoparticles, DOX-NAcHis-GC1 displayed two-fold higher tumor targeting property than DOX-NAcHis-GC3. These data imply that the biodistribution and tumor targeting efficiency between bare and drug-loaded nanoparticles may be greatly different. Therapeutic responses for NAcHis-GC nanoparticles after drug loading were also evaluated. In xenograft animal model, we could find out that DOX-NAcHis-GC1 with higher tumor targeting of DOX has more excellent therapeutic effect than DOX-NAcHis-GC3 and free DOX. These results mean that the hydrophobic core stability might be a critical factor for tumor targeting efficiency of nanoparticles. The present study indicates that by using molecular imaging, we can select more appropriate nanoparticles with the highest tumor targeting properties, leading to exerting more excellent therapeutic results in cancer therapy. Copyright © 2010 Elsevier B.V. All rights reserved.

Stimuli-responsive magnetic nanoparticles for tumor-targeted bimodal imaging and photodynamic/hyperthermia combination therapy

NASA Astrophysics Data System (ADS)

Kim, Kyoung Sub; Kim, Jiyoung; Lee, Joo Young; Matsuda, Shofu; Hideshima, Sho; Mori, Yasurou; Osaka, Tetsuya; Na, Kun

2016-06-01

Despite magnetic nanoparticles having shown great potential in cancer treatment, tremendous challenges related to diagnostic sensitivity and treatment efficacy for clinical application remain. Herein, we designed optimized multifunctional magnetite nanoparticles (AHP@MNPs), composed of Fe3O4 nanoparticles and photosensitizer conjugated hyaluronic acid (AHP), to achieve enhanced tumor diagnosis and therapy. Fe3O4 nanoparticles (MNPs) were synthesized by a facile hydrolysis method. MNPs have higher biocompatibility, controllable particle sizes, and desirable magnetic properties. The fabricated AHP@MNPs have enhanced water solubility (average size: 108.13 +/- 1.08 nm), heat generation properties, and singlet oxygen generation properties upon magnetic and laser irradiation. The AHP@MNPs can target tumors via CD44 receptor-mediated endocytosis, which have enhanced tumor therapeutic effects through photodynamic/hyperthermia-combined treatment without any drugs. We successfully detected tumors implanted in mice via magnetic resonance imaging and optical imaging. Furthermore, we demonstrated the photodynamic/hyperthermia-combined therapeutic efficacy of AHP@MNPs with synergistically enhanced efficacy against cancer.Despite magnetic nanoparticles having shown great potential in cancer treatment, tremendous challenges related to diagnostic sensitivity and treatment efficacy for clinical application remain. Herein, we designed optimized multifunctional magnetite nanoparticles (AHP@MNPs), composed of Fe3O4 nanoparticles and photosensitizer conjugated hyaluronic acid (AHP), to achieve enhanced tumor diagnosis and therapy. Fe3O4 nanoparticles (MNPs) were synthesized by a facile hydrolysis method. MNPs have higher biocompatibility, controllable particle sizes, and desirable magnetic properties. The fabricated AHP@MNPs have enhanced water solubility (average size: 108.13 +/- 1.08 nm), heat generation properties, and singlet oxygen generation properties upon magnetic and laser

High molecular weight chitosan derivative polymeric micelles encapsulating superparamagnetic iron oxide for tumor-targeted magnetic resonance imaging.

PubMed

Xiao, Yunbin; Lin, Zuan Tao; Chen, Yanmei; Wang, He; Deng, Ya Li; Le, D Elizabeth; Bin, Jianguo; Li, Meiyu; Liao, Yulin; Liu, Yili; Jiang, Gangbiao; Bin, Jianping

2015-01-01

Magnetic resonance imaging (MRI) contrast agents based on chitosan derivatives have great potential for diagnosing diseases. However, stable tumor-targeted MRI contrast agents using micelles prepared from high molecular weight chitosan derivatives are seldom reported. In this study, we developed a novel tumor-targeted MRI vehicle via superparamagnetic iron oxide nanoparticles (SPIONs) encapsulated in self-aggregating polymeric folate-conjugated N-palmitoyl chitosan (FAPLCS) micelles. The tumor-targeting ability of FAPLCS/SPIONs was demonstrated in vitro and in vivo. The results of dynamic light scattering experiments showed that the micelles had a relatively narrow size distribution (136.60±3.90 nm) and excellent stability. FAPLCS/SPIONs showed low cytotoxicity and excellent biocompatibility in cellular toxicity tests. Both in vitro and in vivo studies demonstrated that FAPLCS/SPIONs bound specifically to folate receptor-positive HeLa cells, and that FAPLCS/SPIONs accumulated predominantly in established HeLa-derived tumors in mice. The signal intensities of T2-weighted images in established HeLa-derived tumors were reduced dramatically after intravenous micelle administration. Our study indicates that FAPLCS/SPION micelles can potentially serve as safe and effective MRI contrast agents for detecting tumors that overexpress folate receptors.

High molecular weight chitosan derivative polymeric micelles encapsulating superparamagnetic iron oxide for tumor-targeted magnetic resonance imaging

PubMed Central

Xiao, Yunbin; Lin, Zuan Tao; Chen, Yanmei; Wang, He; Deng, Ya Li; Le, D Elizabeth; Bin, Jianguo; Li, Meiyu; Liao, Yulin; Liu, Yili; Jiang, Gangbiao; Bin, Jianping

2015-01-01

Magnetic resonance imaging (MRI) contrast agents based on chitosan derivatives have great potential for diagnosing diseases. However, stable tumor-targeted MRI contrast agents using micelles prepared from high molecular weight chitosan derivatives are seldom reported. In this study, we developed a novel tumor-targeted MRI vehicle via superparamagnetic iron oxide nanoparticles (SPIONs) encapsulated in self-aggregating polymeric folate-conjugated N-palmitoyl chitosan (FAPLCS) micelles. The tumor-targeting ability of FAPLCS/SPIONs was demonstrated in vitro and in vivo. The results of dynamic light scattering experiments showed that the micelles had a relatively narrow size distribution (136.60±3.90 nm) and excellent stability. FAPLCS/SPIONs showed low cytotoxicity and excellent biocompatibility in cellular toxicity tests. Both in vitro and in vivo studies demonstrated that FAPLCS/SPIONs bound specifically to folate receptor-positive HeLa cells, and that FAPLCS/SPIONs accumulated predominantly in established HeLa-derived tumors in mice. The signal intensities of T2-weighted images in established HeLa-derived tumors were reduced dramatically after intravenous micelle administration. Our study indicates that FAPLCS/SPION micelles can potentially serve as safe and effective MRI contrast agents for detecting tumors that overexpress folate receptors. PMID:25709439

A tri-modality image fusion method for target delineation of brain tumors in radiotherapy.

PubMed

Guo, Lu; Shen, Shuming; Harris, Eleanor; Wang, Zheng; Jiang, Wei; Guo, Yu; Feng, Yuanming

2014-01-01

To develop a tri-modality image fusion method for better target delineation in image-guided radiotherapy for patients with brain tumors. A new method of tri-modality image fusion was developed, which can fuse and display all image sets in one panel and one operation. And a feasibility study in gross tumor volume (GTV) delineation using data from three patients with brain tumors was conducted, which included images of simulation CT, MRI, and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) examinations before radiotherapy. Tri-modality image fusion was implemented after image registrations of CT+PET and CT+MRI, and the transparency weight of each modality could be adjusted and set by users. Three radiation oncologists delineated GTVs for all patients using dual-modality (MRI/CT) and tri-modality (MRI/CT/PET) image fusion respectively. Inter-observer variation was assessed by the coefficient of variation (COV), the average distance between surface and centroid (ADSC), and the local standard deviation (SDlocal). Analysis of COV was also performed to evaluate intra-observer volume variation. The inter-observer variation analysis showed that, the mean COV was 0.14(± 0.09) and 0.07(± 0.01) for dual-modality and tri-modality respectively; the standard deviation of ADSC was significantly reduced (p<0.05) with tri-modality; SDlocal averaged over median GTV surface was reduced in patient 2 (from 0.57 cm to 0.39 cm) and patient 3 (from 0.42 cm to 0.36 cm) with the new method. The intra-observer volume variation was also significantly reduced (p = 0.00) with the tri-modality method as compared with using the dual-modality method. With the new tri-modality image fusion method smaller inter- and intra-observer variation in GTV definition for the brain tumors can be achieved, which improves the consistency and accuracy for target delineation in individualized radiotherapy.

Radionuclide 131I-labeled multifunctional dendrimers for targeted SPECT imaging and radiotherapy of tumors

NASA Astrophysics Data System (ADS)

Zhu, Jingyi; Zhao, Lingzhou; Cheng, Yongjun; Xiong, Zhijuan; Tang, Yueqin; Shen, Mingwu; Zhao, Jinhua; Shi, Xiangyang

2015-10-01

We report the synthesis, characterization, and utilization of radioactive 131I-labeled multifunctional dendrimers for targeted single-photon emission computed tomography (SPECT) imaging and radiotherapy of tumors. In this study, amine-terminated poly(amidoamine) dendrimers of generation 5 (G5.NH2) were sequentially modified with 3-(4'-hydroxyphenyl)propionic acid-OSu (HPAO) and folic acid (FA) linked with polyethylene glycol (PEG), followed by acetylation modification of the dendrimer remaining surface amines and labeling of radioactive iodine-131 (131I). The generated multifunctional 131I-G5.NHAc-HPAO-PEG-FA dendrimers were characterized via different methods. We show that prior to 131I labeling, the G5.NHAc-HPAO-PEG-FA dendrimers conjugated with approximately 9.4 HPAO moieties per dendrimer are noncytotoxic at a concentration up to 20 μM and are able to target cancer cells overexpressing FA receptors (FAR), thanks to the modified FA ligands. In the presence of a phenol group, radioactive 131I is able to be efficiently labeled onto the dendrimer platform with good stability and high radiochemical purity, and render the platform with an ability for targeted SPECT imaging and radiotherapy of an FAR-overexpressing xenografted tumor model in vivo. The designed strategy to use the facile dendrimer nanotechnology may be extended to develop various radioactive theranostic nanoplatforms for targeted SPECT imaging and radiotherapy of different types of cancer.We report the synthesis, characterization, and utilization of radioactive 131I-labeled multifunctional dendrimers for targeted single-photon emission computed tomography (SPECT) imaging and radiotherapy of tumors. In this study, amine-terminated poly(amidoamine) dendrimers of generation 5 (G5.NH2) were sequentially modified with 3-(4'-hydroxyphenyl)propionic acid-OSu (HPAO) and folic acid (FA) linked with polyethylene glycol (PEG), followed by acetylation modification of the dendrimer remaining surface amines and

A Lipopeptide-Based αvβ₃ Integrin-Targeted Ultrasound Contrast Agent for Molecular Imaging of Tumor Angiogenesis.

PubMed

Yan, Fei; Xu, Xiuxia; Chen, Yihan; Deng, Zhiting; Liu, Hongmei; Xu, Jianrong; Zhou, Jie; Tan, Guanghong; Wu, Junru; Zheng, Hairong

2015-10-01

The design and fabrication of targeted ultrasound contrast agents are key factors in the success of ultrasound molecular imaging applications. Here, we introduce a transformable αvβ3 integrin-targeted microbubble (MB) by incorporation of iRGD-lipopeptides into the MB membrane for non-invasive ultrasound imaging of tumor angiogenesis. First, the iRGD-lipopeptides were synthesized by conjugating iRGD peptides to distearoylphosphatidylethanolamine-polyethylene glycol 2000-maleimide. The resulting iRGD-lipopeptides were used for fabrication of the iRGD-carrying αvβ3 integrin-targeted MBs (iRGD-MBs). The binding specificity of iRGD-MBs for endothelial cells was found to be significantly stronger than that of control MBs (p < 0.01) under in vitro static and dynamic conditions. The binding of iRGD-MBs on the endothelial cells was competed off by pre-incubation with the anti-αv or anti-β3 antibody (p < 0.01). Ultrasound images taken of mice bearing 4T1 breast tumors after intravenous injections of iRGD-MBs or control MBs revealed strong contrast enhancement within the tumors from iRGD-MBs but not from the control MBs; the mean acoustic signal intensity was 10.71 ± 2.75 intensity units for iRGD-MBs versus 1.13 ± 0.18 intensity units for the control MBs (p < 0.01). The presence of αvβ3 integrin was confirmed by immunofluorescence staining. These data indicate that iRGD-MBs can be used as an ultrasound imaging probe for the non-invasive molecular imaging of tumor angiogenesis, and may have further implications for ultrasound image-guided tumor targeting drug delivery. Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. All rights reserved.

Fluorescence in vivo imaging of live tumor cells with pH-activatable targeted probes via receptor-mediated endocytosis

NASA Astrophysics Data System (ADS)

Asanuma, Daisuke; Urano, Yasuteru; Nagano, Tetsuo; Hama, Yukihiro; Koyama, Yoshinori; Kobayashi, Hisataka

2009-02-01

One goal of molecular imaging is to establish a widely applicable technique for specific detection of tumors with minimal background. Here, we achieve specific in vivo tumor visualization with a newly-designed "activatable" targeted fluorescence probe. This agent is activated after cellular internalization by sensing the pH change in the lysosome. Novel acidic pH-activatable probes based on the BODIPY fluorophore were synthesized, and then conjugated to a cancer-targeting monoclonal antibody, Trastuzumab, or galactosyl serum albumin (GSA). As proof of concept, ex and in vivo imaging of two different tumor mouse models was performed: HER2-overexpressed lung metastasis tumor with Trastuzumab-pH probe conjugates and lectin-overexpressed i.p. disseminated tumor with GSA-pH probe conjugates. These pH-activatable targeted probes were highly specific for tumors with minimal background signal. Because the acidic pH in lysosomes is maintained by the energy-consuming proton pump, only viable cancer cells were successfully visualized. Furthermore, this strategy was also applied to fluorescence endoscopy in tumor mouse models, resulting in specific visualization of tumors as small as submillimeter in size that could hardly detected by naked eyes because of their poor contrast against normal tissues. The design concept can be widely adapted to cancer-specific cell-surface-targeting molecules that result in cellular internalization.

Stroma Targeting Nuclear Imaging and Radiopharmaceuticals

PubMed Central

Shetty, Dinesh; Jeong, Jae-Min; Shim, Hyunsuk

2012-01-01

Malignant transformation of tumor accompanies profound changes in the normal neighboring tissue, called tumor stroma. The tumor stroma provides an environment favoring local tumor growth, invasion, and metastatic spreading. Nuclear imaging (PET/SPECT) measures biochemical and physiologic functions in the human body. In oncology, PET/SPECT is particularly useful for differentiating tumors from postsurgical changes or radiation necrosis, distinguishing benign from malignant lesions, identifying the optimal site for biopsy, staging cancers, and monitoring the response to therapy. Indeed, PET/SPECT is a powerful, proven diagnostic imaging modality that displays information unobtainable through other anatomical imaging, such as CT or MRI. When combined with coregistered CT data, [18F]fluorodeoxyglucose ([18F]FDG)-PET is particularly useful. However, [18F]FDG is not a target-specific PET tracer. This paper will review the tumor microenvironment targeting oncologic imaging such as angiogenesis, invasion, hypoxia, growth, and homing, and also therapeutic radiopharmaceuticals to provide a roadmap for additional applications of tumor imaging and therapy. PMID:22685650

pHLIP-FIRE, a Cell Insertion-Triggered Fluorescent Probe for Imaging Tumors Demonstrates Targeted Cargo Delivery In Vivo

PubMed Central

2015-01-01

We have developed an improved tool for imaging acidic tumors by reporting the insertion of a transmembrane helix: the pHLIP-Fluorescence Insertion REporter (pHLIP-FIRE). In acidic tissues, such as tumors, peptides in the pHLIP family insert as α-helices across cell membranes. The cell-inserting end of the pHLIP-FIRE peptide has a fluorophore–fluorophore or fluorophore–quencher pair. A pair member is released by disulfide cleavage after insertion into the reducing environment inside a cell, resulting in dequenching of the probe. Thus, the fluorescence of the pHLIP-FIRE probe is enhanced upon cell-insertion in the targeted tissues but is suppressed elsewhere due to quenching. Targeting studies in mice bearing breast tumors show strong signaling by pHLIP-FIRE, with a contrast index of ∼17, demonstrating (i) direct imaging of pHLIP insertion and (ii) cargo translocation in vivo. Imaging and targeted cargo delivery should each have clinical applications. PMID:25184440

Double-Targeting Explosible Nanofirework for Tumor Ignition to Guide Tumor-Depth Photothermal Therapy.

PubMed

Zhang, Ming-Kang; Wang, Xiao-Gang; Zhu, Jing-Yi; Liu, Miao-Deng; Li, Chu-Xin; Feng, Jun; Zhang, Xian-Zheng

2018-04-17

This study reports a double-targeting "nanofirework" for tumor-ignited imaging to guide effective tumor-depth photothermal therapy (PTT). Typically, ≈30 nm upconversion nanoparticles (UCNP) are enveloped with a hybrid corona composed of ≈4 nm CuS tethered hyaluronic acid (CuS-HA). The HA corona provides active tumor-targeted functionality together with excellent stability and improved biocompatibility. The dimension of UCNP@CuS-HA is specifically set within the optimal size window for passive tumor-targeting effect, demonstrating significant contributions to both the in vivo prolonged circulation duration and the enhanced size-dependent tumor accumulation compared with ultrasmall CuS nanoparticles. The tumors featuring hyaluronidase (HAase) overexpression could induce the escape of CuS away from UCNP@CuS-HA due to HAase-catalyzed HA degradation, in turn activating the recovery of initially CuS-quenched luminescence of UCNP and also driving the tumor-depth infiltration of ultrasmall CuS for effective PTT. This in vivo transition has proven to be highly dependent on tumor occurrence like a tumor-ignited explosible firework. Together with the double-targeting functionality, the pathology-selective tumor ignition permits precise tumor detection and imaging-guided spatiotemporal control over PTT operation, leading to complete tumor ablation under near infrared (NIR) irradiation. This study offers a new paradigm of utilizing pathological characteristics to design nanotheranostics for precise detection and personalized therapy of tumors. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Dual systemic tumor targeting with ligand-directed phage and Grp78 promoter induces tumor regression.

PubMed

Kia, Azadeh; Przystal, Justyna M; Nianiaris, Nastasia; Mazarakis, Nicholas D; Mintz, Paul J; Hajitou, Amin

2012-12-01

The tumor-specific Grp78 promoter is overexpressed in aggressive tumors. Cancer patients would benefit greatly from application of this promoter in gene therapy and molecular imaging; however, clinical benefit is limited by lack of strategies to target the systemic delivery of Grp78-driven transgenes to tumors. This study aims to assess the systemic efficacy of Grp78-guided expression of therapeutic and imaging transgenes relative to the standard cytomegalovirus (CMV) promoter. Combination of ligand and Grp78 transcriptional targeting into a single vector would facilitate systemic applications of the Grp78 promoter. We generated a dual tumor-targeted phage containing the arginine-glycine-aspartic acid tumor homing ligand and Grp78 promoter. Next, we combined flow cytometry, Western blot analysis, bioluminescence imaging of luciferase, and HSVtk/ganciclovir gene therapy and compared efficacy to conventional phage carrying the CMV promoter in vitro and in vivo in subcutaneous models of rat and human glioblastoma. We show that double-targeted phage provides persistent transgene expression in vitro and in tumors in vivo after systemic administration compared with conventional phage. Next, we showed significant tumor killing in vivo using the HSVtk/ganciclovir gene therapy and found a systemic antitumor effect of Grp78-driven HSVtk against therapy-resistant tumors. Finally, we uncovered a novel mechanism of Grp78 promoter activation whereby HSVtk/ganciclovir therapy upregulates Grp78 and transgene expression via the conserved unfolded protein response signaling cascade. These data validate the potential of Grp78 promoter in systemic cancer gene therapy and report the efficacy of a dual tumor targeting phage that may prove useful for translation into gene therapy and molecular imaging applications.

Towards real-time detection of tumor margins using photothermal imaging of immune-targeted gold nanoparticles

PubMed Central

Jakobsohn, Kobi; Motiei, Menachem; Sinvani, Moshe; Popovtzer, Rachela

2012-01-01

Background One of the critical problems in cancer management is local recurrence of disease. Between 20% and 30% of patients who undergo tumor resection surgery require reoperation due to incomplete excision. Currently, there are no validated methods for intraoperative tumor margin detection. In the present work, we demonstrate the potential use of gold nanoparticles (GNPs) as a novel contrast agent for photothermal molecular imaging of cancer. Methods Phantoms containing different concentrations of GNPs were irradiated with continuous-wave laser and measured with a thermal imaging camera which detected the temperature field of the irradiated phantoms. Results The results clearly demonstrate the ability to distinguish between cancerous cells specifically targeted with GNPs and normal cells. This technique, which allows highly sensitive discrimination between adjacent low GNP concentrations, will allow tumor margin detection while the temperature increases by only a few degrees Celsius (for GNPs in relevant biological concentrations). Conclusion We expect this real-time intraoperative imaging technique to assist surgeons in determining clear tumor margins and to maximize the extent of tumor resection while sparing normal background tissue. PMID:22956871

Fluorescent imaging of cancerous tissues for targeted surgery

PubMed Central

Bu, Lihong; Shen, Baozhong; Cheng, Zhen

2014-01-01

To maximize tumor excision and minimize collateral damage is the primary goal of cancer surgery. Emerging molecular imaging techniques have to “image-guided surgery” developing into “molecular imaging-guided surgery”, which is termed “targeted surgery” in this review. Consequently, the precision of surgery can be advanced from tissue-scale to molecule-scale, enabling “targeted surgery” to be a component of “targeted therapy”. Evidence from numerous experimental and clinical studies has demonstrated significant benefits of fluorescent imaging in targeted surgery with preoperative molecular diagnostic screening. Fluorescent imaging can help to improve intraoperative staging and enable more radical cytoreduction, detect obscure tumor lesions in special organs, highlight tumor margins, better map lymph node metastases, and identify important normal structures intraoperatively. Though limited tissue penetration of fluorescent imaging and tumor heterogeneity are two major hurdles for current targeted surgery, multimodality imaging and multiplex imaging may provide potential solutions to overcome these issues, respectively. Moreover, though many fluorescent imaging techniques and probes have been investigated, targeted surgery remains at a proof-of-principle stage. The impact of fluorescent imaging on cancer surgery will likely be realized through persistent interdisciplinary amalgamation of research in diverse fields. PMID:25064553

A Novel Clinically Translatable Fluorescent Nanoparticle for Targeted Molecular Imaging of Tumors in Living Subjects

PubMed Central

Gao, Jinhao; Chen, Kai; Luong, Richard; Bouley, Donna M.; Mao, Hua; Qiao, Tiecheng; Gambhir, Sanjiv S.; Cheng, Zhen

2011-01-01

The use of quantum dots (QDs) in biomedical research has grown tremendously, yet successful examples of clinical applications are absent due to many clinical concerns. Here, we report on a new type of stable and biocompatible dendron-coated InP/ZnS core/shell QDs as a clinically translatable nanoprobe for molecular imaging applications. The QDs (QD710-Dendron) were demonstrated to hold several significant features: near-infrared (NIR) emission, high stability in biological media, suitable size with possible renal clearance and ability of extravasation. More importantly, a pilot mouse toxicity study confirmed that QD710-Dendron lacks significant toxicity at the doses tested. The acute tumor uptake of QD710-Dendron resulted in good contrast from the surrounding non-tumorous tissues, indicating the possibility of passive targeting of the QDs. The highly specific targeting of QD710-Dendron-RGD2 to integrin αvβ3–positive tumor cells resulted in high tumor uptake and long retention of the nanoprobe at tumor sites. In summary, QD710-Dendron and RGD modified nanoparticles demonstrate small size, high stability, biocompatibility, favorable in vivo pharmacokinetics, and successful tumor imaging properties. These features satisfy the requirements for clinical translation and should promote efforts to further investigate the possibility of using QD710-Dendron based nanoprobes in the clinical setting in the near future. PMID:22172022

Iron oxide core oil-in-water emulsions as a multifunctional nanoparticle platform for tumor targeting and imaging

PubMed Central

Jarzyna, Peter A.; Skajaa, Torjus; Gianella, Anita; Cormode, David P.; Samber, Dan D.; Dickson, Stephen D.; Chen, Wei; Griffioen, Arjan W.; Fayad, Zahi A.; Mulder, Willem J. M.

2009-01-01

Nanoemulsions are increasingly investigated for the delivery of hydrophobic drugs to improve their bioavailability or make their administration possible. In the current study, oil-in-water emulsions with three different mean diameters (30, 60, and 95 nm) were developed as a new multimodality nanoparticle platform for tumor targeting and imaging. To that aim, hydrophobically coated iron oxide particles were included in the soybean oil core of the nanoemulsions to enable their detection with magnetic resonance imaging (MRI), while the conjugation of a near infrared fluorophore allowed optical imaging. The accumulation of this novel nanocomposite in subcutaneous human tumors in nude mice was demonstrated with MRI and fluorescence imaging in vivo, and with Perl’s staining of histological tumor sections ex vivo. PMID:19783295

Nanoparticle Imaging of Integrins on Tumor Cells1

PubMed Central

Montet, Xavier; Montet-Abou, Karin; Reynolds, Fred; Weissleder, Ralph; Josephson, Lee

2006-01-01

Abstract Nanoparticles 10 to 100 nm in size can deliver large payloads to molecular targets, but undergo slow diffusion and/or slow transport through delivery barriers. To examine the feasibility of nanoparticles targeting a marker expressed in tumor cells, we used the binding of cyclic arginine-glycine-aspartic acid (RGD) nanoparticle targeting integrins on BT-20 tumor as a model system. The goals of this study were: 1) to use nanoparticles to image αvβ3 integrins expressed in BT-20 tumor cells by fluorescence-based imaging and magnetic resonance imaging, and, 2) to identify factors associated with the ability of nanoparticles to target tumor cell integrins. Three factors were identified: 1) tumor cell integrin expression (the αvβ3 integrin was expressed in BT-20 cells, but not in 9L cells); 2) nanoparticle pharmacokinetics (the cyclic RGD peptide cross-linked iron oxide had a blood half-life of 180 minutes and was able to escape from the vasculature over its long circulation time); and 3) tumor vascularization (the tumor had a dense capillary bed, with distances of <100 µm between capillaries). These results suggest that nanoparticles could be targeted to the cell surface markers expressed in tumor cells, at least in the case wherein the nanoparticles and the tumor model have characteristics similar to those of the BT-20 tumor employed here. PMID:16611415

In vitro study of novel gadolinium-loaded liposomes guided by GBI-10 aptamer for promising tumor targeting and tumor diagnosis by magnetic resonance imaging.

PubMed

Gu, Meng-Jie; Li, Kun-Feng; Zhang, Lan-Xin; Wang, Huan; Liu, Li-Si; Zheng, Zhuo-Zhao; Han, Nan-Yin; Yang, Zhen-Jun; Fan, Tian-Yuan

2015-01-01

Novel gadolinium-loaded liposomes guided by GBI-10 aptamer were developed and evaluated in vitro to enhance magnetic resonance imaging (MRI) diagnosis of tumor. Nontargeted gadolinium-loaded liposomes were achieved by incorporating amphipathic material, Gd (III) [N,N-bis-stearylamidomethyl-N'-amidomethyl] diethylenetriamine tetraacetic acid, into the liposome membrane using lipid film hydration method. GBI-10, as the targeting ligand, was then conjugated onto the liposome surface to get GBI-10-targeted gadolinium-loaded liposomes (GTLs). Both nontargeted gadolinium-loaded liposomes and GTLs displayed good dispersion stability, optimal size, and zeta potential for tumor targeting, as well as favorable imaging properties with enhanced relaxivity compared with a commercial MRI contrast agent (CA), gadopentetate dimeglumine. The use of GBI-10 aptamer in this liposomal system was intended to result in increased accumulation of gadolinium at the periphery of C6 glioma cells, where the targeting extracellular matrix protein tenascin-C is overexpressed. Increased cellular binding of GTLs to C6 cells was confirmed by confocal microscopy, flow cytometry, and MRI, demonstrating the promise of this novel delivery system as a carrier of MRI contrast agent for the diagnosis of tumor. These studies provide a new strategy furthering the development of nanomedicine for both diagnosis and therapy of tumor.

In vitro study of novel gadolinium-loaded liposomes guided by GBI-10 aptamer for promising tumor targeting and tumor diagnosis by magnetic resonance imaging

PubMed Central

Gu, Meng-Jie; Li, Kun-Feng; Zhang, Lan-Xin; Wang, Huan; Liu, Li-Si; Zheng, Zhuo-Zhao; Han, Nan-Yin; Yang, Zhen-Jun; Fan, Tian-Yuan

2015-01-01

Novel gadolinium-loaded liposomes guided by GBI-10 aptamer were developed and evaluated in vitro to enhance magnetic resonance imaging (MRI) diagnosis of tumor. Nontargeted gadolinium-loaded liposomes were achieved by incorporating amphipathic material, Gd (III) [N,N-bis-stearylamidomethyl-N′-amidomethyl] diethylenetriamine tetraacetic acid, into the liposome membrane using lipid film hydration method. GBI-10, as the targeting ligand, was then conjugated onto the liposome surface to get GBI-10-targeted gadolinium-loaded liposomes (GTLs). Both nontargeted gadolinium-loaded liposomes and GTLs displayed good dispersion stability, optimal size, and zeta potential for tumor targeting, as well as favorable imaging properties with enhanced relaxivity compared with a commercial MRI contrast agent (CA), gadopentetate dimeglumine. The use of GBI-10 aptamer in this liposomal system was intended to result in increased accumulation of gadolinium at the periphery of C6 glioma cells, where the targeting extracellular matrix protein tenascin-C is overexpressed. Increased cellular binding of GTLs to C6 cells was confirmed by confocal microscopy, flow cytometry, and MRI, demonstrating the promise of this novel delivery system as a carrier of MRI contrast agent for the diagnosis of tumor. These studies provide a new strategy furthering the development of nanomedicine for both diagnosis and therapy of tumor. PMID:26316749

A novel clinically translatable fluorescent nanoparticle for targeted molecular imaging of tumors in living subjects.

PubMed

Gao, Jinhao; Chen, Kai; Luong, Richard; Bouley, Donna M; Mao, Hua; Qiao, Tiecheng; Gambhir, Sanjiv S; Cheng, Zhen

2012-01-11

The use of quantum dots (QDs) in biomedical research has grown tremendously, yet successful examples of clinical applications are absent due to many clinical concerns. Here, we report on a new type of stable and biocompatible dendron-coated InP/ZnS core/shell QD as a clinically translatable nanoprobe for molecular imaging applications. The QDs (QD710-Dendron) were demonstrated to hold several significant features: near-infrared (NIR) emission, high stability in biological media, suitable size with possible renal clearance, and ability of extravasation. More importantly, a pilot mouse toxicity study confirmed that QD710-Dendron lacks significant toxicity at the doses tested. The acute tumor uptake of QD710-Dendron resulted in good contrast from the surrounding nontumorous tissues, indicating the possibility of passive targeting of the QDs. The highly specific targeting of QD710-Dendron-RGD(2) to integrin α(v)β(3)-positive tumor cells resulted in high tumor uptake and long retention of the nanoprobe at tumor sites. In summary, QD710-Dendron and RGD-modified nanoparticles demonstrate small size, high stability, biocompatibility, favorable in vivo pharmacokinetics, and successful tumor imaging properties. These features satisfy the requirements for clinical translation and should promote efforts to further investigate the possibility of using QD710-Dendron-based nanoprobes in the clinical setting in the near future. © 2011 American Chemical Society

Tumor-Targeting Multifunctional Rattle-Type Theranostic Nanoparticles for MRI/NIRF Bimodal Imaging and Delivery of Hydrophobic Drugs.

PubMed

Jiao, Yunfeng; Sun, Yangfei; Tang, Xiaoling; Ren, Qingguang; Yang, Wuli

2015-04-24

The development of theranostic systems capable of diagnosis, therapy, and target specificity is considerably significant for accomplishing personalized medicine. Here, a multifunctional rattle-type nanoparticle (MRTN) as an effective biological bimodal imaging and tumor-targeting delivery system is fabricated, and an enhanced loading ability of hydrophobic anticancer drug (paclitaxel) is also realized. The rattle structure with hydrophobic Fe3 O4 as the inner core and mesoporous silica as the shell is obtained by one-step templates removal process, and the size of interstitial hollow space can be easily adjusted. The Fe3 O4 core with hydrophobic poly(tert-butyl acrylate) (PTBA) chains on the surface is not only used as a magnetic resonance imaging (MRI) agent, but contributes to improving hydrophobic drug loading amount. Transferrin (Tf) and a near-infrared fluorescent dye (Cy 7) are successfully modified on the surface of the nanorattle to increase the ability of near-infrared fluorescence (NIRF) imaging and tumor-targeting specificity. In vivo studies show the selective accumulation of MRTN in tumor tissues by Tf-receptor-mediated endocytosis. More importantly, paclitaxel-loaded MRTN shows sustained release character and higher cytotoxicity than the free paclitaxel. This theranostic nanoparticle as an effective MRI/NIRF bimodal imaging probe and drug delivery system shows great potential in cancer diagnosis and therapy. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Novel fluorescent contrast agents for optical imaging of in vivo tumors based on a receptor-targeted dye-peptide conjugate platform

NASA Astrophysics Data System (ADS)

Bugaj, Joseph E.; Achilefu, Samuel I.; Dorshow, Richard B.; Rajagopalan, Raghavan

2001-04-01

We have designed, synthesized, and evaluated the efficacy of novel dye-peptide conjugates that are receptor specific. Contrary to the traditional approach of conjugating dyes to large proteins and antibodies, we used small peptide-dye conjugates that target over-expressed receptors on tumors. Despite the fact that the peptide and the dye probe have similar molecular mass, our results demonstrate that the affinity of the peptide for its receptor and the dye fluorescence properties are both retained. The use of small peptides has several advantages over large biomolecules, including ease of synthesis of a variety of compounds for potential combinatorial screening of new targets, reproducibility of high purity compounds, diffusiveness to solid tumors, and the ability to incorporate a variety of functional groups that modify the pharmacokinetics of the peptide-dye conjugates. The efficacy of these new fluorescent optical contrast agents was evaluated in vivo in well-characterized rat tumor lines expressing somatostatin (sst2) and bombesin receptors. A simple continuous wave optical imaging system was employed. The resulting optical images clearly show that successful specific tumor targeting was achieved. Thus, we have demonstrated that small peptide- dye conjugates are effective as contrast agents for optical imaging of tumors.

Activatable iRGD-based peptide monolith: Targeting, internalization, and fluorescence activation for precise tumor imaging.

PubMed

Cho, Hong-Jun; Lee, Sung-Jin; Park, Sung-Jun; Paik, Chang H; Lee, Sang-Myung; Kim, Sehoon; Lee, Yoon-Sik

2016-09-10

A disulfide-bridged cyclic RGD peptide, named iRGD (internalizing RGD, c(CRGDK/RGPD/EC)), is known to facilitate tumor targeting as well as tissue penetration. After the RGD motif-induced targeting on αv integrins expressed near tumor tissue, iRGD encounters proteolytic cleavage to expose the CendR motif that promotes penetration into cancer cells via the interaction with neuropilin-1. Based on these proteolytic cleavage and internalization mechanism, we designed an iRGD-based monolithic imaging probe that integrates multiple functions (cancer-specific targeting, internalization and fluorescence activation) within a small peptide framework. To provide the capability of activatable fluorescence signaling, we conjugated a fluorescent dye to the N-terminal of iRGD, which was linked to the internalizing sequence (CendR motif), and a quencher to the opposite C-terminal. It turned out that fluorescence activation of the dye/quencher-conjugated monolithic peptide probe requires dual (reductive and proteolytic) cleavages on both disulfide and amide bond of iRGD peptide. Furthermore, the cleavage of the iRGD peptide leading to fluorescence recovery was indeed operative depending on the tumor-related angiogenic receptors (αvβ3 integrin and neuropilin-1) in vitro as well as in vivo. Compared to an 'always fluorescent' iRGD control probe without quencher conjugation, the dye/quencher-conjugated activatable monolithic peptide probe visualized tumor regions more precisely with lower background noise after intravenous injection, owing to the multifunctional responses specific to tumor microenvironment. All these results, along with minimal in vitro and in vivo toxicity profiles, suggest potential of the iRGD-based activatable monolithic peptide probe as a promising imaging agent for precise tumor diagnosis. Copyright © 2016 Elsevier B.V. All rights reserved.

Liposomal nanocarriers for tumor imaging.

PubMed

Erdogan, Suna

2009-04-01

Currently used imaging modalities such as scintigraphy, computed tomography, magnetic resonance imaging and ultrasonography require the sufficient intensity of a corresponding signal from an area of interest to differentiate this area from the surrounding tissues. Targeting of various reporter moieties directly to the specific organs, tissues or tumors provide the highest dose of drug directly where it is needed. Many different types of nanoparticles are currently being studied for applications in nanomedicine. Among particulate drug carriers, liposomes are one of the most extensively studied and possess the most suitable characteristics for encapsulation of many drugs, genes, and diagnostic (imaging) agents. Among the many potential targets for such nanocarriers, tumors have been most often investigated. This review attempts to summarize the currently available information regarding liposomal nanocarriers for cancer imaging.

Spectral imaging based in vivo model system for characterization of tumor microvessel response to vascular targeting agents

NASA Astrophysics Data System (ADS)

Wankhede, Mamta

Functional vasculature is vital for tumor growth, proliferation, and metastasis. Many tumor-specific vascular targeting agents (VTAs) aim to destroy this essential tumor vasculature to induce indirect tumor cell death via oxygen and nutrition deprivation. The tumor angiogenesis-inhibiting anti-angiogenics (AIs) and the established tumor vessel targeting vascular disrupting agents (VDAs) are the two major players in the vascular targeting field. Combination of VTAs with conventional therapies or with each other, have been shown to have additive or supra-additive effects on tumor control and treatment. Pathophysiological changes post-VTA treatment in terms of structural and vessel function changes are important parameters to characterize the treatment efficacy. Despite the abundance of information regarding these parameters acquired using various techniques, there remains a need for a quantitative, real-time, and direct observation of these phenomenon in live animals. Through this research we aspired to develop a spectral imaging based mouse tumor system for real-time in vivo microvessel structure and functional measurements for VTA characterization. A model tumor system for window chamber studies was identified, and then combinatorial effects of VDA and AI were characterized in model tumor system. (Full text of this dissertation may be available via the University of Florida Libraries web site. Please check http://www.uflib.ufl.edu/etd.html)

Radiolabeled, Antibody-Conjugated Manganese Oxide Nanoparticles for Tumor Vasculature Targeted Positron Emission Tomography and Magnetic Resonance Imaging.

PubMed

Zhan, Yonghua; Shi, Sixiang; Ehlerding, Emily B; Graves, Stephen A; Goel, Shreya; Engle, Jonathan W; Liang, Jimin; Tian, Jie; Cai, Weibo

2017-11-08

Manganese oxide nanoparticles (Mn 3 O 4 NPs) have attracted a great deal of attention in the field of biomedical imaging because of their ability to create an enhanced imaging signal in MRI as novel potent T 1 contrast agents. In this study, we present tumor vasculature-targeted imaging in mice using Mn 3 O 4 NPs through conjugation to the anti-CD105 antibody TRC105 and radionuclide copper-64 ( 64 Cu, t 1/2 : 12.7 h). The Mn 3 O 4 conjugated NPs, 64 Cu-NOTA-Mn 3 O 4 @PEG-TRC105, exhibited sufficient stability in vitro and in vivo. Serial positron emission tomography (PET) and magnetic resonance imaging (MRI) studies evaluated the pharmacokinetics and demonstrated targeting of 64 Cu-NOTA-Mn 3 O 4 @PEG-TRC105 to 4T1 murine breast tumors in vivo, compared to 64 Cu-NOTA-Mn 3 O 4 @PEG. The specificity of 64 Cu-NOTA-Mn 3 O 4 @PEG-TRC105 for the vascular marker CD105 was confirmed through in vivo, in vitro, and ex vivo experiments. Since Mn 3 O 4 conjugated NPs exhibited desirable properties for T 1 enhanced imaging and low toxicity, the tumor-specific Mn 3 O 4 conjugated NPs reported in this study may serve as promising multifunctional nanoplatforms for precise cancer imaging and diagnosis.

Thermoacoustic molecular tomography with magnetic nanoparticle contrast agents for targeted tumor detection.

PubMed

Nie, Liming; Ou, Zhongmin; Yang, Sihua; Xing, Da

2010-08-01

The primary feasibility steps of demonstrating the ability of microwave-induced thermoacoustic (TA) in phantoms have been previously reported. However, none were shown to target a diseased site in living subjects in thermoacoustic tomography (TAT) field so far. To determine the expressions of oncogenic surface molecules, it is quite necessary to image tumor lesions and acquire pathogenic status on them via TAT. Compared to biological tissues, iron oxide nanoparticles have a much higher microwave absorbance. Fe3O4/polyaniline (PANI) nanoparticles were prepared via polymerization of aniline in the Fe304 superparamagnetic fluids. Then Fe3O4/PANI was conjugated to folic acid (FA), which can bind specifically to the surface of the folate receptor used as a tumor marker. FA-Fe3O4/PANI targeted tumor was irradiated by pulsed microwave at 6 GHz for thermoacoustic detection and imaging. The effect of the Fe3O4/PANI superparamagnetic nanoparticles for enhancing TAT images was successfully investigated in ex vivo human blood and in vivo mouse tail. Intravenous administration of the targeted nanoparticles to mice bearing tumors showed fivefold greater thermoacoustic signal and much longer elimination time than that of mice injected with nontargeted nanoparticles in the tumor. The specific targeting ability of FA-Fe3O4/PANI to tumor was also verified on fluorescence microscopy. Fabricated iron oxide nanoparticles conjugated with tumor ligands for targeted TAT tumor detection at the molecular level was reported for the first time. The results indicate that thermoacoustic molecular imaging with functionalized iron oxide nanoparticles may contribute to targeted and functional early cancer imaging. Also, the modified iron oxide nanoparticles combined with suitable tumor markers may also be used as novel nanomaterials for targeted and guided cancer thermal therapy.

Dual targeting of integrin αvβ3 and matrix metalloproteinase-2 for optical imaging of tumors and chemotherapeutic delivery

PubMed Central

Crisp, Jessica L.; Savariar, Elamprakash N.; Glasgow, Heather L.; Ellies, Lesley G.; Whitney, Michael A.; Tsien, Roger. Y.

2014-01-01

Activatable cell penetrating peptides (ACPPs) provide a general strategy for molecular targeting by exploiting the extracellular protease activities associated with disease. Previous work used a matrix metalloproteinase (MMP-2 and 9) cleavable sequence in the ACPP to target contrast agents for tumor imaging and fluorescence guided surgery. To improve specificity and sensitivity for MMP-2, an integrin αvβ3 binding domain, cyclic-RGD, was covalently linked to the ACPP. This co-targeting strategy relies on the interaction of MMP-2 with integrin αvβ3, which are known to associate via MMP-2’s hemopexin domain. In U87MG glioblastoma cells in culture, dual targeting greatly improved ACPP uptake compared to either MMP or integrin αvβ3 targeting alone. In vivo, dual-targeted ACPP treatment resulted in tumor contrast of 7.8±1.6, a 10 fold higher tumor fluorescence compared to the negative control peptide, and increased probe penetration into the core of MDA-MB-231 tumors. This platform also significantly improved efficacy of the chemotherapeutic monomethylauristatin E (MMAE) in both MDA-MB-231 orthotopic human and syngeneic Py230 murine breast tumors. Treatment with cyclic-RGD-PLGC(Me)AG-MMAE-ACPP resulted in complete tumor regression in one quarter of MDA-MB-231 tumor bearing mice, compared to no survival in the control groups. This rational mechanism for amplified delivery of imaging and potent chemotherapeutic agents avoids the use of antibodies and may be of considerable generality. PMID:24737028

Dual targeting of integrin αvβ3 and matrix metalloproteinase-2 for optical imaging of tumors and chemotherapeutic delivery.

PubMed

Crisp, Jessica L; Savariar, Elamprakash N; Glasgow, Heather L; Ellies, Lesley G; Whitney, Michael A; Tsien, Roger Y

2014-06-01

Activatable cell-penetrating peptides (ACPP) provide a general strategy for molecular targeting by exploiting the extracellular protease activities associated with disease. Previous work used a matrix metalloproteinase (MMP-2 and 9)-cleavable sequence in the ACPP to target contrast agents for tumor imaging and fluorescence-guided surgery. To improve specificity and sensitivity for MMP-2, an integrin α(v)β(3)-binding domain, cyclic-RGD, was covalently linked to the ACPP. This co-targeting strategy relies on the interaction of MMP-2 with integrin α(v)β(3), which are known to associate via the hemopexin domain of MMP-2. In U87MG glioblastoma cells in culture, dual targeting greatly improved ACPP uptake compared with either MMP or integrin α(v)β(3) targeting alone. In vivo, dual-targeted ACPP treatment resulted in tumor contrast of 7.8 ± 1.6, a 10-fold higher tumor fluorescence compared with the negative control peptide, and increased probe penetration into the core of MDA-MB-231 tumors. This platform also significantly improved efficacy of the chemotherapeutic monomethylauristatin E (MMAE) in both MDA-MB-231 orthotopic human and syngeneic Py230 murine breast tumors. Treatment with cyclic-RGD-PLGC(Me)AG-MMAE-ACPP resulted in complete tumor regression in one quarter of MDA-MB-231 tumor-bearing mice, compared with no survival in the control groups. This rational mechanism for amplified delivery of imaging and potent chemotherapeutic agents avoids the use of antibodies and may be of considerable generality. ©2014 American Association for Cancer Research.

[Molecular imaging of tumor blood vessels].

PubMed

Tilki, D; Singer, B; Seitz, M; Stief, C G; Ergün, S

2007-09-01

In the past three decades many efforts have been undertaken to understand the mechanisms of tumor angiogenesis. The introduction of the anti-angiogenic drugs in tumor therapy during the last few years necessitates the establishment of new techniques enabling molecular imaging of vascular remodeling. Tumor imaging by X-ray, CT, MRI and ultrasound has to be improved by coupling with molecular markers targeting the tumor vessels. The determination of tumor size as commonly used is not appropriate since the extended necrosis under anti-angiogenic therapy does not result in a reduction of tumor diameter. But remodeling of the tumor vessels under anti-angiogenic therapy obviously occurs at an early stage and seems to be a convincing parameter for tumor imaging. Despite the enormous progress in this field during the last few years the resolution is still not high enough to evaluate the remodeling of the microtumor vessels. Thus, new imaging approaches are needed to overcome this issue.

An improved 99mTc-HYNIC-(Ser)3-LTVSPWY peptide with EDDA/tricine as co-ligands for targeting and imaging of HER2 overexpression tumor.

PubMed

Khodadust, Fatemeh; Ahmadpour, Sajjad; Aligholikhamseh, Nazan; Abedi, Seyed Mohammad; Hosseinimehr, Seyed Jalal

2018-01-20

Overexpression of human epidermal receptor 2 (HER2) has given the opportunity for targeting and delivering of imaging radiotracers. The aim of this study was to evaluate the 99m Tc-HYNIC-(EDDA/tricine)-(Ser) 3 -LTVSPWY peptide for tumor targeting and imaging of tumor with overexpression of HER2. The HYNIC-(Ser) 3 -LTVSPWY was labeled with 99m Tc in presence of EDDA/tricine mixture as co-ligands. The in vitro and in vivo studies of this radiolabeled peptide were performed for cellular specific binding and tumor targeting. The high radiochemical purity of 99m Tc-HYNIC (EDDA/tricine)-(Ser) 3 -LTVSPWY was obtained to be 99%. It exhibited high stability in normal saline and human serum. In HER2 binding affinity study, a significant reduction in uptake of radiolabeled peptide (7.7 fold) was observed by blocking SKOV-3 cells receptors with unlabeled peptide. The K D and B max values for this radiolabeled peptide were determined as 3.3 ± 1.0 nM and 2.9 ± 0.3 × 10 6 CPM/pMol, respectively. Biodistribution study revealed tumor to blood and tumor to muscle ratios about 6.9 and 4 respectively after 4 h. Tumor imaging by gamma camera demonstrated considerable high contrast tumor uptake. This developed 99m Tc-HYNIC-(Ser) 3 -LTVSPWY peptide selectively targeted on HER2 tumor and exhibited a high target uptake combined with acceptable low background activity for tumor imaging in mice. The results of this study and its comparison with another study showed that 99m Tc-HYNIC-(EDDA/tricine)-(Ser) 3 -LTVSPWY is much better than previously reported radiolabeled peptide as 99m Tc-CSSS-LTVSPWY for HER2 overexpression tumor targeting and imaging. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Hyaluronic acid-modified hydrothermally synthesized iron oxide nanoparticles for targeted tumor MR imaging.

PubMed

Li, Jingchao; He, Yao; Sun, Wenjie; Luo, Yu; Cai, Hongdong; Pan, Yunqi; Shen, Mingwu; Xia, Jindong; Shi, Xiangyang

2014-04-01

We report a polyethyleneimine (PEI)-mediated approach to synthesizing hyaluronic acid (HA)-targeted magnetic iron oxide nanoparticles (Fe3O4 NPs) for in vivo targeted tumor magnetic resonance (MR) imaging applications. In this work, Fe3O4 NPs stabilized by PEI were first synthesized via a one-pot hydrothermal method. The formed PEI-stabilized Fe3O4 NPs were then modified with fluorescein isothiocyanate (FI) and HA with two different molecular weights to obtain two different Fe3O4 NPs (Fe3O4-PEI-FI-HA6K and Fe3O4-PEI-FI-HA31K NPs) with a size of 15-16 nm. The formed HA-modified multifunctional Fe3O4 NPs were characterized via different techniques. We show that the multifunctional Fe3O4 NPs are water-dispersible and colloidal stable in different aqueous media. In vitro cell viability and hemolysis studies reveal that the particles are quite cytocompatible and hemocompatible in the given concentration range. Furthermore, confocal microscopy and flow cytometry data demonstrate that HA-targeted Fe3O4 NPs are able to be uptaken specifically by cancer cells overexpressing CD44 receptors, and be used as efficient probes for targeted MR imaging of cancer cells in vitro and xenografted tumor models in vivo. With the tunable amine-based conjugation chemistry, the PEI-stabilized Fe3O4 NPs may be functionalized with other biological ligands or drugs for diagnosis and therapy of different biological systems. Copyright © 2014 Elsevier Ltd. All rights reserved.

Synthesis, characterization and two-photon PDT efficacy studies of triads incorporating tumor targeting and imaging components

NASA Astrophysics Data System (ADS)

Spangler, C. W.; Starkey, J.; Rebane, A.; Drobizhev, M.; Meng, F.; Gong, A.

2008-02-01

Over the past three years we have described the rationale for using new photosensitizers (PS) with greatly enhanced multi-photon absorption. In particular, we have synthesized new porphyrin-based photosensitizers that also incorporate small molecule targeting agents that direct the ensemble to over-expressed tumor receptor sites, as well as Near-infrared imaging agents that will allow practical image-guided two-photon PDT in the tissue transparency window (750-1000 nm) at laser fluences that are harmless to surrounding healthy tissue. We have previously shown (PW2006) successful treatment of human breast cancer models (MDA-MB-231) in SCID mice, and have recently extended these studies to the treatment of both human small cell (SC) (NCI-H69) and non-small cell (NSC) (A-459) models in SCID mice. We have demonstrated that lung cancer xenografts can be successfully treated by irradiating from the side of the mouse opposite the implanted tumor, thereby passing through ca. 2 cm of mouse skin, tissue and organs before encountering the bulk tumor. These results suggest that this technology can be used to treat deep subcutaneous spontaneous tumors in larger animal models (e.g. canine). We would also emphasize that the synthetic route to these triads attaches the targeting moiety in the last step of the synthesis, and can be easily changed, thus allowing a myriad of targeting agents to be employed, opening the door to the possibility of patient-specific PDT.

MRI-visible liposome nanovehicles for potential tumor-targeted delivery of multimodal therapies

NASA Astrophysics Data System (ADS)

Ren, Lili; Chen, Shizhen; Li, Haidong; Zhang, Zhiying; Ye, Chaohui; Liu, Maili; Zhou, Xin

2015-07-01

Real-time diagnosis and monitoring of disease development, and therapeutic responses to treatment, are possible by theranostic magnetic resonance imaging (MRI). Here we report the synthesis of a multifunctional liposome, which contains Gd-DOTA (an MRI probe), paclitaxel and c(RGDyk) (a targeted peptide). This nanoparticle overcame the insolubility of paclitaxel, reduced the side effects of FDA-approved formulation of PTX-Cre (Taxol®) and improved drug delivery efficiency to the tumor. c(RGDyk) modification greatly enhanced the cytotoxicity of the drug in tumor cells A549. The T1 relaxivity in tumor cells treated with the targeted liposome formulation was increased 16-fold when compared with the non-targeted group. In vivo, the tumors in mice were visualized using T1-weighted imaging after administration of the liposome. Also the tumor growth could be inhibited well after the treatment. Fluorescence images in vitro and ex vivo also showed the targeting effect of this liposome in tumor cells, indicating that this nanovehicle could limit the off-target side effects of anticancer drugs and contrast agents. These findings lay the foundation for further tumor inhibition study and application of this delivery vehicle in cancer therapy settings.

Novel dual-mode nanobubbles as potential targeted contrast agents for female tumors exploration.

PubMed

Yang, Hengli; Zhou, Tian; Cai, Wenbin; Yi, Xiaomin; Liu, Xi; Wang, Yixiao; Zhang, Li; Duan, Yunyou

2016-10-01

The purpose of this study was to prepare tumor-specific dual-mode nanobubbles as both ultrasound contrast agents (UCAs) and near-infrared fluorescence (NIRF) imaging agents for female tumors. Recent studies have demonstrated the conjugation of anti-tumor ligands on the surface of nanobubbles for use as molecule-targeting ultrasound contrast agents for tumor visualization. However, this complicated procedure has also posed a challenge to nanobubble stability. Thus, in the present study, we combined the fluorescent dye, NIRF IR-780 iodide, which has lipid solubility and tumor-targeting characteristics, with the phospholipid film of nanobubbles that we constructed. We then characterized the physical features of the IR-780-nanobubbles, observed their tumor-targeting capacity in multiple female tumor cell types in vitro, and verified their capability for use in tumor-specific ultrasound contrast imaging and NIRF imaging in vivo. The results showed that the new IR-780-nanobubbles had a uniform nano-size (442.5 ± 48.6 nm) and stability and that they were safe and effective at NIRF imaging and ultrasound imaging in vitro. The IR-780-nanobubbles were found to automatically accumulate on different female tumor cells in vitro with a considerable targeting rate (close to 40 %) but did not accumulate on cardiac muscle cells used as a negative control. Importantly, the IR-780-nanobubbles can detect female tumors precisely via dual-mode imaging in vivo. In conclusion, the new dual-mode IR-780-nanobubbles are stable and have potential advantages in non-invasive tumor-specific detection for female tumors via contrast-enhanced ultrasound and NIRF imaging.

Multimodality Non-Rigid Image Registration for Planning, Targeting and Monitoring during CT-guided Percutaneous Liver Tumor Cryoablation

PubMed Central

Elhawary, Haytham; Oguro, Sota; Tuncali, Kemal; Morrison, Paul R.; Tatli, Servet; Shyn, Paul B.; Silverman, Stuart G.; Hata, Nobuhiko

2010-01-01

Rationale and Objectives To develop non-rigid image registration between pre-procedure contrast enhanced MR images and intra-procedure unenhanced CT images, to enhance tumor visualization and localization during CT-guided liver tumor cryoablation procedures. Materials and Methods After IRB approval, a non-rigid registration (NRR) technique was evaluated with different pre-processing steps and algorithm parameters and compared to a standard rigid registration (RR) approach. The Dice Similarity Coefficient (DSC), Target Registration Error (TRE), 95% Hausdorff distance (HD) and total registration time (minutes) were compared using a two-sided Student’s t-test. The entire registration method was then applied during five CT-guided liver cryoablation cases with the intra-procedural CT data transmitted directly from the CT scanner, with both accuracy and registration time evaluated. Results Selected optimal parameters for registration were section thickness of 5mm, cropping the field of view to 66% of its original size, manual segmentation of the liver, B-spline control grid of 5×5×5 and spatial sampling of 50,000 pixels. Mean 95% HD of 3.3mm (2.5x improvement compared to RR, p<0.05); mean DSC metric of 0.97 (13% increase); and mean TRE of 4.1mm (2.7x reduction) were measured. During the cryoablation procedure registration between the pre-procedure MR and the planning intra-procedure CT took a mean time of 10.6 minutes, the MR to targeting CT image took 4 minutes and MR to monitoring CT took 4.3 minutes. Mean registration accuracy was under 3.4mm. Conclusion Non-rigid registration allowed improved visualization of the tumor during interventional planning, targeting and evaluation of tumor coverage by the ice ball. Future work is focused on reducing segmentation time to make the method more clinically acceptable. PMID:20817574

Fluorescence-Guided Probes of Aptamer-Targeted Gold Nanoparticles with Computed Tomography Imaging Accesses for in Vivo Tumor Resection.

PubMed

Li, Cheng-Hung; Kuo, Tsung-Rong; Su, Hsin-Jan; Lai, Wei-Yun; Yang, Pan-Chyr; Chen, Jinn-Shiun; Wang, Di-Yan; Wu, Yi-Chun; Chen, Chia-Chun

2015-10-28

Recent development of molecular imaging probes for fluorescence-guided surgery has shown great progresses for determining tumor margin to execute the tissue resection. Here we synthesize the fluorescent gold nanoparticles conjugated with diatrizoic acid and nucleolin-targeted AS1411 aptamer. The nanoparticle conjugates exhibit high water-solubility, good biocompatibility, visible fluorescence and strong X-ray attenuation for computed tomography (CT) contrast enhancement. The fluorescent nanoparticle conjugates are applied as a molecular contrast agent to reveal the tumor location in CL1-5 tumor-bearing mice by CT imaging. Furthermore, the orange-red fluorescence emitting from the conjugates in the CL1-5 tumor can be easily visualized by the naked eyes. After the resection, the IVIS measurements show that the fluorescence signal of the nanoparticle conjugates in the tumor is greatly enhanced in comparison to that in the controlled experiment. Our work has shown potential application of functionalized nanoparticles as a dual-function imaging agent in clinical fluorescence-guided surgery.

Fluorescence-Guided Probes of Aptamer-Targeted Gold Nanoparticles with Computed Tomography Imaging Accesses for in Vivo Tumor Resection

PubMed Central

Li, Cheng-Hung; Kuo, Tsung-Rong; Su, Hsin-Jan; Lai, Wei-Yun; Yang, Pan-Chyr; Chen, Jinn-Shiun; Wang, Di-Yan; Wu, Yi-Chun; Chen, Chia-Chun

2015-01-01

Recent development of molecular imaging probes for fluorescence-guided surgery has shown great progresses for determining tumor margin to execute the tissue resection. Here we synthesize the fluorescent gold nanoparticles conjugated with diatrizoic acid and nucleolin-targeted AS1411 aptamer. The nanoparticle conjugates exhibit high water-solubility, good biocompatibility, visible fluorescence and strong X-ray attenuation for computed tomography (CT) contrast enhancement. The fluorescent nanoparticle conjugates are applied as a molecular contrast agent to reveal the tumor location in CL1-5 tumor-bearing mice by CT imaging. Furthermore, the orange-red fluorescence emitting from the conjugates in the CL1-5 tumor can be easily visualized by the naked eyes. After the resection, the IVIS measurements show that the fluorescence signal of the nanoparticle conjugates in the tumor is greatly enhanced in comparison to that in the controlled experiment. Our work has shown potential application of functionalized nanoparticles as a dual-function imaging agent in clinical fluorescence-guided surgery. PMID:26507179

Novel lactoferrin-conjugated amphiphilic poly(aminoethyl ethylene phosphate)/poly(L-lactide) copolymer nanobubbles for tumor-targeting ultrasonic imaging

PubMed Central

Luo, Binhua; Liang, Huageng; Zhang, Shengwei; Qin, Xiaojuan; Liu, Xuhan; Liu, Wei; Zeng, Fuqing; Wu, Yun; Yang, Xiangliang

2015-01-01

In the study reported here, a novel amphiphilic poly(aminoethyl ethylene phosphate)/poly(L-lactide) (PAEEP-PLLA) copolymer was synthesized by ring-opening polymerization reaction. The perfluoropentane-filled PAEEP-PLLA nanobubbles (NBs) were prepared using the O1/O2/W double-emulsion and solvent-evaporation method, with the copolymer as the shell and liquid perfluoropentane as the core of NBs. The prepared NBs were further conjugated with lactoferrin (Lf) for tumor-cell targeting. The resulting Lf-conjugated amphiphilic poly(aminoethyl ethylene phosphate)/poly(L-lactide) nanobubbles (Lf-PAEEP-PLLA NBs) were characterized by photon correlation spectroscopy, polyacrylamide gel electrophoresis, Fourier transform infrared spectroscopy, and transmission electron microscopy. The average size of the Lf-PAEEP-PLLA NBs was 328.4±5.1 nm, with polydispersity index of 0.167±0.020, and zeta potential of −12.6±0.3 mV. Transmission electron microscopy imaging showed that the Lf-PAEEP-PLLA NBs had a near-spherical structure, were quite monodisperse, and there was a clear interface between the copolymer shell and the liquid core inside the NBs. The Lf-PAEEP-PLLA NBs also exhibited good biocompatibility in cytotoxicity and hemolysis studies and good stability during storage. The high cellular uptake of Lf-PAEEP-PLLA NBs in C6 cells (low-density lipoprotein receptor-related protein 1-positive cells) at concentrations of 0–20 µg/mL indicated that the Lf provided effective targeting for brain-tumor cells. The in vitro acoustic behavior of Lf-PAEEP-PLLA NBs was evaluated using a B-mode clinical ultrasound imaging system. In vivo ultrasound imaging was performed on tumor-bearing BALB/c nude mice, and compared with SonoVue® microbubbles, a commercial ultrasonic contrast agent. Both in vitro and in vivo ultrasound imaging indicated that the Lf-PAEEP-PLLA NBs possessed strong, long-lasting, and tumor-enhanced ultrasonic contrast ability. Taken together, these results indicate that

Novel lactoferrin-conjugated amphiphilic poly(aminoethyl ethylene phosphate)/poly(L-lactide) copolymer nanobubbles for tumor-targeting ultrasonic imaging.

PubMed

Luo, Binhua; Liang, Huageng; Zhang, Shengwei; Qin, Xiaojuan; Liu, Xuhan; Liu, Wei; Zeng, Fuqing; Wu, Yun; Yang, Xiangliang

2015-01-01

In the study reported here, a novel amphiphilic poly(aminoethyl ethylene phosphate)/poly(L-lactide) (PAEEP-PLLA) copolymer was synthesized by ring-opening polymerization reaction. The perfluoropentane-filled PAEEP-PLLA nanobubbles (NBs) were prepared using the O1/O2/W double-emulsion and solvent-evaporation method, with the copolymer as the shell and liquid perfluoropentane as the core of NBs. The prepared NBs were further conjugated with lactoferrin (Lf) for tumor-cell targeting. The resulting Lf-conjugated amphiphilic poly(aminoethyl ethylene phosphate)/poly(L-lactide) nanobubbles (Lf-PAEEP-PLLA NBs) were characterized by photon correlation spectroscopy, polyacrylamide gel electrophoresis, Fourier transform infrared spectroscopy, and transmission electron microscopy. The average size of the Lf-PAEEP-PLLA NBs was 328.4±5.1 nm, with polydispersity index of 0.167±0.020, and zeta potential of -12.6±0.3 mV. Transmission electron microscopy imaging showed that the Lf-PAEEP-PLLA NBs had a near-spherical structure, were quite monodisperse, and there was a clear interface between the copolymer shell and the liquid core inside the NBs. The Lf-PAEEP-PLLA NBs also exhibited good biocompatibility in cytotoxicity and hemolysis studies and good stability during storage. The high cellular uptake of Lf-PAEEP-PLLA NBs in C6 cells (low-density lipoprotein receptor-related protein 1-positive cells) at concentrations of 0-20 µg/mL indicated that the Lf provided effective targeting for brain-tumor cells. The in vitro acoustic behavior of Lf-PAEEP-PLLA NBs was evaluated using a B-mode clinical ultrasound imaging system. In vivo ultrasound imaging was performed on tumor-bearing BALB/c nude mice, and compared with SonoVue(®) microbubbles, a commercial ultrasonic contrast agent. Both in vitro and in vivo ultrasound imaging indicated that the Lf-PAEEP-PLLA NBs possessed strong, long-lasting, and tumor-enhanced ultrasonic contrast ability. Taken together, these results indicate that Lf

A review of NIR dyes in cancer targeting and imaging.

PubMed

Luo, Shenglin; Zhang, Erlong; Su, Yongping; Cheng, Tianmin; Shi, Chunmeng

2011-10-01

The development of multifunctional agents for simultaneous tumor targeting and near infrared (NIR) fluorescence imaging is expected to have significant impact on future personalized oncology owing to the very low tissue autofluorescence and high tissue penetration depth in the NIR spectrum window. Cancer NIR molecular imaging relies greatly on the development of stable, highly specific and sensitive molecular probes. Organic dyes have shown promising clinical implications as non-targeting agents for optical imaging in which indocyanine green has long been implemented in clinical use. Recently, significant progress has been made on the development of unique NIR dyes with tumor targeting properties. Current ongoing design strategies have overcome some of the limitations of conventional NIR organic dyes, such as poor hydrophilicity and photostability, low quantum yield, insufficient stability in biological system, low detection sensitivity, etc. This potential is further realized with the use of these NIR dyes or NIR dye-encapsulated nanoparticles by conjugation with tumor specific ligands (such as small molecules, peptides, proteins and antibodies) for tumor targeted imaging. Very recently, natively multifunctional NIR dyes that can preferentially accumulate in tumor cells without the need of chemical conjugation to tumor targeting ligands have been developed and these dyes have shown unique optical and pharmaceutical properties for biomedical imaging with superior signal-to-background contrast index. The main focus of this article is to provide a concise overview of newly developed NIR dyes and their potential applications in cancer targeting and imaging. The development of future multifunctional agents by combining targeting, imaging and even therapeutic routes will also be discussed. We believe these newly developed multifunctional NIR dyes will broaden current concept of tumor targeted imaging and hold promise to make an important contribution to the diagnosis

Tumor-targeted nanomedicines for cancer theranostics

PubMed Central

Lammers, Twan; Shi, Yang

2017-01-01

Chemotherapeutic drugs have multiple drawbacks, including severe side effects and suboptimal therapeutic efficacy. Nanomedicines assist in improving the biodistribution and the target accumulation of chemotherapeutic drugs, and are therefore able to enhance the balance between efficacy and toxicity. Multiple different types of nanomedicines have been evaluated over the years, including liposomes, polymer-drug conjugates and polymeric micelles, which rely on strategies such as passive targeting, active targeting and triggered release for improved tumor-directed drug delivery. Based on the notion that tumors and metastases are highly heterogeneous, it is important to integrate imaging properties in nanomedicine formulations in order to enable non-invasive and quantitative assessment of targeting efficiency. By allowing for patient pre-selection, such next generation nanotheranostics are useful for facilitating clinical translation and personalizing nanomedicine treatments. PMID:27865762

M13 phage-functionalized single-walled carbon nanotubes as nanoprobes for second near-infrared window fluorescence imaging of targeted tumors

PubMed Central

HAM, MOON-HO; QI, JIFA; BARONE, PAUL W.; STRANO, MICHAEL S.; BELCHER, ANGELA M.

2014-01-01

Second near-infrared (NIR) window light (950-1,400 nm) is attractive for in vivo fluorescence imaging due to its deep penetration depth in tissues and low tissue autofluorescence. Here we show genetically engineered multifunctional M13 phage can assemble fluorescent single-walled carbon nanotubes (SWNTs) and ligands for targeted fluorescence imaging of tumors. M13-SWNT probe is detectable in deep tissues even at a low dosage of 2 μg/mL and up to 2.5 cm in tissue-like phantoms. Moreover, targeted probes show specific and up to four-fold improved uptake in prostate specific membrane antigen positive prostate tumors compared to control non-targeted probes. This M13 phage-based second NIR window fluorescence imaging probe has great potential for specific detection and therapy monitoring of hard-to-detect areas. PMID:22268625

Evaluation of (99m)Tc-HYNIC-TMTP1 as a tumor-homing imaging agent targeting metastasis with SPECT.

PubMed

Li, Fei; Cheng, Teng; Dong, Qingjian; Wei, Rui; Zhang, Zhenzhong; Luo, Danfeng; Ma, Xiangyi; Wang, Shixuan; Gao, Qinglei; Ma, Ding; Zhu, Xiaohua; Xi, Ling

2015-03-01

TMTP1 (NVVRQ) is a novel tumor-homing peptide, which specifically targets tumor metastases, even at the early stage of occult metastasis foci. Fusing TMTP1 to therapeutic peptides or proteins can increase its anti-cancer efficacy both in vivo and in vitro. Here, we labeled TMTP1 with (99m)Tc to evaluate its targeting properties in an ovarian cancer xenograft tumor mouse model and a gastric cancer xenograft mouse model. The invasion ability of SKOV3 and highly metastatic SKOV3.ip cell lines were performed by the Transwell Invasion Assays, and then Rhodamine-TMTP1 was used to detect its affinity to these two cells. Using the co-ligand ethylenediamine-N, N'-diacetic acid (EDDA) and the bifunctional chelator 6-hydrazinonicotinic acid (HYNIC), the TMTP1 peptide was labeled with (99m)Tc. A cell-binding assay was performed by incubating cancer cells with (99m)Tc-HYNIC-TMTP1 with or without an excess dose of cold HYNIC-TMTP1. To evaluate the probe in vivo, nude mice bearing SKOV3, SKOV3.ip and MNK-45 tumor cells were established and subjected to SPECT imaging after injection with (99m)Tc-HYNIC-TMTP1. Ex vivo γ-counting of dissected tissues from the mice was used to evaluate its biodistribution. (99m)Tc-HYNIC-TMTP1 was successfully synthesized. The radiotracer also exhibited high hydrophilicity and excellent stability in vitro and in vivo. It has strong affinity to highly metastatic cancer cell lines but not to poorly metastatic cell lines. After mice were injected with (99m)Tc-HYNIC-TMTP1, non-invasive SPECT imaging detected SKOV3.ip and MNK-45 xenograft tumors but not SKOV3 xenograft tumors. This result can be inhibited by excess HYNIC-TMTP1. The uptake of (99m)Tc-HYNIC-TMTP1 in SKOV3.ip xenograft tumors was 0.182±0.017% ID/g at 2h p.i. with high renal uptake (74.32±15.05% ID/g at 2h p.i.). (99m)Tc-HYNIC-TMTP1 biodistribution and SPECT imaging demonstrated its ability to target highly metastatic tumors. Therefore, metastasis can be non-invasively investigated by SPECT

Recent Developments in Active Tumor Targeted Multifunctional Nanoparticles for Combination Chemotherapy in Cancer Treatment and Imaging

PubMed Central

Glasgow, Micah D. K.; Chougule, Mahavir B.

2016-01-01

Nanotechnology and combination therapy are two major fields that show great promise in the treatment of cancer. The delivery of drugs via nanoparticles helps to improve drug’s therapeutic effectiveness while reducing adverse side effects associated with high dosage by improving their pharmacokinetics. Taking advantage of molecular markers over-expressing on tumor tissues compared to normal cells, an “active” molecular marker targeted approach would be beneficial for cancer therapy. These actively targeted nanoparticles would increase drug concentration at the tumor site, improving efficacy while further reducing chemo-resistance. The multidisciplinary approach may help to improve the overall efficacy in cancer therapy. This review article summarizes recent developments of targeted multifunctional nanoparticles in the delivery of various drugs for a combinational chemotherapy approach to cancer treatment and imaging. PMID:26554150

Integrin-Targeted Hybrid Fluorescence Molecular Tomography/X-ray Computed Tomography for Imaging Tumor Progression and Early Response in Non-Small Cell Lung Cancer.

PubMed

Ma, Xiaopeng; Phi Van, Valerie; Kimm, Melanie A; Prakash, Jaya; Kessler, Horst; Kosanke, Katja; Feuchtinger, Annette; Aichler, Michaela; Gupta, Aayush; Rummeny, Ernst J; Eisenblätter, Michel; Siveke, Jens; Walch, Axel K; Braren, Rickmer; Ntziachristos, Vasilis; Wildgruber, Moritz

2017-01-01

Integrins play an important role in tumor progression, invasion and metastasis. Therefore we aimed to evaluate a preclinical imaging approach applying ανβ3 integrin targeted hybrid Fluorescence Molecular Tomography/X-ray Computed Tomography (FMT-XCT) for monitoring tumor progression as well as early therapy response in a syngeneic murine Non-Small Cell Lung Cancer (NSCLC) model. Lewis Lung Carcinomas were grown orthotopically in C57BL/6 J mice and imaged in-vivo using a ανβ3 targeted near-infrared fluorescence (NIRF) probe. ανβ3-targeted FMT-XCT was able to track tumor progression. Cilengitide was able to substantially block the binding of the NIRF probe and suppress the imaging signal. Additionally mice were treated with an established chemotherapy regimen of Cisplatin and Bevacizumab or with a novel MEK inhibitor (Refametinib) for 2 weeks. While μCT revealed only a moderate slowdown of tumor growth, ανβ3 dependent signal decreased significantly compared to non-treated mice already at one week post treatment. ανβ3 targeted imaging might therefore become a promising tool for assessment of early therapy response in the future. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Review on near-infrared heptamethine cyanine dyes as theranostic agents for tumor imaging, targeting, and photodynamic therapy

NASA Astrophysics Data System (ADS)

Shi, Changhong; Wu, Jason Boyang; Pan, Dongfeng

2016-05-01

A class of near-infrared fluorescence (NIRF) heptamethine cyanine dyes that are taken up and accumulated specifically in cancer cells without chemical conjugation have recently emerged as promising tools for tumor imaging and targeting. In addition to their fluorescence and nuclear imaging-based tumor-imaging properties, these dyes can be developed as drug carriers to safely deliver chemotherapy drugs to tumors. They can also be used as effective agents for photodynamic therapy with remarkable tumoricidal activity via photodependent cytotoxic activity. The preferential uptake of dyes into cancer but not normal cells is co-operatively mediated by the prevailing activation of a group of organic anion-transporting polypeptides on cancer cell membranes, as well as tumor hypoxia and increased mitochondrial membrane potential in cancer cells. Such mechanistic explorations have greatly advanced the current application and future development of NIRF dyes and their derivatives as anticancer theranostic agents. This review summarizes current knowledge and emerging advances in NIRF dyes, including molecular characterization, photophysical properties, multimodal development and uptake mechanisms, and their growing potential for preclinical and clinical use.

Folate-bovine serum albumin functionalized polymeric micelles loaded with superparamagnetic iron oxide nanoparticles for tumor targeting and magnetic resonance imaging.

PubMed

Li, Huan; Yan, Kai; Shang, Yalei; Shrestha, Lochan; Liao, Rufang; Liu, Fang; Li, Penghui; Xu, Haibo; Xu, Zushun; Chu, Paul K

2015-03-01

Polymeric micelles functionalized with folate conjugated bovine serum albumin (FA-BSA) and loaded with superparamagnetic iron oxide nanoparticles (SPIONs) are investigated as a specific contrast agent for tumor targeting and magnetic resonance imaging (MRI) in vitro and in vivo. The SPIONs-loaded polymeric micelles are produced by self-assembly of amphiphilic poly(HFMA-co-MOTAC)-g-PEGMA copolymers and oleic acid modified Fe3O4 nanoparticles and functionalized with FA-BSA by electrostatic interaction. The FA-BSA modified magnetic micelles have a hydrodynamic diameter of 196.1 nm, saturation magnetization of 5.5 emu/g, and transverse relaxivity of 167.0 mM(-1) S(-1). In vitro MR imaging, Prussian blue staining, and intracellular iron determination studies demonstrate that the folate-functionalized magnetic micelles have larger cellular uptake against the folate-receptor positive hepatoma cells Bel-7402 than the unmodified magnetic micelles. In vivo MR imaging conducted on nude mice bearing the Bel-7402 xenografts after bolus intravenous administration reveals excellent tumor targeting and MR imaging capabilities, especially at 24h post-injection. These findings suggest the potential of FA-BSA modified magnetic micelles as targeting MRI probe in tumor detection. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Diffusion and perfusion weighted magnetic resonance imaging for tumor volume definition in radiotherapy of brain tumors.

PubMed

Guo, Lu; Wang, Gang; Feng, Yuanming; Yu, Tonggang; Guo, Yu; Bai, Xu; Ye, Zhaoxiang

2016-09-21

Accurate target volume delineation is crucial for the radiotherapy of tumors. Diffusion and perfusion magnetic resonance imaging (MRI) can provide functional information about brain tumors, and they are able to detect tumor volume and physiological changes beyond the lesions shown on conventional MRI. This review examines recent studies that utilized diffusion and perfusion MRI for tumor volume definition in radiotherapy of brain tumors, and it presents the opportunities and challenges in the integration of multimodal functional MRI into clinical practice. The results indicate that specialized and robust post-processing algorithms and tools are needed for the precise alignment of targets on the images, and comprehensive validations with more clinical data are important for the improvement of the correlation between histopathologic results and MRI parameter images.

Hybrid protein-inorganic nanoparticles: From tumor-targeted drug delivery to cancer imaging.

PubMed

Elzoghby, Ahmed O; Hemasa, Ayman L; Freag, May S

2016-12-10

Recently, a great interest has been paid to the development of hybrid protein-inorganic nanoparticles (NPs) for drug delivery and cancer diagnostics in order to combine the merits of both inorganic and protein nanocarriers. This review primarily discusses the most outstanding advances in the applications of the hybrids of naturally-occurring proteins with iron oxide, gadolinium, gold, silica, calcium phosphate NPs, carbon nanotubes, and quantum dots in drug delivery and cancer imaging. Various strategies that have been utilized for the preparation of protein-functionalized inorganic NPs and the mechanisms involved in the drug loading process are discussed. How can the protein functionalization overcome the limitations of colloidal stability, poor dispersibility and toxicity associated with inorganic NPs is also investigated. Moreover, issues relating to the influence of protein hybridization on the cellular uptake, tumor targeting efficiency, systemic circulation, mucosal penetration and skin permeation of inorganic NPs are highlighted. A special emphasis is devoted to the novel approaches utilizing the protein-inorganic nanohybrids in combined cancer therapy, tumor imaging, and theranostic applications as well as stimuli-responsive drug release from the nanohybrids. Copyright © 2016 Elsevier B.V. All rights reserved.

Tumor Targeting via Sialic Acid: [68Ga]DOTA-en-pba as a New Tool for Molecular Imaging of Cancer with PET.

PubMed

Tsoukalas, Charalambos; Geninatti-Crich, Simonetta; Gaitanis, Anastasios; Tsotakos, Theodoros; Paravatou-Petsotas, Maria; Aime, Silvio; Jiménez-Juárez, Rogelio; Anagnostopoulos, Constantinos D; Djanashvili, Kristina; Bouziotis, Penelope

2018-02-20

The aim of this study was to demonstrate the potential of Ga-68-labeled macrocycle (DOTA-en-pba) conjugated with phenylboronic vector for tumor recognition by positron emission tomography (PET), based on targeting of the overexpressed sialic acid (Sia). The imaging reporter DOTA-en-pba was synthesized and labeled with Ga-68 at high efficiency. Cell binding assay on Mel-C and B16-F10 melanoma cells was used to evaluate melanin production and Sia overexpression to determine the best model for demonstrating the capability of [ 68 Ga]DOTA-en-pba to recognize tumors. The in vivo PET imaging was done with B16-F10 tumor-bearing SCID mice injected with [ 68 Ga]DOTA-en-pba intravenously. Tumor, blood, and urine metabolites were assessed to evaluate the presence of a targeting agent. The affinity of [ 68 Ga]DOTA-en-pba to Sia was demonstrated on B16-F10 melanoma cells, after the production of melanin as well as Sia overexpression was proved to be up to four times higher in this cell line compared to that in Mel-C cells. Biodistribution studies in B16-F10 tumor-bearing SCID mice showed blood clearance at the time points studied, while uptake in the tumor peaked at 60 min post-injection (6.36 ± 2.41 % ID/g). The acquired PET images were in accordance with the ex vivo biodistribution results. Metabolite assessment on tumor, blood, and urine samples showed that [ 68 Ga]DOTA-en-pba remains unmetabolized up to at least 60 min post-injection. Our work is the first attempt for in vivo imaging of cancer by targeting overexpression of sialic acid on cancer cells with a radiotracer in PET.

Feasibility of Pathology-Correlated Lung Imaging for Accurate Target Definition of Lung Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stroom, Joep; Blaauwgeers, Hans; Baardwijk, Angela van

2007-09-01

Purpose: To accurately define the gross tumor volume (GTV) and clinical target volume (GTV plus microscopic disease spread) for radiotherapy, the pretreatment imaging findings should be correlated with the histopathologic findings. In this pilot study, we investigated the feasibility of pathology-correlated imaging for lung tumors, taking into account lung deformations after surgery. Methods and Materials: High-resolution multislice computed tomography (CT) and positron emission tomography (PET) scans were obtained for 5 patients who had non-small-cell lung cancer (NSCLC) before lobectomy. At the pathologic examination, the involved lung lobes were inflated with formalin, sectioned in parallel slices, and photographed, and microscopic sectionsmore » were obtained. The GTVs were delineated for CT and autocontoured at the 42% PET level, and both were compared with the histopathologic volumes. The CT data were subsequently reformatted in the direction of the macroscopic sections, and the corresponding fiducial points in both images were compared. Hence, the lung deformations were determined to correct the distances of microscopic spread. Results: In 4 of 5 patients, the GTV{sub CT} was, on average, 4 cm{sup 3} ({approx}53%) too large. In contrast, for 1 patient (with lymphangitis carcinomatosa), the GTV{sub CT} was 16 cm{sup 3} ({approx}40%) too small. The GTV{sub PET} was too small for the same patient. Regarding deformations, the volume of the well-inflated lung lobes on pathologic examination was still, on average, only 50% of the lobe volume on CT. Consequently, the observed average maximal distance of microscopic spread (5 mm) might, in vivo, be as large as 9 mm. Conclusions: Our results have shown that pathology-correlated lung imaging is feasible and can be used to improve target definition. Ignoring deformations of the lung might result in underestimation of the microscopic spread.« less

A radiogallium-DOTA-based bivalent peptidic ligand targeting a chemokine receptor, CXCR4, for tumor imaging.

PubMed

Sano, Kohei; Masuda, Ryo; Hisada, Hayato; Oishi, Shinya; Shimokawa, Kenta; Ono, Masahiro; Fujii, Nobutaka; Saji, Hideo; Mukai, Takahiro

2014-03-01

We have developed a novel radiogallium (Ga)-DOTA-based bivalent peptidic ligand targeting a chemokine receptor, CXCR4, for tumor imaging. A CXCR4 imaging probe with two CXCR4 antagonists (Ac-TZ14011) on Ga-DOTA core, Ga-DOTA-TZ2, was synthesized, and the affinity and binding to CXCR4 was evaluated in CXCR4 expressing cells in vitro. The affinity of Ga-DOTA-TZ2 for CXCR4 was 20-fold greater than the corresponding monovalent probe, Ga-DOTA-TZ1. (67)Ga-DOTA-TZ2 showed the significantly higher accumulation in CXCR4-expressing tumor cells compared with (67)Ga-DOTA-TZ1, suggesting the bivalent effect enhances its binding to CXCR4. The incorporation of two CXCR4 antagonists to Ga-DOTA could be effective in detecting CXCR4-expressing tumors. Copyright © 2014 Elsevier Ltd. All rights reserved.

Therapeutic targeting of tumors with imageable GFP-expressing Salmonella typhimurium auxotrophic mutants

NASA Astrophysics Data System (ADS)

Hoffman, Robert M.; Hayashi, Katsuhiro; Zhao, Ming

2008-02-01

Tumor targeting Salmonella typhimurium has been developed. These bacteria were mutagenized and a strain auxotrophic for leucine and arguine was selected. This strain was also engineered to express GFP. This train, termed A1, could target prostate tumors in nude mouse models and inhibit their growth. A1 was passaged through a tumor and re-isolated and termed A1-R. A1-R had greater antitumor efficacy and could cure breast, prostate, pancreatic, and lung tumors in nude mouse models.

Tumor homing indocyanine green encapsulated micelles for near infrared and photoacoustic imaging of tumors.

PubMed

Uthaman, Saji; Bom, Joon-suk; Kim, Hyeon Sik; John, Johnson V; Bom, Hee-Seung; Kim, Seon-Jong; Min, Jung-Joon; Kim, Il; Park, In-Kyu

2016-05-01

Photoacoustic imaging (PAI) is an emerging analytical modality that is under intense preclinical development for the early diagnosis of various medical conditions, including cancer. However, the lack of specific tumor targeting by various contrast agents used in PAI obstructs its clinical applications. In this study, we developed indocyanine green (ICG)-encapsulated micelles specific for the CD 44 receptor and used in near infrared and photoacoustic imaging of tumors. ICG was hydrophobically modified prior to loading into hyaluronic acid (HA)-based micelles utilized for CD 44 based-targeting. We investigated the physicochemical characteristics of prepared HA only and ICG-encapsulated HA micelles (HA-ICG micelles). After intravenous injection of tumor-bearing mice, the bio-distribution and in vivo photoacoustic images of ICG-encapsulated HA micelles accumulating in tumors were also investigated. Our study further encourages the application of this HA-ICG-based nano-platform as a tumor-specific contrast agent for PAI. © 2016 Wiley Periodicals, Inc.

Tumor detection and elimination by a targeted gallium corrole

PubMed Central

Agadjanian, Hasmik; Ma, Jun; Rentsendorj, Altan; Valluripalli, Vinod; Hwang, Jae Youn; Mahammed, Atif; Farkas, Daniel L.; Gray, Harry B.; Gross, Zeev; Medina-Kauwe, Lali K.

2009-01-01

Sulfonated gallium(III) corroles are intensely fluorescent macrocyclic compounds that spontaneously assemble with carrier proteins to undergo cell entry. We report in vivo imaging and therapeutic efficacy of a tumor-targeted corrole noncovalently assembled with a heregulin-modified protein directed at the human epidermal growth factor receptor (HER). Systemic delivery of this protein-corrole complex results in tumor accumulation, which can be visualized in vivo owing to intensely red corrole fluorescence. Targeted delivery in vivo leads to tumor cell death while normal tissue is spared. These findings contrast with the effects of doxorubicin, which can elicit cardiac damage during therapy and required direct intratumoral injection to yield similar levels of tumor shrinkage compared with the systemically delivered corrole. The targeted complex ablated tumors at >5 times a lower dose than untargeted systemic doxorubicin, and the corrole did not damage heart tissue. Complexes remained intact in serum and the carrier protein elicited no detectable immunogenicity. The sulfonated gallium(III) corrole functions both for tumor detection and intervention with safety and targeting advantages over standard chemotherapeutic agents. PMID:19342490

Cell-Permeable, MMP-2 Activatable, Nickel Ferrite and His-Tagged Fusion Protein Self-Assembled Fluorescent Nanoprobe for Tumor Magnetic-Targeting and Imaging.

PubMed

Sun, Lu; Xie, Shuping; Qi, Jing; Liu, Ergang; Liu, Di; Liu, Quan; Chen, Sunhui; He, Huining; Yang, Victor C

2017-11-15

Matrix metalloproteinases (MMPs) activatable imaging probe has been explored for tumor detection. However, activation of the probe is mainly done in the extracellular space without intracellular uptake of the probe for more sensitivity. Although cell-penetrating peptides (CPPs) have been demonstrated to enable intracellular delivery of the imaging probe, they nevertheless encounter off-target delivery of the cargos to normal tissues. Herein, we have developed a dual MMP-2-activatable and tumor cell-permeable magnetic nanoprobe to simultaneously achieve selective and intracellular tumor imaging. This novel imaging probe was constructed by self-assembling a hexahistidine-tagged (His-tagged) fluorescent fusion protein chimera and nickel ferrite nanoparticles via a chelation mechanism. The His-tagged fluorescent protein chimera consisted of a red fluorescent protein mCherry that acted as the fluorophore, the low-molecular-weight protamine peptide as the CPP, and the MMP-2 cleavage sequence fused with the hexahistidine tag, whereas the nickel ferrite nanoparticles functioned as the His-tagged protein binder and also the fluorescent quencher. Both in vitro and in vivo results revealed that this imaging probe would not only remain nonpermeable to normal tissues, thereby offsetting the nonselective cellular uptake, but was also suppressed of fluorescent signals during magnetic tumor-targeting in the circulation, primarily because of the masking of the CPP activity and quenching of the fluorophore by the associated NiFe 2 O 4 nanoparticles. However, these properties were recovered or "turned on" by the action of tumor-associated MMP-2 stimuli, leading to cell penetration of the nanoprobes as well as fluorescence restoration and visualization within the tumor cells. In this regard, the presented tumor-activatable and cell-permeable system deems to be an appealing platform to achieve selective tumor imaging and intracellular protein delivery. Its impact is therefore

Effect of Patient Set-up and Respiration motion on Defining Biological Targets for Image-Guided Targeted Radiotherapy

NASA Astrophysics Data System (ADS)

McCall, Keisha C.

Identification and monitoring of sub-tumor targets will be a critical step for optimal design and evaluation of cancer therapies in general and biologically targeted radiotherapy (dose-painting) in particular. Quantitative PET imaging may be an important tool for these applications. Currently radiotherapy planning accounts for tumor motion by applying geometric margins. These margins create a motion envelope to encompass the most probable positions of the tumor, while also maintaining the appropriate tumor control and normal tissue complication probabilities. This motion envelope is effective for uniform dose prescriptions where the therapeutic dose is conformed to the external margins of the tumor. However, much research is needed to establish the equivalent margins for non-uniform fields, where multiple biological targets are present and each target is prescribed its own dose level. Additionally, the size of the biological targets and close proximity make it impractical to apply planning margins on the sub-tumor level. Also, the extent of high dose regions must be limited to avoid excessive dose to the surrounding tissue. As such, this research project is an investigation of the uncertainty within quantitative PET images of moving and displaced dose-painting targets, and an investigation of the residual errors that remain after motion management. This included characterization of the changes in PET voxel-values as objects are moved relative to the discrete sampling interval of PET imaging systems (SPECIFIC AIM 1). Additionally, the repeatability of PET distributions and the delineating dose-painting targets were measured (SPECIFIC AIM 2). The effect of imaging uncertainty on the dose distributions designed using these images (SPECIFIC AIM 3) has also been investigated. This project also included analysis of methods to minimize motion during PET imaging and reduce the dosimetric impact of motion/position-induced imaging uncertainty (SPECIFIC AIM 4).

Clearance and Biodistribution of Liposomally Encapsulated Nitroxides: A Model for Targeted Delivery of Electron Paramagnetic Resonance Imaging Probes to Tumors

PubMed Central

Burks, Scott R.; Legenzov, Eric A.; Rosen, Gerald M.

2011-01-01

Electron paramagnetic resonance (EPR) imaging using nitroxides as molecular probes is potentially a powerful tool for the detection and physiological characterization of micrometastatic lesions. Encapsulating nitroxides in anti-HER2 immunoliposomes at high concentrations to take advantage of the “self-quenching” phenomenon of nitroxides allows generation of robust EPR signals in HER2-overexpressing breast tumor cells with minimal background from indifferent tissues or circulating liposomes. We investigated the in vivo pharmacological properties of nitroxides encapsulated in sterically stabilized liposomes designed for long circulation times. We show that circulation times of nitroxides can be extended from hours to days; this increases the proportion of liposomes in circulation to enhance tumor targeting. Furthermore, nitroxides encapsulated in sterically stabilized anti-HER2 immunoliposomes can be delivered to HER2-overexpressing tumors at micromolar concentrations, which should be imageable by EPR. Lastly, after in vivo administration, liposomally encapsulated nitroxide signal also appears in the liver, spleen, and kidneys. Although these organs are spatially distinct and would not hinder tumor imaging in our model, understanding nitroxide signal retention in these organs is essential for further improvements in EPR imaging contrast between tumors and other tissues. These results lay the foundation to use liposomally delivered nitroxides and EPR imaging to visualize tumor cells in vivo. PMID:21737567

M13 phage-functionalized single-walled carbon nanotubes as nanoprobes for second near-infrared window fluorescence imaging of targeted tumors.

PubMed

Yi, Hyunjung; Ghosh, Debadyuti; Ham, Moon-Ho; Qi, Jifa; Barone, Paul W; Strano, Michael S; Belcher, Angela M

2012-03-14

Second near-infrared (NIR) window light (950-1400 nm) is attractive for in vivo fluorescence imaging due to its deep penetration depth in tissues and low tissue autofluorescence. Here we show genetically engineered multifunctional M13 phage can assemble fluorescent single-walled carbon nanotubes (SWNTs) and ligands for targeted fluorescence imaging of tumors. M13-SWNT probe is detectable in deep tissues even at a low dosage of 2 μg/mL and up to 2.5 cm in tissue-like phantoms. Moreover, targeted probes show specific and up to 4-fold improved uptake in prostate specific membrane antigen positive prostate tumors compared to control nontargeted probes. This M13 phage-based second NIR window fluorescence imaging probe has great potential for specific detection and therapy monitoring of hard-to-detect areas. © 2012 American Chemical Society

Folate and Heptamethine Cyanine Modified Chitosan-Based Nanotheranostics for Tumor Targeted Near-Infrared Fluorescence Imaging and Photodynamic Therapy.

PubMed

Zhang, Yingying; Lv, Tingting; Zhang, Huijuan; Xie, Xiaodong; Li, Ziying; Chen, Haijun; Gao, Yu

2017-07-10

Folate (FA) and heptamethine cyanine (Cy7)-modified chitosan (CF7) was synthesized by click chemistry and its self-assembled nanoparticles (CF7Ns) were developed for tumor-specific imaging and photodynamic therapy. The characterization spectrum confirmed CF7 had a good FA and Cy7 conjugation efficacy. The diameter of CF7Ns measured by DLS was about 291.6 nm, and the morphology observed with AFM showed filamentous clusters of particles. The results of targeting ability of CF7Ns demonstrated enhanced targeting behaviors of CF7Ns compared with non-FA-modified nanoparticles C7Ns in FA receptor-positive HeLa cells. The cytotoxicity and cell apoptosis assay showed that CF7Ns under near-infrared light irradiation led to more apoptotic cell death in HeLa cells to improve the therapeutic efficacy. The mechanisms of the photodynamic effects of CF7Ns were demonstrated through measurement of intracellular reactive oxygen species and the apoptosis-related cytokines. These results suggested that CF7Ns are promising tumor targeting carriers for simultaneous fluorescence imaging and photodynamic therapy.

PET imaging of tumor angiogenesis in mice with VEGF-A targeted 86Y-CHX-A″-DTPA-bevacizumab

PubMed Central

Nayak, Tapan K.; Garmestani, Kayhan; Baidoo, Kwamena E.; Milenic, Diane E.; Brechbiel, Martin W.

2010-01-01

Bevacizumab is a humanized monoclonal antibody that binds to tumor-secreted VEGF-A and inhibits tumor angiogenesis. In 2004, the antibody was approved by the United States FDA for the treatment of metastatic colorectal carcinoma in combination with chemotherapy. This report describes the preclinical evaluation of a radioimmunoconjugate, 86Y-CHX-A″-DTPA-bevacizumab, for potential use in PET imaging of VEGF-A tumor angiogenesis and as a surrogate marker for 90Y based radioimmunotherapy. Bevacizumab was conjugated to CHX-A″-DTPA and radiolabeled with 86Y. In vivo biodistribution and PET imaging studies were performed on mice bearing VEGF-A secreting human colorectal (LS-174T), human ovarian (SKOV-3) and VEGF-A negative human mesothelioma (MSTO-211H) xenografts. Biodistribution and PET imaging studies demonstrated high specific tumor uptake of the radioimmunoconjugate. In mice bearing VEGF-A secreting LS-174T, SKOV-3 and VEGF-A negative MSTO-211H tumors, the tumor uptake at 3 d post-injection (p.i) was 13.6 ± 1.5, 17.4 ± 1.7 and 6.8 ± 0.7 % ID/g, respectively. The corresponding tumor uptake in mice co-injected with 0.05 mg cold bevacizumab were 5.8 ± 1.3, 8.9 ± 1.9 and 7.4 ± 1.0 % ID/g, respectively at the same time point, demonstrating specific blockage of the target in VEGF-A secreting tumors. The LS-174T and SKOV3 tumors were clearly visualized by PET imaging after injecting 1.8–2.0 MBq 86Y-CHX-A″-DTPA-bevacizumab. Organ uptake quantified by PET closely correlated (r2=0.87, p=0.64, n=18) to values determined by biodistribution studies. This preclinical study demonstrates the potential of the radioimmunoconjugate, 86Y-CHX-A″-DTPA-bevacizumab, for non-invasive assessment of the VEGF-A tumor angiogenesis status and as a surrogate marker for 90Y-CHX-A″-DTPA-bevacizumab radioimmunotherapy. PMID:20473899

Photoacoustic imaging of hepatocellular carcinoma targeting gold nanoshells (Conference Presentation)

NASA Astrophysics Data System (ADS)

Zhou, Quan; Chen, Yan; Li, Zhao; Zhou, Juan; Duan, Xiyu; Wang, Thomas D.

2017-02-01

Plasmonic gold nanoshell (GNS) probe penetrates into tumors for deep imaging, enables superior photoacoustic contrast. Glypican-3 (GPC3) specific peptide (Kd = 71 nM) conjugated gold nanoshell (λabs=770nm) was used to detect HCC xenograft tumors in mice with photoacoustic imaging. This targeting probe demonstrated tumor uptake after 1 hr and cleared in 12 hrs. Images at a mean (±SD) depth of 9.7±1.4 mm from 0 to 2.1 cm beneath the skin revealed increased PA signal from tumors. Highest tumor uptake and tumor to normal tissue ratio occurred at 2 hrs post injection (T/B = 4.45±0.22, n = 8). Molecular targeting GNS showed potential as a simple, effective and rapid technique for noninvasive in vivo monitoring HCC tumor growth and GPC3 expression.

VEGFR2-Targeted Ultrasound Imaging Agent Enhances the Detection of Ovarian Tumors at Early Stage in Laying Hens, a Preclinical Model of Spontaneous Ovarian Cancer.

PubMed

Barua, Animesh; Yellapa, Aparna; Bahr, Janice M; Machado, Sergio A; Bitterman, Pincas; Basu, Sanjib; Sharma, Sameer; Abramowicz, Jacques S

2015-07-01

Tumor-associated neoangiogenesis (TAN) is an early event in ovarian cancer (OVCA) development. Increased expression of vascular endothelial growth factor receptor 2 (VEGFR2) by TAN vessels presents a potential target for early detection by ultrasound imaging. The goal of this study was to examine the suitability of VEGFR2-targeted ultrasound contrast agents in detecting spontaneous OVCA in laying hens. Effects of VEGFR2-targeted contrast agents in enhancing the intensity of ultrasound imaging from spontaneous ovarian tumors in hens were examined in a cross-sectional study. Enhancement in the intensity of ultrasound imaging was determined before and after injection of VEGFR2-targeted contrast agents. All ultrasound images were digitally stored and analyzed off-line. Following scanning, ovarian tissues were collected and processed for histology and detection of VEGFR2-expressing microvessels. Enhancement in visualization of ovarian morphology was detected by gray-scale imaging following injection of VEGFR2-targeted contrast agents. Compared with pre-contrast, contrast imaging enhanced the intensities of ultrasound imaging significantly (p < 0.0001) irrespective of the pathological status of ovaries. In contrast to normal hens, the intensity of ultrasound imaging was significantly (p < 0.0001) higher in hens with early stage OVCA and increased further in hens with late stage OVCA. Higher intensities of ultrasound imaging in hens with OVCA were positively correlated with increased (p < 0.0001) frequencies of VEGFR2-expressing microvessels. The results of this study suggest that VEGFR2-targeted contrast agents enhance the visualization of spontaneous ovarian tumors in hens at early and late stages of OVCA. The laying hen may be a suitable model to test new imaging agents and develop targeted therapeutics. © The Author(s) 2014.

Ratiometric spectral imaging for fast tumor detection and chemotherapy monitoring in vivo

PubMed Central

Hwang, Jae Youn; Gross, Zeev; Gray, Harry B.; Medina-Kauwe, Lali K.; Farkas, Daniel L.

2011-01-01

We report a novel in vivo spectral imaging approach to cancer detection and chemotherapy assessment. We describe and characterize a ratiometric spectral imaging and analysis method and evaluate its performance for tumor detection and delineation by quantitatively monitoring the specific accumulation of targeted gallium corrole (HerGa) into HER2-positive (HER2 +) breast tumors. HerGa temporal accumulation in nude mice bearing HER2 + breast tumors was monitored comparatively by a. this new ratiometric imaging and analysis method; b. established (reflectance and fluorescence) spectral imaging; c. more commonly used fluorescence intensity imaging. We also tested the feasibility of HerGa imaging in vivo using the ratiometric spectral imaging method for tumor detection and delineation. Our results show that the new method not only provides better quantitative information than typical spectral imaging, but also better specificity than standard fluorescence intensity imaging, thus allowing enhanced in vivo outlining of tumors and dynamic, quantitative monitoring of targeted chemotherapy agent accumulation into them. PMID:21721808

Effective Integration of Targeted Tumor Imaging and Therapy Using Functionalized InP QDs with VEGFR2 Monoclonal Antibody and miR-92a Inhibitor.

PubMed

Wu, Yi-Zhou; Sun, Jie; Zhang, Yaqin; Pu, Maomao; Zhang, Gen; He, Nongyue; Zeng, Xin

2017-04-19

Rapid diagnosis and targeted drug treatment require agents that possess multiple functions. Nanomaterials that facilitate optical imaging and direct drug delivery have shown great promise for effective cancer treatment. In this study, we first modified near-infrared fluorescent indium phosphide quantum dots (InP QDs) with a vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody to afford targeted drug delivery function. Then, a miR-92a inhibitor, an antisense microRNA that enhances the expression of tumor suppressor p63, was attached to the VEGFR2-InP QDs via electrostatic interactions. The functionalized InP nanocomposite (IMAN) selectively targets tumor sites and allows for infrared imaging in vivo. We further explored the mechanism of this active targeting. The IMAN was endocytosed and delivered in the form of microvesicles via VEGFR2-CD63 signaling. Moreover, the IMAN induced apoptosis of human myelogenous leukemia cells through the p63 pathway in vitro and in vivo. These results indicate that the IMAN may provide a new and promising chemotherapy strategy against cancer cells, particularly by its active targeting function and utility in noninvasive three-dimensional tumor imaging.

Phosphatidylserine-targeted liposome for enhanced glioma-selective imaging.

PubMed

Zhang, Liang; Habib, Amyn A; Zhao, Dawen

2016-06-21

Phosphatidylserine (PS), which is normally intracellular, becomes exposed on the outer surface of viable endothelial cells (ECs) of tumor vasculature. Utilizing a PS-targeting antibody, we have recently established a PS-targeted liposomal (PS-L) nanoplatform that has demonstrated to be highly tumor-selective. Because of the vascular lumen-exposed PS that is immediately accessible without a need to penetrate the intact blood brain barrier (BBB), we hypothesize that the systemically administered PS-L binds specifically to tumor vascular ECs, becomes subsequently internalized into the cells and then enables its cargos to be efficiently delivered to glioma parenchyma. To test this, we exploited the dual MRI/optical imaging contrast agents-loaded PS-L and injected it intravenously into mice bearing intracranial U87 glioma. At 24 h, both in vivo optical imaging and MRI depicted enhanced tumor contrast, distinct from the surrounding normal brain. Intriguingly, longitudinal MRI revealed temporal and spatial intratumoral distribution of the PS-L by following MRI contrast changes, which appeared punctate in tumor periphery at an earlier time point (4 h), but became clustering and disseminated throughout the tumor at 24 h post injection. Importantly, glioma-targeting specificity of the PS-L was antigen specific, since a control probe of irrelevant specificity showed minimal accumulation in the glioma. Together, these results indicate that the PS-L nanoplatform enables the enhanced, glioma-targeted delivery of imaging contrast agents by crossing the tumor BBB efficiently, which may also serve as a useful nanoplatform for anti-glioma drugs.

Clickable and imageable multiblock polymer micelles with magnetically guided and PEG-switched targeting and release property for precise tumor theranosis.

PubMed

Wei, Jing; Shuai, Xiaoyu; Wang, Rui; He, Xueling; Li, Yiwen; Ding, Mingming; Li, Jiehua; Tan, Hong; Fu, Qiang

2017-11-01

Targeted delivery of therapeutics and diagnostics using nanotechnology holds great promise to minimize the side effects of conventional chemotherapy and enable specific and real-time detection of diseases. To realize this goal, we report a clickable and imageable nanovehicle assembled from multiblock polyurethanes (MPUs). The soft segments of the polymers are based on detachable poly(ethylene glycol) (PEG) and degradable poly(ε-caprolactone) (PCL), and the hard segments are constructed from lysine- and cystine-derivatives bearing reduction-responsive disulfide linkages and click-active alkynyl moieties, allowing for post-conjugation of targeting ligands via a click chemistry. It was found that the cleavage of PEG corona bearing a pH-sensitive benzoic-imine linkage (BPEG) could act as an on-off switch, which is capable of activating the clicked targeting ligands under extracellular acidic condition, followed by triggering the core degradation and payload release within tumor cells. In combination with superparamagnetic iron oxide nanoparticles (SPION) clustered within the micellar core, the MPUs exhibit excellent magnetic resonance imaging (MRI) contrast effects and T 2 relaxation in vitro, as well as magnetically guided MR imaging and multimodal targeting of therapeutics to tumor precisely, leading to significant inhibition of cancer with minimal side effect. This work provides a safe and versatile platform for the further development of smart theranostic systems for potential magnetically-targeted and imaging-guided personalized medicine. Copyright © 2017 Elsevier Ltd. All rights reserved.

Molecular Targeted Viral Nanoparticles as Tools for Imaging Cancer

PubMed Central

Cho, C.F.; Sourabh, S.; Simpson, E.J.; Steinmetz, N.F.; Luyt, L.G.; Lewis, J.D.

2015-01-01

Viral nanoparticles (VNPs) are a novel class of bionanomaterials that harness the natural biocompatibility of viruses for the development of therapeutics, vaccines, and imaging tools. The plant virus, cowpea mosaic virus (CPMV), has been successfully engineered to create novel cancer-targeted imaging agents by incorporating fluorescent dyes, polyethylene glycol (PEG) polymers, and targeting moieties. Using straightforward conjugation strategies, VNPs with high selectivity for cancer-specific molecular targets can be synthesized for in vivo imaging of tumors. Here we describe the synthesis and purification of CPMV-based VNPs, the functionalization of these VNPs using click chemistry, and their use for imaging xenograft tumors in animal models. VNPs decorated with fluorescent dyes, PEG, and targeting ligands can be synthesized in one day, and imaging studies can be performed over hours, days, or weeks, depending on the application. PMID:24243252

Dynamic magnetic resonance imaging assessment of vascular targeting agent effects in rat intracerebral tumor models

PubMed Central

Muldoon, Leslie L.; Gahramanov, Seymur; Li, Xin; Marshall, Deborah J.; Kraemer, Dale F.; Neuwelt, Edward A.

2011-01-01

We used dynamic MRI to evaluate the effects of monoclonal antibodies targeting brain tumor vasculature. Female athymic rats with intracerebral human tumor xenografts were untreated or treated with intetumumab, targeting αV-integrins, or bevacizumab, targeting vascular endothelial growth factor (n = 4–6 per group). Prior to treatment and at 1, 3, and 7 days after treatment, we performed standard MRI to assess tumor volume, dynamic susceptibility-contrast MRI with the blood-pool iron oxide nanoparticle ferumoxytol to evaluate relative cerebral blood volume (rCBV), and dynamic contrast-enhanced MRI to assess tumor vascular permeability. Tumor rCBV increased by 27 ± 13% over 7 days in untreated rats; intetumumab increased tumor rCBV by 65 ± 10%, whereas bevacizumab reduced tumor rCBV by 31 ± 10% at 7 days (P < .001 for group and day). Similarly, intetumumab increased brain tumor vascular permeability compared with controls at 3 and 7 days after treatment, whereas bevacizumab decreased tumor permeability within 24 hours (P = .0004 for group, P = .0081 for day). All tumors grew over the 7-day assessment period, but bevacizumab slowed the increase in tumor volume on MRI. We conclude that the vascular targeting agents intetumumab and bevacizumab had diametrically opposite effects on dynamic MRI of tumor vasculature in rat brain tumor models. Targeting αV-integrins increased tumor vascular permeability and blood volume, whereas bevacizumab decreased both measures. These findings have implications for chemotherapy delivery and antitumor efficacy. PMID:21123368

99mTc-HYNIC-(tricine/EDDA)-FROP peptide for MCF-7 breast tumor targeting and imaging.

PubMed

Ahmadpour, Sajjad; Noaparast, Zohreh; Abedi, Seyed Mohammad; Hosseinimehr, Seyed Jalal

2018-02-19

Breast cancer is the most common malignancy among women in the world. Development of novel tumor-specific radiopharmaceuticals for early breast tumor diagnosis is highly desirable. In this study we developed 99m Tc-HYNIC-(tricine/EDDA)-Lys-FROP peptide with the ability of specific binding to MCF-7 breast tumor. The FROP-1 peptide was conjugated with the bifunctional chelator hydrazinonicotinamide (HYNIC) and labeled with 99m Tc using tricine/EDDA co-ligand. The cellular specific binding of 99m Tc-HYNIC-FROP was evaluated on different cell lines as well as with blocking experiment on MCF-7 (human breast adenocarcinoma). The tumor targeting and imaging of this labeled peptide were performed on MCF-7 tumor bearing mice. Radiochemical purity for 99m Tc-HYNIC-(tricine/EDDA)-FROP was 99% which was determined with ITLC method. This radiolabeled peptide showed high stability in normal saline and serum about 98% which was monitored with HPLC method. In saturation binding experiments, the binding constant (K d ) to MCF-7 cells was determined to be 158 nM. Biodistribution results revealed that the 99m Tc-HYNIC-FROP was mainly exerted from urinary route. The maximum tumor uptake was found after 30 min post injection (p.i.); however maximum tumor/muscle ratio was seen at 15 min p.i. The tumor uptake of this labeled peptide was specific and blocked by co-injection of excess FROP. According to the planar gamma imaging result, tumor was clearly visible due to the tumor uptake of 99m Tc-HYNIC-(tricine/EDDA)-FROP in mouse after 15 min p.i. The 99m Tc-HYNIC-(tricine/EDDA)-FROP is considered a promising probe with high specific binding to MCF-7 breast cancer cells.

Receptor-Targeted Nanoparticles for In Vivo Imaging of Breast Cancer

PubMed Central

Yang, Lily; Peng, Xiang-Hong; Wang, Y. Andrew; Wang, Xiaoxia; Cao, Zehong; Ni, Chunchun; Karna, Prasanthi; Zhang, Xinjian; Wood, William C.; Gao, Xiaohu; Nie, Shuming; Mao, Hui

2009-01-01

Purpose Cell surface receptor-targeted magnetic iron oxide (IO) nanoparticles provide molecular magnetic resonance imaging (MRI) contrast agents for improving specificity of the detection of human cancer. Experimental design The present study reports the development of a novel targeted IO nanoparticle using a recombinant peptide containing the amino-terminal fragment (ATF) of urokinase plasminogen activator conjugated to IO nanoparticles (ATF-IO). This nanoparticle targets urokinase plasminogen activator receptor (uPAR), which is overexpressed in breast cancer tissues. Results ATF-IO nanoparticles are able to specifically bind to and be internalized by uPAR-expressing tumor cells. Systemic delivery of ATF-IO nanoparticles into mice bearing subcutaneous and intraperitoneal mammary tumors leads to the accumulation of the particles in tumors, generating a strong MRI contrast detectable by a clinical MRI scanner at a field strength of 3 Tesla. Target specificity of ATF-IO nanoparticles demonstrated by in vivo MRI is further confirmed by near infrared (NIR) fluorescence imaging of the mammary tumors using NIR dye-labeled ATF peptides conjugated to IO nanoparticles. Furthermore, mice administered ATF-IO nanoparticles exhibit lower uptake of the particles in the liver and spleen compared to those receiving non-targeted IO nanoparticles. Conclusions Our results suggest that uPAR-targeted ATF-IO nanoparticles have potential as molecularly-targeted, dual modality imaging agents for in vivo imaging of breast cancer. PMID:19584158

PIRATE: pediatric imaging response assessment and targeting environment

NASA Astrophysics Data System (ADS)

Glenn, Russell; Zhang, Yong; Krasin, Matthew; Hua, Chiaho

2010-02-01

By combining the strengths of various imaging modalities, the multimodality imaging approach has potential to improve tumor staging, delineation of tumor boundaries, chemo-radiotherapy regime design, and treatment response assessment in cancer management. To address the urgent needs for efficient tools to analyze large-scale clinical trial data, we have developed an integrated multimodality, functional and anatomical imaging analysis software package for target definition and therapy response assessment in pediatric radiotherapy (RT) patients. Our software provides quantitative tools for automated image segmentation, region-of-interest (ROI) histogram analysis, spatial volume-of-interest (VOI) analysis, and voxel-wise correlation across modalities. To demonstrate the clinical applicability of this software, histogram analyses were performed on baseline and follow-up 18F-fluorodeoxyglucose (18F-FDG) PET images of nine patients with rhabdomyosarcoma enrolled in an institutional clinical trial at St. Jude Children's Research Hospital. In addition, we combined 18F-FDG PET, dynamic-contrast-enhanced (DCE) MR, and anatomical MR data to visualize the heterogeneity in tumor pathophysiology with the ultimate goal of adaptive targeting of regions with high tumor burden. Our software is able to simultaneously analyze multimodality images across multiple time points, which could greatly speed up the analysis of large-scale clinical trial data and validation of potential imaging biomarkers.

PEGylated Peptide-Based Imaging Agents for Targeted Molecular Imaging.

PubMed

Wu, Huizi; Huang, Jiaguo

2016-01-01

Molecular imaging is able to directly visualize targets and characterize cellular pathways with a high signal/background ratio, which requires a sufficient amount of agents to uptake and accumulate in the imaging area. The design and development of peptide based agents for imaging and diagnosis as a hot and promising research topic that is booming in the field of molecular imaging. To date, selected peptides have been increasingly developed as agents by coupling with different imaging moieties (such as radiometals and fluorophore) with the help of sophisticated chemical techniques. Although a few successes have been achieved, most of them have failed mainly caused by their fast renal clearance and therefore low tumor uptakes, which may limit the effectively tumor retention effect. Besides, several peptide agents based on nanoparticles have also been developed for medical diagnostics. However, a great majority of those agents shown long circulation times and accumulation over time into the reticuloendothelial system (RES; including spleen, liver, lymph nodes and bone marrow) after systematic administration, such long-term severe accumulation probably results in the possible likelihood of toxicity and potentially induces health hazards. Recently reported design criteria have been proposed not only to enhance binding affinity in tumor region with long retention, but also to improve clearance from the body in a reasonable amount of time. PEGylation has been considered as one of the most successful modification methods to prolong tumor retention and improve the pharmacokinetic and pharmacodynamic properties for peptide-based imaging agents. This review summarizes an overview of PEGylated peptides imaging agents based on different imaging moieties including radioisotopes, fluorophores, and nanoparticles. The unique concepts and applications of various PEGylated peptide-based imaging agents are introduced for each of several imaging moieties. Effects of PEGylation on

A novel Tc-99 m and fluorescence labeled peptide as a multimodal imaging agent for targeting angiogenesis in a murine tumor model.

PubMed

Kim, Myoung Hyoun; Kim, Chang Guhn; Kim, Seul-Gi; Kim, Dae-Weung

2016-11-01

The serine-aspartic acid-valine (SDV) peptide binds specifically to integrin α V β 3 . In the present study, we successfully developed a TAMRA-GHEG-ECG-SDV peptide labeled with both Tc-99 m and TAMRA to target the integrin α V β 3 of tumor cells; furthermore, we evaluated the diagnostic performance of Tc-99 m TAMRA-GHEG-ECG-SDV as a dual-modality imaging agent for tumor of the murine model. TAMRA-GHEG-ECG-SDV was synthesized using Fmoc solid-phase peptide synthesis. Radiolabeling of TAMRA-GHEG-ECG-SDV with Tc-99 m was done using ligand exchange methods. Labeling stability and cytotoxicity studies were performed. Gamma camera imaging, biodistribution and ex vivo imaging studies were performed in murine models with HT-1080 and HT-29 tumors. A tumor tissue slide was prepared and analyzed using confocal microscopy. After radiolabeling procedures with Tc-99 m, the Tc-99 m TAMRA-GHEG-ECG-SDV complexes were prepared in high yield (>99%). In the gamma camera imaging study, a substantial uptake of Tc-99 m TAMRA-GHEG-ECG-SDV into HT-1080 tumor (integrin α V β 3 positive) and low uptake of Tc-99 m TAMRA-GHEG-ECG-SDV into HT-29 tumor (integrin α V β 3 negative) were demonstrated. A competition study revealed that HT-1080 tumor uptake was effectively blocked by the co-injection of an excess concentration of SDV. Specific uptake of Tc-99 m TAMRA-GHEG-ECG-SDV was confirmed by biodistribution, ex vivo imaging and confocal microscopy studies. Our in vivo and in vitro studies revealed substantial uptake of Tc-99 m TAMRA-GHEG-ECG-SDV in the integrin α V β 3 -positive tumor. Tc-99 m TAMRA-GHEG-ECG-SDV could be a good candidate for a dual-modality imaging agent targeting tumor angiogenesis. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Imaging a moving lung tumor with megavoltage cone beam computed tomography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gayou, Olivier, E-mail: ogayou@wpahs.org; Colonias, Athanasios

2015-05-15

Purpose: Respiratory motion may affect the accuracy of image guidance of radiation treatment of lung cancer. A cone beam computed tomography (CBCT) image spans several breathing cycles, resulting in a blurred object with a theoretical size equal to the sum of tumor size and breathing motion. However, several factors may affect this theoretical relationship. The objective of this study was to analyze the effect of tumor motion on megavoltage (MV)-CBCT images, by comparing target sizes on simulation and pretreatment images of a large cohort of lung cancer patients. Methods: Ninety-three MV-CBCT images from 17 patients were analyzed. Internal target volumesmore » were contoured on each MV-CBCT dataset [internal target volume (ITV{sub CB})]. Their extent in each dimension was compared to that of two volumes contoured on simulation 4-dimensional computed tomography (4D-CT) images: the combination of the tumor contours of each phase of the 4D-CT (ITV{sub 4D}) and the volume contoured on the average CT calculated from the 4D-CT phases (ITV{sub ave}). Tumor size and breathing amplitude were assessed by contouring the tumor on each CBCT raw projection where it could be unambiguously identified. The effect of breathing amplitude on the quality of the MV-CBCT image reconstruction was analyzed. Results: The mean differences between the sizes of ITV{sub CB} and ITV{sub 4D} were −1.6 ± 3.3 mm (p < 0.001), −2.4 ± 3.1 mm (p < 0.001), and −7.2 ± 5.3 mm (p < 0.001) in the anterior/posterior (AP), left/right (LR), and superior/inferior (SI) directions, respectively, showing that MV-CBCT underestimates the full target size. The corresponding mean differences between ITV{sub CB} and ITV{sub ave} were 0.3 ± 2.6 mm (p = 0.307), 0.0 ± 2.4 mm (p = 0.86), and −4.0 ± 4.3 mm (p < 0.001), indicating that the average CT image is more representative of what is visible on MV-CBCT in the AP and LR directions. In the SI directions, differences between ITV{sub CB} and ITV{sub ave

Imaging Metastasis Using an Integrin-Targeting Chain-Shaped Nanoparticle

PubMed Central

Peiris, Pubudu M.; Toy, Randall; Doolittle, Elizabeth; Pansky, Jenna; Abramowski, Aaron; Tam, Morgan; Vicente, Peter; Tran, Emily; Hayden, Elliott; Camann, Andrew; Mayer, Aaron; Erokwu, Bernadette O.; Berman, Zachary; Wilson, David; Baskaran, Harihara; Flask, Chris A.; Keri, Ruth A.; Karathanasis, Efstathios

2012-01-01

While the enhanced permeability and retention effect may promote the preferential accumulation of nanoparticles into well-vascularized primary tumors, it is ineffective in the case of metastases hidden within a large population of normal cells. Due to their small size, high dispersion to organs, and low vascularization, metastatic tumors are less accessible to targeted nanoparticles. To tackle these challenges, we designed a nanoparticle for vascular targeting based on an αvβ3 integrin-targeted nanochain particle composed of four iron oxide nanospheres chemically linked in a linear assembly. The chain-shaped nanoparticles enabled enhanced ‘sensing’ of the tumor-associated remodeling of the vascular bed offering increased likelihood of specific recognition of metastatic tumors. Compared to spherical nanoparticles, the chain-shaped nanoparticles resulted in superior targeting of αvβ3 integrin due to geometrically enhanced multivalent docking. We performed multimodal in vivo imaging (Fluorescence Molecular Tomography and Magnetic Resonance Imaging) in a non-invasive and quantitative manner, which showed that the nanoparticles targeted metastases in the liver and lungs with high specificity in a highly aggressive breast tumor model in mice. PMID:23005348

Estimation of error in maximal intensity projection-based internal target volume of lung tumors: a simulation and comparison study using dynamic magnetic resonance imaging.

PubMed

Cai, Jing; Read, Paul W; Baisden, Joseph M; Larner, James M; Benedict, Stanley H; Sheng, Ke

2007-11-01

To evaluate the error in four-dimensional computed tomography (4D-CT) maximal intensity projection (MIP)-based lung tumor internal target volume determination using a simulation method based on dynamic magnetic resonance imaging (dMRI). Eight healthy volunteers and six lung tumor patients underwent a 5-min MRI scan in the sagittal plane to acquire dynamic images of lung motion. A MATLAB program was written to generate re-sorted dMRI using 4D-CT acquisition methods (RedCAM) by segmenting and rebinning the MRI scans. The maximal intensity projection images were generated from RedCAM and dMRI, and the errors in the MIP-based internal target area (ITA) from RedCAM (epsilon), compared with those from dMRI, were determined and correlated with the subjects' respiratory variability (nu). Maximal intensity projection-based ITAs from RedCAM were comparatively smaller than those from dMRI in both phantom studies (epsilon = -21.64% +/- 8.23%) and lung tumor patient studies (epsilon = -20.31% +/- 11.36%). The errors in MIP-based ITA from RedCAM correlated linearly (epsilon = -5.13nu - 6.71, r(2) = 0.76) with the subjects' respiratory variability. Because of the low temporal resolution and retrospective re-sorting, 4D-CT might not accurately depict the excursion of a moving tumor. Using a 4D-CT MIP image to define the internal target volume might therefore cause underdosing and an increased risk of subsequent treatment failure. Patient-specific respiratory variability might also be a useful predictor of the 4D-CT-induced error in MIP-based internal target volume determination.

Optical and nuclear imaging of glioblastoma with phosphatidylserine-targeted nanovesicles.

PubMed

Blanco, Víctor M; Chu, Zhengtao; LaSance, Kathleen; Gray, Brian D; Pak, Koon Yan; Rider, Therese; Greis, Kenneth D; Qi, Xiaoyang

2016-05-31

Multimodal tumor imaging with targeted nanoparticles potentially offers both enhanced specificity and sensitivity, leading to more precise cancer diagnosis and monitoring. We describe the synthesis and characterization of phenol-substituted, lipophilic orange and far-red fluorescent dyes and a simple radioiodination procedure to generate a dual (optical and nuclear) imaging probe. MALDI-ToF analyses revealed high iodination efficiency of the lipophilic reporters, achieved by electrophilic aromatic substitution using the chloramide 1,3,4,6-tetrachloro-3α,6α-diphenyl glycoluril (Iodogen) as the oxidizing agent in an organic/aqueous co-solvent mixture. Upon conjugation of iodine-127 or iodine-124-labeled reporters to tumor-targeting SapC-DOPS nanovesicles, optical (fluorescent) and PET imaging was performed in mice bearing intracranial glioblastomas. In addition, tumor vs non-tumor (normal brain) uptake was compared using iodine-125. These data provide proof-of-principle for the potential value of SapC-DOPS for multimodal imaging of glioblastoma, the most aggressive primary brain tumor.

Interrogating Tumor Metabolism and Tumor Microenvironments Using Molecular Positron Emission Tomography Imaging. Theranostic Approaches to Improve Therapeutics

PubMed Central

Jacobson, Orit

2013-01-01

Positron emission tomography (PET) is a noninvasive molecular imaging technology that is becoming increasingly important for the measurement of physiologic, biochemical, and pharmacological functions at cellular and molecular levels in patients with cancer. Formation, development, and aggressiveness of tumor involve a number of molecular pathways, including intrinsic tumor cell mutations and extrinsic interaction between tumor cells and the microenvironment. Currently, evaluation of these processes is mainly through biopsy, which is invasive and limited to the site of biopsy. Ongoing research on specific target molecules of the tumor and its microenvironment for PET imaging is showing great potential. To date, the use of PET for diagnosing local recurrence and metastatic sites of various cancers and evaluation of treatment response is mainly based on [18F]fluorodeoxyglucose ([18F]FDG), which measures glucose metabolism. However, [18F]FDG is not a target-specific PET tracer and does not give enough insight into tumor biology and/or its vulnerability to potential treatments. Hence, there is an increasing need for the development of selective biologic radiotracers that will yield specific biochemical information and allow for noninvasive molecular imaging. The possibility of cancer-associated targets for imaging will provide the opportunity to use PET for diagnosis and therapy response monitoring (theranostics) and thus personalized medicine. This article will focus on the review of non-[18F]FDG PET tracers for specific tumor biology processes and their preclinical and clinical applications. PMID:24064460

Targeting the tumor microenvironment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kenny, P.A.; Lee, G.Y.; Bissell, M.J.

2006-11-07

Despite some notable successes cancer remains, for the most part, a seemingly intractable problem. There is, however, a growing appreciation that targeting the tumor epithelium in isolation is not sufficient as there is an intricate mutually sustaining synergy between the tumor epithelial cells and their surrounding stroma. As the details of this dialogue emerge, new therapeutic targets have been proposed. The FDA has already approved drugs targeting microenvironmental components such as VEGF and aromatase and many more agents are in the pipeline. In this article, we describe some of the 'druggable' targets and processes within the tumor microenvironment and reviewmore » the approaches being taken to disrupt these interactions.« less

Molecular imaging of tumor blood vessels in prostate cancer.

PubMed

Tilki, Derya; Seitz, Michael; Singer, Bernhard B; Irmak, Ster; Stief, Christian G; Reich, Oliver; Ergün, Süleyman

2009-05-01

In the past three decades many efforts have been undertaken to understand the mechanisms of tumor angiogenesis. The introduction of anti-angiogenic drugs in tumor therapy during the last few years necessitates the establishment of new techniques enabling molecular imaging of tumor vascular remodelling. The determination of tumor size as commonly used is not appropriate since the extended necrosis under anti-angiogenic therapy does not necessarily result in the reduction of tumor diameter. The basis for the molecular imaging of tumor blood vessels is the remodelling of the tumor vessels under anti-angiogenic therapy which obviously occurs at an early stage and seems to be a convincing parameter. Beside the enormous progress in this field during the last few years the resolution is still not high enough to evaluate the remodelling of the micro tumor vessels. New imaging approaches combining specific molecular markers for tumor vessels with the different imaging techniques are needed to overcome this issue as exemplarily discussed for prostate cancer in this review. Molecular contrast agents targeting the vasculature will allow clinicians the visualization of vascular remodelling processes taking place under anti-angiogenic therapy and improve tumor diagnosis and follow-up.

Interleukin 16- (IL-16-) Targeted Ultrasound Imaging Agent Improves Detection of Ovarian Tumors in Laying Hens, a Preclinical Model of Spontaneous Ovarian Cancer.

PubMed

Barua, Animesh; Yellapa, Aparna; Bahr, Janice M; Adur, Malavika K; Utterback, Chet W; Bitterman, Pincas; Basu, Sanjib; Sharma, Sameer; Abramowicz, Jacques S

2015-01-01

Limited resolution of transvaginal ultrasound (TVUS) scanning is a significant barrier to early detection of ovarian cancer (OVCA). Contrast agents have been suggested to improve the resolution of TVUS scanning. Emerging evidence suggests that expression of interleukin 16 (IL-16) by the tumor epithelium and microvessels increases in association with OVCA development and offers a potential target for early OVCA detection. The goal of this study was to examine the feasibility of IL-16-targeted contrast agents in enhancing the intensity of ultrasound imaging from ovarian tumors in hens, a model of spontaneous OVCA. Contrast agents were developed by conjugating biotinylated anti-IL-16 antibodies with streptavidin coated microbubbles. Enhancement of ultrasound signal intensity was determined before and after injection of contrast agents. Following scanning, ovarian tissues were processed for the detection of IL-16 expressing cells and microvessels. Compared with precontrast, contrast imaging enhanced ultrasound signal intensity significantly in OVCA hens at early (P < 0.05) and late stages (P < 0.001). Higher intensities of ultrasound signals in OVCA hens were associated with increased frequencies of IL-16 expressing cells and microvessels. These results suggest that IL-16-targeted contrast agents improve the visualization of ovarian tumors. The laying hen may be a suitable model to test new imaging agents and develop targeted anti-OVCA therapeutics.

A pretargeting system for tumor PET imaging and radioimmunotherapy

PubMed Central

Kraeber-Bodéré, Françoise; Rousseau, Caroline; Bodet-Milin, Caroline; Frampas, Eric; Faivre-Chauvet, Alain; Rauscher, Aurore; Sharkey, Robert M.; Goldenberg, David M.; Chatal, Jean-François; Barbet, Jacques

2015-01-01

Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy. It was assumed that directly-radiolabled antibodies could be replaced by an unlabeled immunoconjugate capable of binding both a tumor-specific antigen and a small molecular weight molecule. The small molecular weight molecule would carry the radioactive payload and would be injected after the bispecific immunoconjugate. It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios. It was subsequently shown that pretargeting also held promise for tumor therapy, translating improved tumor-to-normal tissue contrast ratios into more specific delivery of absorbed radiation doses. Many technical approaches have been proposed to implement pretargeting, and two have been extensively documented. One is based on the avidin-biotin system, and the other on bispecific antibodies binding a tumor-specific antigen and a hapten. Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency. This article reviews the historical and recent preclinical and clinical advances in the use of bispecific-antibody-based pretargeting for radioimmunodetection and radioimmunotherapy of cancer. The results of recent evaluation of pretargeting in PET imaging also are discussed. PMID:25873896

Estimation of Error in Maximal Intensity Projection-Based Internal Target Volume of Lung Tumors: A Simulation and Comparison Study Using Dynamic Magnetic Resonance Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cai Jing; Read, Paul W.; Baisden, Joseph M.

Purpose: To evaluate the error in four-dimensional computed tomography (4D-CT) maximal intensity projection (MIP)-based lung tumor internal target volume determination using a simulation method based on dynamic magnetic resonance imaging (dMRI). Methods and Materials: Eight healthy volunteers and six lung tumor patients underwent a 5-min MRI scan in the sagittal plane to acquire dynamic images of lung motion. A MATLAB program was written to generate re-sorted dMRI using 4D-CT acquisition methods (RedCAM) by segmenting and rebinning the MRI scans. The maximal intensity projection images were generated from RedCAM and dMRI, and the errors in the MIP-based internal target area (ITA)more » from RedCAM ({epsilon}), compared with those from dMRI, were determined and correlated with the subjects' respiratory variability ({nu}). Results: Maximal intensity projection-based ITAs from RedCAM were comparatively smaller than those from dMRI in both phantom studies ({epsilon} = -21.64% {+-} 8.23%) and lung tumor patient studies ({epsilon} = -20.31% {+-} 11.36%). The errors in MIP-based ITA from RedCAM correlated linearly ({epsilon} = -5.13{nu} - 6.71, r{sup 2} = 0.76) with the subjects' respiratory variability. Conclusions: Because of the low temporal resolution and retrospective re-sorting, 4D-CT might not accurately depict the excursion of a moving tumor. Using a 4D-CT MIP image to define the internal target volume might therefore cause underdosing and an increased risk of subsequent treatment failure. Patient-specific respiratory variability might also be a useful predictor of the 4D-CT-induced error in MIP-based internal target volume determination.« less

Bioresponsive and fluorescent hyaluronic acid-iodixanol nanogels for targeted X-ray computed tomography imaging and chemotherapy of breast tumors.

PubMed

Zhu, Yaqin; Wang, Xiuxiu; Chen, Jing; Zhang, Jian; Meng, Fenghua; Deng, Chao; Cheng, Ru; Feijen, Jan; Zhong, Zhiyuan

2016-12-28

Nanotheranostics is a rapidly growing field combining disease diagnosis and therapy, which ultimately may add in the development of 'personalized medicine'. Here, we designed and developed bioresponsive and fluorescent hyaluronic acid-iodixanol nanogels (HAI-NGs) for targeted X-ray computed tomography (CT) imaging and chemotherapy of MCF-7 human breast tumors. HAI-NGs were obtained with a small size of ca. 90nm, bright green fluoresence and high serum stability from hyaluronic acid-cystamine-tetrazole and reductively degradable polyiodixanol-methacrylate via nanoprecipitation and a photo-click crosslinking reaction. Notably, paclitaxel (PTX)-loaded HAI-NGs showed a fast glutathione-responsive drug release. Confocal microscopy displayed efficient uptake of HAI-NGs by CD44 overexpressing MCF-7 cells via a receptor-mediated mechanism. MTT assays revealed that HAI-NGs were nontoxic to MCF-7 cells even at a high concentration of 1mg/mL whereas PTX-loaded HAI-NGs exhibited strong inhibition of MCF-7 cells. The in vivo pharmcokinetics, near-infrared imaging and biodistribution studies revealed that HAI-NGs significantly prolonged the blood circulation time and enhanced tumor accumulation of PTX. Interestingly, significantly enhanced CT imaging was observed for MCF-7 breast tumors in nude mice via either intratumoral or intravenous injection of HAI-NGs as compared to iodixanol. HAI-NGs fluoresence was distributed thoughout the whole tumor indicating deep tumor penetration. PTX-loaded HAI-NGs showed effective suppression of tumor growth with little systemic toxicity. HAI-NGs appear as a "smart" theranostic nanoplatform for the treatment of CD44 positive tumors. Copyright © 2016 Elsevier B.V. All rights reserved.

Synthesis of tumor necrosis factor α for use as a mirror-image phage display target.

PubMed

Petersen, Mark E; Jacobsen, Michael T; Kay, Michael S

2016-06-21

Tumor Necrosis Factor alpha (TNFα) is an inflammatory cytokine that plays a central role in the pathogenesis of chronic inflammatory disease. Here we describe the chemical synthesis of l-TNFα along with the mirror-image d-protein for use as a phage display target. The synthetic strategy utilized native chemical ligation and desulfurization to unite three peptide segments, followed by oxidative folding to assemble the 52 kDa homotrimeric protein. This synthesis represents the foundational step for discovering an inhibitory d-peptide with the potential to improve current anti-TNFα therapeutic strategies.

Oligo-branched peptides for tumor targeting: from magic bullets to magic forks.

PubMed

Falciani, Chiara; Pini, Alessandro; Bracci, Luisa

2009-02-01

Selective targeting of tumor cells is the final goal of research and drug discovery for cancer diagnosis, imaging and therapy. After the invention of hybridoma technology, the concept of magic bullet was introduced into the field of oncology, referring to selective killing of tumor cells, by specific antibodies. More recently, small molecules and peptides have also been proposed as selective targeting agents. We analyze the state of the art of tumor-selective agents that are presently available and tested in clinical settings. A novel approach based on 'armed' oligo-branched peptides as tumor targeting agents, is discussed and compared with existing tumor-selective therapies mediated by antibodies, small molecules or monomeric peptides. Oligo-branched peptides could be novel drugs that combine the advantages of antibodies and small molecules.

Comparative assessment of a 99mTc labeled H1299.2-HYNIC peptide bearing two different co-ligands for tumor-targeted imaging.

PubMed

Torabizadeh, Seyedeh Atekeh; Abedi, Seyed Mohammad; Noaparast, Zohreh; Hosseinimehr, Seyed Jalal

2017-05-01

Peptides are a class of targeting agents that bind to cancer-specific cell surfaces. Since they specifically target cancer cells, they could be used as molecular imaging tools. In this study, the 15-mer peptide Ac-H1299.2 (YAAWPASGAWTGTAP) was conjugated with HYNIC via lysine amino acid on C-terminus and labeled with 99m Tc using tricine and EDDA/tricine as the co-ligands. These radiotracers were evaluated for potential utilization in diagnostic imaging of ovarian cancer cells (SKOV-3). The cell-specificity of these radiolabeled peptides was determined based on their binding on an ovarian cancer cell line (SKOV-3), and displaying a low affinity for lung adenocarcinoma cell line (A549) and breast cancer cell line (MCF7). Biodistribution studies were conducted in normal mice as well as in nude mice bearing SKOV-3 ovarian cancer xenografts. HYNIC-peptide was labeled with 99m Tc with more than 99% efficiency and showed high stability in buffer and serum. We observed nanomolar binding affinities for both radiolabeled peptides. The tumor uptakes were 3.27%±0.46% and 1.55%±0.20% for tricine and 2.34±1.1% and 1.09%±0.18% for EDDA/tricine at 1 and 4h after injection, respectively. A higher tumor to background ratio and lower radioactivity in the blood were observed for EDDA/tricine co-ligands, leading to clear tumor visualization in imaging with injection of this peptide. This new 99m Tc-labeled peptide selectively targeted ovarian cancer and introduction of a (EDDA/tricine) as a co-ligand improved the pharmacokinetics of 99m Tc-labeled H1299.2 for tumor imaging in animals. Copyright © 2017 Elsevier Ltd. All rights reserved.

Improved tumor identification using dual tracer molecular imaging in fluorescence guided brain surgery

NASA Astrophysics Data System (ADS)

Xu, Xiaochun; Torres, Veronica; Straus, David; Brey, Eric M.; Byrne, Richard W.; Tichauer, Kenneth M.

2015-03-01

Brain tumors represent a leading cause of cancer death for people under the age of 40 and the probability complete surgical resection of brain tumors remains low owing to the invasive nature of these tumors and the consequences of damaging healthy brain tissue. Molecular imaging is an emerging approach that has the potential to improve the ability for surgeons to correctly discriminate between healthy and cancerous tissue; however, conventional molecular imaging approaches in brain suffer from significant background signal in healthy tissue or an inability target more invasive sections of the tumor. This work presents initial studies investigating the ability of novel dual-tracer molecular imaging strategies to be used to overcome the major limitations of conventional "single-tracer" molecular imaging. The approach is evaluated in simulations and in an in vivo mice study with animals inoculated orthotopically using fluorescent human glioma cells. An epidermal growth factor receptor (EGFR) targeted Affibody-fluorescent marker was employed as a targeted imaging agent, and the suitability of various FDA approved untargeted fluorescent tracers (e.g. fluorescein & indocyanine green) were evaluated in terms of their ability to account for nonspecific uptake and retention of the targeted imaging agent. Signal-to-background ratio was used to measure and compare the amount of reporter in the tissue between targeted and untargeted tracer. The initial findings suggest that FDA-approved fluorescent imaging agents are ill-suited to act as untargeted imaging agents for dual-tracer fluorescent guided brain surgery as they suffer from poor delivery to the healthy brain tissue and therefore cannot be used to identify nonspecific vs. specific uptake of the targeted imaging agent where current surgery is most limited.

An intelligent re-shieldable targeting system for enhanced tumor accumulation.

PubMed

Hu, Zhenpeng; Ma, Jinlong; Fu, Fei; Cui, Chen; Li, Xiaomin; Wang, Xinyu; Wang, Wei; Wan, Yeda; Yuan, Zhi

2017-12-28

Programmed ligand targeting strategy promotes the blood circulation stability of nanoparticles by shielding the ligand. However, the irreversible shielding causes the deshielded nanoparticles to be easily recognized and cleared by the reticuloendothelial system (RES), impeding their further retention in the tumor. Here, we for the first time prove the superiority of the intelligent re-shieldable targeting system that is based on the pH-responsive self-assembly/disassembly of gold nanoparticles. The system can enhance the stability of gold nanoparticles in the blood circulation (2.6-fold at 24h), reduce uptake by the RES (35% lower) and improve tumor accumulation (41% higher by analysis of gold content in tumor) effectively compared with the conventional irreversible system. Furthermore, preliminary study indicates that the system could be applied as computed tomography contrast agent in tumor imaging. The in vivo validity of the intelligent re-shieldable targeting system provides inspiration for the design of nanomaterials for cancer diagnosis and treatment. Copyright © 2017. Published by Elsevier B.V.

Preferential tumor cellular uptake and retention of indocyanine green for in vivo tumor imaging.

PubMed

Onda, Nobuhiko; Kimura, Masayuki; Yoshida, Toshinori; Shibutani, Makoto

2016-08-01

Indocyanine green (ICG) is a fluorescent agent approved for clinical applications by the Food and Drug Administration and European Medicines Agency. This study examined the mechanism of tumor imaging using intravenously administered ICG. The in vivo kinetics of intravenously administered ICG were determined in tumor xenografts using microscopic approaches that enabled both spatio-temporal and high-magnification analyses. The mechanism of ICG-based tumor imaging was examined at the cellular level in six phenotypically different human colon cancer cell lines exhibiting different grades of epithelioid organization. ICG fluorescence imaging detected xenograft tumors, even those < 1 mm in size, based on their preferential cellular uptake and retention of the dye following its rapid tissue-non-specific delivery, in contrast to its rapid clearance by normal tissue. Live-cell imaging revealed that cellular ICG uptake is temperature-dependent and occurs after ICG binding to the cellular membrane, a pattern suggesting endocytic uptake as the mechanism. Cellular ICG uptake correlated inversely with the formation of tight junctions. Intracellular ICG was entrapped in the membrane traffic system, resulting in its slow turnover and prolonged retention by tumor cells. Our results suggest that tumor-specific imaging by ICG involves non-specific delivery of the dye to tissues followed by preferential tumor cellular uptake and retention. The tumor cell-preference of ICG is driven by passive tumor cell-targeting, the inherent ability of ICG to bind to cell membranes, and the high endocytic activity of tumor cells in association with the disruption of their tight junctions. © 2016 UICC.

Molecular Imaging of Tumors Using a Quantitative T1 Mapping Technique via Magnetic Resonance Imaging

PubMed Central

Herrmann, Kelsey; Johansen, Mette L.; Craig, Sonya E.; Vincent, Jason; Howell, Michael; Gao, Ying; Lu, Lan; Erokwu, Bernadette; Agnes, Richard S.; Lu, Zheng-Rong; Pokorski, Jonathan K.; Basilion, James; Gulani, Vikas; Griswold, Mark; Flask, Chris; Brady-Kalnay, Susann M.

2015-01-01

Magnetic resonance imaging (MRI) of glioblastoma multiforme (GBM) with molecular imaging agents would allow for the specific localization of brain tumors. Prior studies using T1-weighted MR imaging demonstrated that the SBK2-Tris-(Gd-DOTA)3 molecular imaging agent labeled heterotopic xenograft models of brain tumors more intensely than non-specific contrast agents using conventional T1-weighted imaging techniques. In this study, we used a dynamic quantitative T1 mapping strategy to more objectively compare intra-tumoral retention of the SBK2-Tris-(Gd-DOTA)3 agent over time in comparison to non-targeted control agents. Our results demonstrate that the targeted SBK2-Tris-(Gd-DOTA)3 agent, a scrambled-Tris-(Gd-DOTA)3 control agent, and the non-specific clinical contrast agent Optimark™ all enhanced flank tumors of human glioma cells with similar maximal changes on T1 mapping. However, the retention of the agents differs. The non-specific agents show significant recovery within 20 min by an increase in T1 while the specific agent SBK2-Tris-(Gd-DOTA)3 is retained in the tumors and shows little recovery over 60 min. The retention effect is demonstrated by percent change in T1 values and slope calculations as well as by calculations of gadolinium concentration in tumor compared to muscle. Quantitative T1 mapping demonstrates the superior binding and retention in tumors of the SBK2-Tris-(Gd-DOTA)3 agent over time compared to the non-specific contrast agent currently in clinical use. PMID:26435847

Fluorescence Imaging/Agents in Tumor Resection.

PubMed

Stummer, Walter; Suero Molina, Eric

2017-10-01

Intraoperative fluorescence imaging allows real-time identification of diseased tissue during surgery without being influenced by brain shift and surgery interruption. 5-Aminolevulinic acid, useful for malignant gliomas and other tumors, is the most broadly explored compound approved for fluorescence-guided resection. Intravenous fluorescein sodium has recently received attention, highlighting tumor tissue based on extravasation at the blood-brain barrier (defective in many brain tumors). Fluorescein in perfused brain, unselective extravasation in brain perturbed by surgery, and propagation with edema are concerns. Fluorescein is not approved but targeted fluorochromes with affinity to brain tumor cells, in development, may offer future advantages. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Developing Targeted Hybrid Imaging Probes by Chelator Scaffolding

PubMed Central

2017-01-01

Positron emission tomography (PET) as well as optical imaging (OI) with peptide receptor targeting probes have proven their value for oncological applications but also show restrictions depending on the clinical field of interest. Therefore, the combination of both methods, particularly in a single molecule, could improve versatility in clinical routine. This proof of principle study aims to show that a chelator, Fusarinine C (FSC), can be utilized as scaffold for novel dimeric dual-modality imaging agents. Two targeting vectors (a minigastrin analogue (MG11) targeting cholecystokinin-2 receptor overexpression (CCK2R) or integrin αVβ3 targeting cyclic pentapeptides (RGD)) and a near-infrared fluorophore (Sulfo-Cyanine7) were conjugated to FSC. The probes were efficiently labeled with gallium-68 and in vitro experiments including determination of logD, stability, protein binding, cell binding, internalization, and biodistribution studies as well as in vivo micro-PET/CT and optical imaging in U-87MG αVβ3- and A431-CCK2R expressing tumor xenografted mice were carried out. Novel bioconjugates showed high receptor affinity and highly specific targeting properties at both receptors. Ex vivo biodistribution and micro-PET/CT imaging studies revealed specific tumor uptake accompanied by slow blood clearance and retention in nontargeted tissues (spleen, liver, and kidneys) leading to visualization of tumors at early (30 to 120 min p.i.). Excellent contrast in corresponding optical imaging studies was achieved especially at delayed time points (24 to 72 h p.i.). Our findings show the proof of principle of chelator scaffolding for hybrid imaging agents and demonstrate FSC being a suitable bifunctional chelator for this approach. Improvements to fine-tune pharmacokinetics are needed to translate this into a clinical setting. PMID:28462989

Preclinical evaluation of a novel cyanine dye for tumor imaging with in vivo photoacoustic imaging.

PubMed

Temma, Takashi; Onoe, Satoru; Kanazaki, Kengo; Ono, Masahiro; Saji, Hideo

2014-09-01

Photoacoustic imaging (PA imaging or PAI) has shown great promise in the detection and monitoring of cancer. Although nanocarrier-based contrast agents have been studied for use in PAI, small molecule contrast agents are required due to their ease of preparation, costeffectiveness, and low toxicity. Here, we evaluated the usefulness of a novel cyanine dye IC7-1-Bu as a PAI contrast agent without conjugated targeting moieties for in vivo tumor imaging in a mice model. Basic PA characteristics of IC7-1-Bu were compared with indocyanine green (ICG), a Food and Drug Administration approved dye, in an aqueous solution. We evaluated the tumor accumulation profile of IC7-1-Bu and ICG by in vivo fluorescence imaging. In vivo PAI was then performed with a photoacoustic tomography system 24 and 48 h after intravenous injection of IC7-1-Bu into tumor bearing mice. IC7-1-Bu showed about a 2.3-fold higher PA signal in aqueous solution compared with that of ICG. Unlike ICG, IC7-1-Bu showed high tumor fluorescence after intravenous injection. In vivo PAI provided a tumor to background PA signal ratio of approximately 2.5 after intravenous injection of IC7-1-Bu. These results indicate that IC7-1-Bu is a promising PAI contrast agent for cancer imaging without conjugation of targeting moieties.

A Functional Iron Oxide Nanoparticles Modified with PLA-PEG-DG as Tumor-Targeted MRI Contrast Agent.

PubMed

Xiong, Fei; Hu, Ke; Yu, Haoli; Zhou, Lijun; Song, Lina; Zhang, Yu; Shan, Xiuhong; Liu, Jianping; Gu, Ning

2017-08-01

Tumor targeting could greatly promote the performance of magnetic nanomaterials as MRI (Magnetic Resonance Imaging) agent for tumor diagnosis. Herein, we reported a novel magnetic nanoparticle modified with PLA (poly lactic acid)-PEG (polyethylene glycol)-DG (D-glucosamine) as Tumor-targeted MRI Contrast Agent. In this work, we took use of the D-glucose passive targeting on tumor cells, combining it on PLA-PEG through amide reaction, and then wrapped the PLA-PEG-DG up to the Fe 3 O 4 @OA NPs. The stability and anti phagocytosis of Fe 3 O 4 @OA@PLA-PEG-DG was tested in vitro; the MRI efficiency and toxicity was also detected in vivo. These functional magnetic nanoparticles demonstrated good biocompatibility and stability both in vitro and in vivo. Cell experiments showed that Fe 3 O 4 @OA@PLA-PEG-DG nanoparticles exist good anti phagocytosis and high targetability. In vivo MRI images showed that the contrast effect of Fe 3 O 4 @OA@PLA-PEG-DG nanoparticles prevailed over the commercial non tumor-targeting magnetic nanomaterials MRI agent at a relatively low dose. The DG can validly enhance the tumor-targetting effect of Fe 3 O 4 @OA@PLA-PEG nanoparticle. Maybe MRI agents with DG can hold promise as tumor-targetting development in the future.

Tumor cell membrane-targeting pH-dependent electron donor-acceptor fluorescence systems with low background signals.

PubMed

Han, Liang; Liu, Mingming; Ye, Deyong; Zhang, Ning; Lim, Ed; Lu, Jing; Jiang, Chen

2014-03-01

Minimizing the background signal is crucial for developing tumor-imaging techniques with sufficient specificity and sensitivity. Here we use pH difference between healthy tissues and tumor and tumor targeting delivery to achieve this goal. We synthesize fluorophore-dopamine conjugate as pH-dependent electron donor-acceptor fluorescence system. Fluorophores are highly sensitive to electron-transfer processes, which can alter their optical properties. The intrinsic redox properties of dopamine are oxidation of hydroquinone to quinone at basic pH and reduction of quinone to hydroquinone at acidic pH. Quinone can accept electron then quench fluorescence. We design tumor cell membrane-targeting carrier for delivery. We demonstrate quenched fluorophore-quinone can be specially transferred to tumor extracellular environment and tumor-accumulated fluorophore can be activated by acidic pH. These tumor-targeting pH-dependent electron donor-acceptor fluorescence systems may offer new opportunity for developing tumor-imaging techniques. Copyright © 2014 Elsevier Ltd. All rights reserved.

Comparison of Kinetic Models for Dual-Tracer Receptor Concentration Imaging in Tumors

PubMed Central

Hamzei, Nazanin; Samkoe, Kimberley S; Elliott, Jonathan T; Holt, Robert W; Gunn, Jason R; Hasan, Tayyaba; Pogue, Brian W; Tichauer, Kenneth M

2014-01-01

Molecular differences between cancerous and healthy tissue have become key targets for novel therapeutics specific to tumor receptors. However, cancer cell receptor expression can vary within and amongst different tumors, making strategies that can quantify receptor concentration in vivo critical for the progression of targeted therapies. Recently a dual-tracer imaging approach capable of providing quantitative measures of receptor concentration in vivo was developed. It relies on the simultaneous injection and imaging of receptor-targeted tracer and an untargeted tracer (to account for non-specific uptake of the targeted tracer). Early implementations of this approach have been structured on existing “reference tissue” imaging methods that have not been optimized for or validated in dual-tracer imaging. Using simulations and mouse tumor model experimental data, the salient findings in this study were that all widely used reference tissue kinetic models can be used for dual-tracer imaging, with the linearized simplified reference tissue model offering a good balance of accuracy and computational efficiency. Moreover, an alternate version of the full two-compartment reference tissue model can be employed accurately by assuming that the K1s of the targeted and untargeted tracers are similar to avoid assuming an instantaneous equilibrium between bound and free states (made by all other models). PMID:25414912

In vivo imaging of tumor vascular endothelial cells

NASA Astrophysics Data System (ADS)

Zhao, Dawen; Stafford, Jason H.; Zhou, Heling; Thorpe, Philip E.

2013-02-01

Phosphatidylserine (PS), normally restricted to the inner leaflet of the plasma membrane, becomes exposed on the outer surface of viable (non-apoptotic) endothelial cells in tumor blood vessels, probably in response to oxidative stresses present in the tumor microenvironment. In the present study, we optically imaged exposed PS on tumor vasculature in vivo using PGN635, a novel human monoclonal antibody that targets PS. PGN635 F(ab')2 was labeled with the near infrared (NIR) dye, IRDye 800CW. Human glioma U87 cells or breast cancer MDA-MB-231 cells were implanted subcutaneously or orthotopically into nude mice. When the tumors reached ~5 mm in diameter, 800CW- PGN635 was injected via a tail vein and in vivo dynamic NIR imaging was performed. For U87 gliomas, NIR imaging allowed clear detection of tumors as early as 4 h later, which improved over time to give a maximal tumor/normal ratio (TNR = 2.9 +/- 0.5) 24 h later. Similar results were observed for orthotopic MDA-MB-231 breast tumors. Localization of 800CW-PGN635 to tumors was antigen specific since 800CW-Aurexis, a control probe of irrelevant specificity, did not localize to the tumors, and pre-administration of unlabeled PGN635 blocked the uptake of 800CW-PGN635. Fluorescence microscopy confirmed that 800CW-PGN635 was binding to PS-positive tumor vascular endothelium. Our studies suggest that tumor vasculature can be successfully imaged in vivo to provide sensitive tumor detection.

Styrene-maleic acid-copolymer conjugated zinc protoporphyrin as a candidate drug for tumor-targeted therapy and imaging.

PubMed

Fang, Jun; Tsukigawa, Kenji; Liao, Long; Yin, Hongzhuan; Eguchi, Kanami; Maeda, Hiroshi

2016-01-01

Previous studies indicated the potential of zinc protoporphyrin (ZnPP) as an antitumor agent targeting to the tumor survival factor heme oxygenase-1, and/or for photodynamic therapy (PDT). In this study, to achieve tumor-targeted delivery, styrene-maleic acid-copolymer conjugated ZnPP (SMA-ZnPP) was synthesized via amide bond, which showed good water solubility, having ZnPP loading of 15%. More importantly, it forms micelles in aqueous solution with a mean particle size of 111.6 nm, whereas it has an apparent Mw of 65 kDa. This micelle formation was not detracted by serum albumin, suggesting it is stable in circulation. Further SMA-ZnPP conjugate will behave as an albumin complex in blood with much larger size (235 kDa) by virtue of the albumin binding property of SMA. Consequently, SMA-ZnPP conjugate exhibited prolonged circulating retention and preferential tumor accumulation by taking advantage of enhanced permeability and retention (EPR) effect. Clear tumor imaging was thus achieved by detecting the fluorescence of ZnPP. In addition, the cytotoxicity and PDT effect of SMA-ZnPP conjugate was confirmed in human cervical cancer HeLa cells. Light irradiation remarkably increased the cytotoxicity (IC50, from 33 to 5 μM). These findings may provide new options and knowledge for developing ZnPP based anticancer theranostic drugs.

Dual-Targeting Lactoferrin-Conjugated Polymerized Magnetic Polydiacetylene-Assembled Nanocarriers with Self-Responsive Fluorescence/Magnetic Resonance Imaging for In Vivo Brain Tumor Therapy.

PubMed

Fang, Jen-Hung; Chiu, Tsung-Lang; Huang, Wei-Chen; Lai, Yen-Ho; Hu, Shang-Hsiu; Chen, You-Yin; Chen, San-Yuan

2016-03-01

Maintaining a high concentration of therapeutic agents in the brain is difficult due to the restrictions of the blood-brain barrier (BBB) and rapid removal from blood circulation. To enable controlled drug release and enhance the blood-brain barrier (BBB)-crossing efficiency for brain tumor therapy, a new dual-targeting magnetic polydiacetylene nanocarriers (PDNCs) delivery system modified with lactoferrin (Lf) is developed. The PDNCs are synthesized using the ultraviolet (UV) cross-linkable 10,12-pentacosadiynoic acid (PCDA) monomers through spontaneous assembling onto the surface of superparamagnetic iron oxide (SPIO) nanoparticles to form micelles-polymerized structures. The results demonstrate that PDNCs will reduce the drug leakage and further control the drug release, and display self-responsive fluorescence upon intracellular uptake for cell trafficking and imaging-guided tumor treatment. The magnetic Lf-modified PDNCs with magnetic resonance imaging (MRI) and dual-targeting ability can enhance the transportation of the PDNCs across the BBB for tracking and targeting gliomas. An enhanced therapeutic efficiency can be obtained using Lf-Cur (Curcumin)-PDNCs by improving the retention time of the encapsulated Cur and producing fourfold higher Cur amounts in the brain compared to free Cur. Animal studies also confirm that Lf targeting and controlled release act synergistically to significantly suppress tumors in orthotopic brain-bearing rats. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Toward real-time tumor margin identification in image-guided robotic brain tumor resection

NASA Astrophysics Data System (ADS)

Hu, Danying; Jiang, Yang; Belykh, Evgenii; Gong, Yuanzheng; Preul, Mark C.; Hannaford, Blake; Seibel, Eric J.

2017-03-01

For patients with malignant brain tumors (glioblastomas), a safe maximal resection of tumor is critical for an increased survival rate. However, complete resection of the cancer is hard to achieve due to the invasive nature of these tumors, where the margins of the tumors become blurred from frank tumor to more normal brain tissue, but in which single cells or clusters of malignant cells may have invaded. Recent developments in fluorescence imaging techniques have shown great potential for improved surgical outcomes by providing surgeons intraoperative contrast-enhanced visual information of tumor in neurosurgery. The current near-infrared (NIR) fluorophores, such as indocyanine green (ICG), cyanine5.5 (Cy5.5), 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX), are showing clinical potential to be useful in targeting and guiding resections of such tumors. Real-time tumor margin identification in NIR imaging could be helpful to both surgeons and patients by reducing the operation time and space required by other imaging modalities such as intraoperative MRI, and has the potential to integrate with robotically assisted surgery. In this paper, a segmentation method based on the Chan-Vese model was developed for identifying the tumor boundaries in an ex-vivo mouse brain from relatively noisy fluorescence images acquired by a multimodal scanning fiber endoscope (mmSFE). Tumor contours were achieved iteratively by minimizing an energy function formed by a level set function and the segmentation model. Quantitative segmentation metrics based on tumor-to-background (T/B) ratio were evaluated. Results demonstrated feasibility in detecting the brain tumor margins at quasi-real-time and has the potential to yield improved precision brain tumor resection techniques or even robotic interventions in the future.

Magnetic Resonance Imaging of Tumor Associated Macrophages: Clinical Translation.

PubMed

Aghighi, Maryam; Theruvath, Ashok Joseph; Pareek, Anuj; Pisani, Laura; Alford, Raphael; Muehe, Anne Monika; Sethi, Tarsheen K; Holdsworth, Samantha J; Hazard, Florette K; Gratzinger, Dita; Luna-Fineman, Sandra; Advani, Ranjana H; Spunt, Sheri L; Daldrup-Link, Heike E

2018-05-15

Tumor associated macrophages (TAM) in malignant tumors have been linked to tumor aggressiveness and represent a new target for cancer immunotherapy. As new TAM-targeted immunotherapies are entering clinical trials, it is important to detect and quantify TAM with non-invasive imaging techniques. The purpose of this study was to determine if ferumoxytol-enhanced MRI can detect TAM in lymphomas and bone sarcomas of pediatric patients and young adults. In a first-in-patient , IRB-approved prospective clinical trial, 25 pediatric and young adult patients with lymphoma or bone sarcoma underwent ferumoxytol-enhanced MRI. To confirm ferumoxytol enhancement, five pilot patients (2 lymphoma, 3 bone sarcoma) underwent pre- and post-contrast MRI. Subsequently, 20 patients (10 lymphoma, 10 bone sarcoma) underwent ferumoxytol-enhanced MRI 24-48 hours after intravenous injection, followed by tumor biopsy/resection and macrophage staining. To determine if ferumoxytol-MRI can differentiate tumors with different TAM content, we compared T2* relaxation times of lymphomas and bone sarcomas. Tumor T2* values of 20 patients were correlated with CD68+ and CD163+ TAM quantities on histopathology. Significant ferumoxytol tumor enhancement was noted on post-contrast scans compared to pre-contrast scans ( P = 0.036). Bone sarcomas and lymphomas demonstrated significantly different MRI enhancement and TAM density ( P < 0.05). Within each tumor group, T2* signal enhancement on MR images correlated significantly with the density of CD68+ and CD163+ TAM ( P < 0.05). Ferumoxytol-enhanced MRI is immediately clinically applicable and could be used to stratify patients with TAM-rich tumors to immune-targeted therapies and to monitor tumor response to these therapies. Copyright ©2018, American Association for Cancer Research.

PET Imaging of 64Cu-DOTA-scFv-Anti-PSMA Lipid Nanoparticles (LNPs): Enhanced Tumor Targeting over Anti-PSMA scFv or Untargeted LNPs

PubMed Central

Wong, Patty; Li, Lin; Chea, Junie; Delgado, Melissa K.; Crow, Desiree; Poku, Erasmus; Szpikowska, Barbara; Bowles, Nicole; Channappa, Divya; Colcher, David; Wong, Jeffrey Y.C.; Shively, John E.; Yazaki, Paul J.

2017-01-01

Introduction Single chain (scFv) antibodies are ideal targeting ligands due to their modular structure, high antigen specificity and affinity. These monovalent ligands display rapid tumor targeting but have limitations due to their fast urinary clearance. Methods An anti-prostate membrane antigen (PSMA) scFv with a site-specific cysteine was expressed and evaluated in a prostate cancer xenograft model by Cu-64 PET imaging. To enhance tumor accumulation, the scFv-cys was conjugated to the co-polymer DSPE-PEG-maleimide that spontaneously assembled into a homogeneous multivalent lipid nanoparticle (LNP). Results The targeted LNP exhibited a 2-fold increase in tumor uptake compared to the scFv alone using two different thiol ester chemistries. The anti-PSMA scFv-LNP exhibited a 1.6 fold increase in tumor targeting over the untargeted LNP. Conclusions The targeted anti-PSMA scFv-LNP showed enhanced tumor accumulation over the scFv alone or the untargeted DOTA-micelle providing evidence for the development of this system for drug delivery. Advances in Knowledge and implications for patient care Anti-tumor scFv antibody fragments have not achieved their therapeutic potential due to their fast blood clearance. Conjugation to a LNP enables multivalency to the tumor antigen as well as increased molecular size for chemotherapy drug delivery. PMID:28126683

Multimodal imaging guided preclinical trials of vascular targeting in prostate cancer

PubMed Central

Kalmuk, James; Folaron, Margaret; Buchinger, Julian; Pili, Roberto; Seshadri, Mukund

2015-01-01

The high mortality rate associated with castration-resistant prostate cancer (CRPC) underscores the need for improving therapeutic options for this patient population. The purpose of this study was to examine the potential of vascular targeting in prostate cancer. Experimental studies were carried out in subcutaneous and orthotopic Myc-CaP prostate tumors implanted into male FVB mice to examine the efficacy of a novel microtubule targeted vascular disrupting agent (VDA), EPC2407 (Crolibulin™). A non-invasive multimodality imaging approach based on magnetic resonance imaging (MRI), bioluminescence imaging (BLI), and ultrasound (US) was utilized to guide preclinical trial design and monitor tumor response to therapy. Imaging results were correlated with histopathologic assessment, tumor growth and survival analysis. Contrast-enhanced MRI revealed potent antivascular activity of EPC2407 against subcutaneous and orthotopic Myc-CaP tumors. Longitudinal BLI of Myc-CaP tumors expressing luciferase under the androgen response element (Myc-CaP/ARE-luc) revealed changes in AR signaling and reduction in intratumoral delivery of luciferin substrate following castration suggestive of reduced blood flow. This reduction in blood flow was validated by US and MRI. Combination treatment resulted in sustained vascular suppression, inhibition of tumor regrowth and conferred a survival benefit in both models. These results demonstrate the therapeutic potential of vascular targeting in combination with androgen deprivation against prostate cancer. PMID:26203773

Theranostic Unimolecular Micelles Based on Brush-Shaped Amphiphilic Block Copolymers for Tumor-Targeted Drug Delivery and Positron Emission Tomography Imaging

PubMed Central

2015-01-01

Brush-shaped amphiphilic block copolymers were conjugated with a monoclonal antibody against CD105 (i.e., TRC105) and a macrocyclic chelator for 64Cu-labeling to generate multifunctional theranostic unimolecular micelles. The backbone of the brush-shaped amphiphilic block copolymer was poly(2-hydroxyethyl methacrylate) (PHEMA) and the side chains were poly(l-lactide)-poly(ethylene glycol) (PLLA-PEG). The doxorubicin (DOX)-loaded unimolecular micelles showed a pH-dependent drug release profile and a uniform size distribution. A significantly higher cellular uptake of TRC105-conjugated micelles was observed in CD105-positive human umbilical vein endothelial cells (HUVEC) than nontargeted micelles due to CD105-mediated endocytosis. In contrast, similar and extremely low cellular uptake of both targeted and nontargeted micelles was observed in MCF-7 human breast cancer cells (CD105-negative). The difference between the in vivo tumor accumulation of 64Cu-labeled TRC105-conjugated micelles and that of nontargeted micelles was studied in 4T1 murine breast tumor-bearing mice, by serial positron emission tomography (PET) imaging and validated by biodistribution studies. These multifunctional unimolecular micelles offer pH-responsive drug release, noninvasive PET imaging capability, together with both passive and active tumor-targeting abilities, thus making them a desirable nanoplatform for cancer theranostics. PMID:24628452

Magnetic Gold Nanoparticle-Labeled Heparanase Monoclonal Antibody and its Subsequent Application for Tumor Magnetic Resonance Imaging

NASA Astrophysics Data System (ADS)

Li, Ning; Jie, Meng-Meng; Yang, Min; Tang, Li; Chen, Si-Yuan; Sun, Xue-Mei; Tang, Bo; Yang, Shi-Ming

2018-04-01

Heparanase (HPA) is ubiquitously expressed in various metastatic malignant tumors; previous studies have demonstrated that HPA was a potential tumor-associated antigen (TAA) for tumor immunotherapy. We sought to evaluate the feasibility of HPA as a common TAA for magnetic resonance imaging (MRI) of tumor metastasis and its potential application in tumor molecular imaging. We prepared a targeted probe based on magnetic gold nanoparticles coupled with an anti-HPA antibody for the specific detection of HPA by MRI. The specificity of the targeted probe was validated in vitro by incubation of the probe with various tumor cells, and the probe was able to selectively detect HPA (+) cells. We found the probes displayed significantly reduced signal intensity in several tumor cells, and the signal intensity decreased significantly after the targeted probe was injected in tumor-bearing nude mice. In the study, we demonstrated that the HPA&GoldMag probe had excellent physical and chemical properties and immune activities and could specifically target many tumor cell tissues both in vitro and in vivo. This may provide an experimental base for molecular imaging of tumor highly expressing heparanase using HPA mAbs.

LyP-1 ultrasonic microbubbles targeting to cancer cell as tumor bio-acoustics markers or drug carriers: targeting efficiency evaluation in, microfluidic channels.

PubMed

Li, Xiang; Jin, Qiaofeng; Chen, Tan; Zhang, Baoyue; Zheng, Rongqin; Wang, Zhanhui; Zheng, Hairong

2009-01-01

Using ultrasonic contrast microbubbles as acoustic biomarkers and drug carrier vehicles by conjugating tumor specific antibody to microbubbles has shown great potential in ultrasonic tumor molecular imaging or drug-delivery and therapy. Microbubble probe targeting efficiency is one of the major challenges. In this study, we developed a novel method to evaluate the targeting capability and efficiency of microbubbles to cells, and more specifically, microbubbles binding LyP-1 (a cyclic nonapeptide acid peptide) target to cancer cell within a microfluidic system. The micro cell sieves within the microfludic channels could trap the tumor cells and enhance the microbubble's interaction with the cell. Assisted with the controllable fluid shear stress, the microbubble's targeting to the cell and the corresponding affinity efficiency could be quantitatively evaluated under a florescent microscope. The system provides a useful low-cost high efficient in vitro platform for studying microbubble-cell interaction for ultrasonic tumor molecular imaging or drug-delivery and therapy.

99mTc-D(LPR): A novel retro-inverso peptide for VEGF receptor-1 targeted tumor imaging.

PubMed

Rezazadeh, Farzaneh; Sadeghzadeh, Nourollah; Abedi, Seyed Mohammad; Abediankenari, Saeid

2018-05-31

The aim of this study was to evaluate the ability of D (LPR), a novel retro-inverso peptidomimetic derivative for imaging colon cancer. Two different D (LPR) analogs were designed and compared based on conjugation of HYNIC at peptide's C or N terminal and then labeled with technetium-99m using tricine/EDDA as an exchange coligands. The radiolabeled conjugates were assessed for in vitro stability in saline and serum. The VEGFR-1 and NRP-1 receptors affinity, in vitro internalization and also dissociation Constance was evaluated. SPCET imaging and biodistribution studies were performed in nude mice bearing HT-29 xenograft tumors. Both peptides labeled with technetium-99m in high radiochemical yield (˃97%). Peptide stability studies indicated a high metabolic stability of the radiopeptides in solution and serum. In vitro blocking studies demonstrated specific binding and internalization of [ 99m Tc]Tc-HYNIC-peptides in cultured HUVEC cells. The K d value for 99m Tc-peptide 1 and 99m Tc-peptide 2 were found to be 56.8 ± 12.9 nM and 71.6 ± 17.9 nM respectively. The tumor to muscle ratio was significant at 0.5 and 1 h after injection (4.5 and 4 for 99m Tc-peptide 1 and 4.9 and 4.4 for 99m Tc-peptide 2 at 0.5 and 1 h p.i. respectively). SPECT imaging studies revealed that both radioconjugates had prominent activity accumulation in VEGFR-1 and NRP-1 expressing HT-29 tumors. This study is the first instance of using a radiolabeled retro-inverso peptide for tumor imaging which is a promising tool to improve the performance of fragile peptide probes in vivo as imaging agents and warrant further investigations in other peptide-target systems. Copyright © 2018 Elsevier Inc. All rights reserved.

Polymeric micelles and nanoemulsions as tumor-targeted drug carriers: Insight through intravital imaging.

PubMed

Rapoport, Natalya; Gupta, Roohi; Kim, Yoo-Shin; O'Neill, Brian E

2015-05-28

Intravital imaging of nanoparticle extravasation and tumor accumulation has revealed, for the first time, detailed features of carrier and drug behavior in circulation and tissue that suggest new directions for optimization of drug nanocarriers. Using intravital fluorescent microscopy, the extent of the extravasation, diffusion in the tissue, internalization by tissue cells, and uptake by the RES system were studied for polymeric micelles, nanoemulsions, and nanoemulsion-encapsulated drug. Discrimination of vascular and tissue compartments in the processes of micelle and nanodroplet extravasation and tissue accumulation was possible. A simple 1-D continuum model was suggested that allowed discriminating between various kinetic regimes of nanocarrier (or released drug) internalization in tumors of various sizes and cell density. The extravasation and tumor cell internalization occurred much faster for polymeric micelles than for nanoemulsion droplets. Fast micelle internalization resulted in the formation of a perivascular fluorescent coating around blood vessels. A new mechanism of micelle extravasation and internalization was suggested, based on the fast extravasation and internalization rates of copolymer unimers while maintaining micelle/unimer equilibrium in the circulation. The data suggested that to be therapeutically effective, nanoparticles with high internalization rate should manifest fast diffusion in the tumor tissue in order to avoid generation of concentration gradients that induce drug resistance. However an extra-fast diffusion should be avoided as it may result in the flow of extravasated nanoparticles from the tumor to normal organs, which would compromise targeting efficiency. The extravasation kinetics were different for nanodroplets and nanodroplet-encapsulated drug F-PTX suggesting a premature release of some fraction of the drug from the carrier. In conclusion, the development of an "ideal" drug carrier should involve the optimization of both

Glucosylated polyethylenimine as a tumor-targeting gene carrier.

PubMed

Park, In-Kyu; Cook, Seung-Eun; Kim, You-Kyoung; Kim, Hyun-Woo; Cho, Myung-Haing; Jeong, Hwan-Jeong; Kim, Eun-Mi; Nah, Jae-Woon; Bom, Hee-Seung; Cho, Chong-Su

2005-11-01

Glucosylated polyethylenimine (GPEI) was synthesized as a tumor-targeting gene carrier through facilitative glucose metabolism by tumor glucose transporter. Particle sizes of GPEI/DNA complex increased in proportion to glucose content of GPEI, whereas surface charge of the complex was not dependent on glucosylation, partially due to inefficient shielding of the short hydrophilic group introduced. GPEI with higher glucosylation (36 mol-%) had no cytotoxic effect on cells even at polymer concentrations higher than 200 microg/mL. Compared to unglucosylated PEI, glucosylation induced less than one-order decrease of transfection efficiency. Transfection of GPEI/DNA complex into tumor cells possibly occurred through specific interaction between glucose-related cell receptors and glucose moiety of GPEI. Gamma imaging technique revealed GPEI/DNA complex was distributed in liver, spleen, and tumors.

In vivo tumor-targeted dual-modal fluorescence/CT imaging using a nanoprobe co-loaded with an aggregation-induced emission dye and gold nanoparticles.

PubMed

Zhang, Jimei; Li, Chan; Zhang, Xu; Huo, Shuaidong; Jin, Shubin; An, Fei-Fei; Wang, Xiaodan; Xue, Xiangdong; Okeke, C I; Duan, Guiyun; Guo, Fengguang; Zhang, Xiaohong; Hao, Jifu; Wang, Paul C; Zhang, Jinchao; Liang, Xing-Jie

2015-02-01

As an intensely studied computed tomography (CT) contrast agent, gold nanoparticle has been suggested to be combined with fluorescence imaging modality to offset the low sensitivity of CT. However, the strong quenching of gold nanoparticle on fluorescent dyes requires complicated design and shielding to overcome. Herein, we report a unique nanoprobe (M-NPAPF-Au) co-loading an aggregation-induced emission (AIE) red dye and gold nanoparticles into DSPE-PEG(2000) micelles for dual-modal fluorescence/CT imaging. The nanoprobe was prepared based on a facile method of "one-pot ultrasonic emulsification". Surprisingly, in the micelles system, fluorescence dye (NPAPF) efficiently overcame the strong fluorescence quenching of shielding-free gold nanoparticles and retained the crucial AIE feature. In vivo studies demonstrated the nanoprobe had superior tumor-targeting ability, excellent fluorescence and CT imaging effects. The totality of present studies clearly indicates the significant potential application of M-NPAPF-Au as a dual-modal non-invasive fluorescence/X-ray CT nanoprobe for in vivo tumor-targeted imaging and diagnosis. Copyright © 2014 Elsevier Ltd. All rights reserved.

Ultrasound molecular imaging of ovarian cancer with CA-125 targeted nanobubble contrast agents.

PubMed

Gao, Yong; Hernandez, Christopher; Yuan, Hai-Xia; Lilly, Jacob; Kota, Pavan; Zhou, Haoyan; Wu, Hanping; Exner, Agata A

2017-10-01

Ultrasound is frequently utilized in diagnosis of gynecologic malignancies such as ovarian cancer. Because epithelial ovarian cancer (EOC) is often characterized by overexpression of cancer antigen 125 (CA-125), ultrasound contrast agents able to target this molecular signature could be a promising complementary strategy. In this work, we demonstrate application of CA-125-targeted echogenic lipid and surfactant-stabilized nanobubbles imaged with standard clinical contrast harmonic ultrasound for imaging of CA-125 positive OVCAR-3 tumors in mice. Surface functionalization of the nanobubbles with a CA-125 antibody achieved rapid significantly (P < 0.05) enhanced tumor accumulation, higher peak ultrasound signal intensity and slower wash out rates in OVCAR-3 tumors compared to CA-125 negative SKOV-3 tumors. Targeted nanobubbles also exhibited increased tumor retention and prolonged echogenicity compared to untargeted nanobubbles. Data suggest that ultrasound molecular imaging using CA-125 antibody-conjugated nanobubbles may contribute to improved diagnosis of EOC. Copyright © 2017 Elsevier Inc. All rights reserved.

Synthesis and characterization of theranostic poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymer targeting tumor angiogenesis: tumor localization visualized by positron emission tomography.

PubMed

Yuan, Jianchao; Zhang, Haiyuan; Kaur, Harpreet; Oupicky, David; Peng, Fangyu

2013-05-01

Poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymers were synthesized and characterized for tumor localization in vivo as a theranostic scaffold for cancer imaging and anticancer drug delivery targeting tumor angiogenesis. Tumor localization of the poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymers was visualized in mice bearing human prostate cancer xenografts by positron emission tomography (PET) using a microPET scanner. PET quantitative analysis demonstrated that tumor 64Cu radioactivity (2.75 ± 0.34 %ID/g) in tumor-bearing mice 3 hours following intravenous injection of the poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymers was significantly higher than the tumor 64Cu radioactivity (1.29 ± 0.26 %ID/g) in tumor-bearing mice injected with the nontargeted poly(HPMA)-DOTA-64Cu copolymers (p = .004). The poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymers hold potential as a theranostic scaffold for cancer imaging and radiochemotherapy of prostate cancer targeting tumor angiogenesis by noninvasive tracking with PET.

Molecular imaging-guided photothermal/photodynamic therapy against tumor by iRGD-modified indocyanine green nanoparticles.

PubMed

Yan, Fei; Wu, Hao; Liu, Hongmei; Deng, Zhiting; Liu, Hong; Duan, Wanlu; Liu, Xin; Zheng, Hairong

2016-02-28

Multifunctional near-infrared (NIR) nanoparticles demonstrate great potential in tumor theranostic applications. To achieve the sensitive detection and effective phototherapy in the early stage of tumor genesis, it is highly desirable to improve the targeting of NIR theranostic agents to biomarkers and to enhance their accumulation in tumor. Here we report a novel targeted multifunctional theranostic nanoparticle, internalized RGD (iRGD)-modified indocyanine green (ICG) liposomes (iRGD-ICG-LPs), for molecular imaging-guided photothermal therapy (PTT) and photodynamic therapy (PDT) therapy against breast tumor. The iRGD peptides with high affinity to αvβ3 integrin and effective tumor-internalized property were firstly used to synthesize iRGD-PEG2000-DSPE lipopeptides, which were further utilized to fabricate the targeted ICG liposomes. The results indicated that iRGD-ICG-LPs exhibited excellent stability and could provide an accurate and sensitive detection of breast tumor through NIR fluorescence molecular imaging. We further employed this nanoparticle for tumor theranostic application, demonstrating significantly higher tumor accumulation and tumor inhibition efficacy through PTT/PDT effects. Histological analysis further revealed much more apoptotic cells, confirming the advantageous anti-tumor effect of iRGD-ICG-LPs over non-targeted ICG-LPs. Notably, the targeting therapy mediated by iRGD provides almost equivalent anti-tumor efficacy at a 12.5-fold lower drug dose than that by monoclonal antibody, and no tumor recurrence and obvious treatment-induced toxicity were observed in our study. Our study provides a promising strategy to realize the sensitive detection and effective treatment of tumors by integrating molecular imaging into PTT/PDT therapy. Copyright © 2015. Published by Elsevier B.V.

Dual-Energy CT Imaging of Tumor Liposome Delivery After Gold Nanoparticle-Augmented Radiation Therapy

PubMed Central

Ashton, Jeffrey R.; Castle, Katherine D.; Qi, Yi; Kirsch, David G.; West, Jennifer L.; Badea, Cristian T.

2018-01-01

Gold nanoparticles (AuNPs) are emerging as promising agents for both cancer therapy and computed tomography (CT) imaging. AuNPs absorb x-rays and subsequently release low-energy, short-range photoelectrons during external beam radiation therapy (RT), increasing the local radiation dose. When AuNPs are near tumor vasculature, the additional radiation dose can lead to increased vascular permeability. This work focuses on understanding how tumor vascular permeability is influenced by AuNP-augmented RT, and how this effect can be used to improve the delivery of nanoparticle chemotherapeutics. Methods: Dual-energy CT was used to quantify the accumulation of both liposomal iodine and AuNPs in tumors following AuNP-augmented RT in a mouse model of primary soft tissue sarcoma. Mice were injected with non-targeted AuNPs, RGD-functionalized AuNPs (vascular targeting), or no AuNPs, after which they were treated with varying doses of RT. The mice were injected with either liposomal iodine (for the imaging study) or liposomal doxorubicin (for the treatment study) 24 hours after RT. Increased tumor liposome accumulation was assessed by dual-energy CT (iodine) or by tracking tumor treatment response (doxorubicin). Results: A significant increase in vascular permeability was observed for all groups after 20 Gy RT, for the targeted and non-targeted AuNP groups after 10 Gy RT, and for the vascular-targeted AuNP group after 5 Gy RT. Combining targeted AuNPs with 5 Gy RT and liposomal doxorubicin led to a significant tumor growth delay (tumor doubling time ~ 8 days) compared to AuNP-augmented RT or chemotherapy alone (tumor doubling time ~3-4 days). Conclusions: The addition of vascular-targeted AuNPs significantly improved the treatment effect of liposomal doxorubicin after RT, consistent with the increased liposome accumulation observed in tumors in the imaging study. Using this approach with a liposomal drug delivery system can increase specific tumor delivery of chemotherapeutics

In vivo cation exchange in quantum dots for tumor-specific imaging.

PubMed

Liu, Xiangyou; Braun, Gary B; Qin, Mingde; Ruoslahti, Erkki; Sugahara, Kazuki N

2017-08-24

In vivo tumor imaging with nanoprobes suffers from poor tumor specificity. Here, we introduce a nanosystem, which allows selective background quenching to gain exceptionally tumor-specific signals. The system uses near-infrared quantum dots and a membrane-impermeable etchant, which serves as a cation donor. The etchant rapidly quenches the quantum dots through cation exchange (ionic etching), and facilitates renal clearance of metal ions released from the quantum dots. The quantum dots are intravenously delivered into orthotopic breast and pancreas tumors in mice by using the tumor-penetrating iRGD peptide. Subsequent etching quenches excess quantum dots, leaving a highly tumor-specific signal provided by the intact quantum dots remaining in the extravascular tumor cells and fibroblasts. No toxicity is noted. The system also facilitates the detection of peritoneal tumors with high specificity upon intraperitoneal tumor targeting and selective etching of excess untargeted quantum dots. In vivo cation exchange may be a promising strategy to enhance specificity of tumor imaging.The imaging of tumors in vivo using nanoprobes has been challenging due to the lack of sufficient tumor specificity. Here, the authors develop a tumor-specific quantum dot system that permits in vivo cation exchange to achieve selective background quenching and high tumor-specific imaging.

Dual integrin and gastrin-releasing peptide receptor targeted tumor imaging using 18F-labeled PEGylated RGD-bombesin heterodimer 18F-FB-PEG3-Glu-RGD-BBN.

PubMed

Liu, Zhaofei; Yan, Yongjun; Chin, Frederic T; Wang, Fan; Chen, Xiaoyuan

2009-01-22

Radiolabeled RGD and bombesin peptides have been extensively investigated for tumor integrin alpha(v)beta(3) and GRPR imaging, respectively. Due to the fact that many tumors are both integrin and GRPR positive, we designed and synthesized a heterodimeric peptide Glu-RGD-BBN, which is expected to be advantageous over the monomeric peptides for dual-receptor targeting. A PEG(3) spacer was attached to the glutamate alpha-amino group of Glu-RGD-BBN to enhance the (18)F labeling yield and to improve the in vivo kinetics. PEG(3)-Glu-RGD-BBN possesses the comparable GRPR and integrin alpha(v)beta(3) receptor-binding affinities as the corresponding monomers, respectively. The dual-receptor targeting properties of (18)F-FB-PEG(3)-Glu-RGD-BBN were observed in PC-3 tumor model. (18)F-FB-PEG(3)-Glu-RGD-BBN with high tumor contrast and favorable pharmacokinetics is a promising PET tracer for dual integrin and GRPR positive tumor imaging. This heterodimer strategy may also be an applicable method to develop other molecules with improved in vitro and in vivo characterizations for tumor diagnosis and therapy.

In vivo near-infrared fluorescence imaging of FAP-expressing tumors with activatable FAP-targeted, single-chain Fv-immunoliposomes.

PubMed

Rüger, Ronny; Tansi, Felista L; Rabenhold, Markus; Steiniger, Frank; Kontermann, Roland E; Fahr, Alfred; Hilger, Ingrid

2014-07-28

Molecular and cellular changes that precede the invasive growth of solid tumors include the release of proteolytic enzymes and peptides in the tumor stroma, the recruitment of phagocytic and lymphoid infiltrates and alteration of the extracellular matrix. The reactive tumor stroma consists of a large number of myofibroblasts, characterized by high expression of fibroblast activation protein alpha (FAP). FAP, a type-II transmembrane sialoglycoprotein is an attractive target in diagnosis and therapy of several pathologic disorders especially cancer. In the underlying work, a fluorescence-activatable liposome (fluorescence-quenched during circulation and fluorescence activation upon cellular uptake), bearing specific single-chain Fv fragments directed against FAP (scFv'FAP) was developed, and its potential for use in fluorescence diagnostic imaging of FAP-expressing tumor cells was evaluated by whole body fluorescence imaging. The liposomes termed anti-FAP-IL were prepared via post-insertion of ligand-phospholipid-conjugates into preformed DY-676-COOH-containing liposomes. The anti-FAP-IL revealed a homogeneous size distribution and showed specific interaction and binding with FAP-expressing cells in vitro. The high level of fluorescence quenching of the near-infrared fluorescent dye sequestered in the aqueous interior of the liposomes enables fluorescence imaging exclusively upon uptake and degradation by cells, which results in fluorescence activation. Only FAP-expressing cells were able to take up and activate fluorescence of anti-FAP-IL in vitro. Furthermore, anti-FAP-IL accumulated selectively in FAP-expressing xenograft models in vivo, as demonstrated by blocking experiments using free scFv'FAP. The local tumor fluorescence intensities were in agreement with the intrinsic degree of FAP-expression in different xenograft models. Thus, anti-FAP-IL can serve as a suitable in vivo diagnostic tool for pathological disorders accompanied by high FAP

Radiotherapy planning for glioblastoma based on a tumor growth model: improving target volume delineation.

PubMed

Unkelbach, Jan; Menze, Bjoern H; Konukoglu, Ender; Dittmann, Florian; Le, Matthieu; Ayache, Nicholas; Shih, Helen A

2014-02-07

Glioblastoma differ from many other tumors in the sense that they grow infiltratively into the brain tissue instead of forming a solid tumor mass with a defined boundary. Only the part of the tumor with high tumor cell density can be localized through imaging directly. In contrast, brain tissue infiltrated by tumor cells at low density appears normal on current imaging modalities. In current clinical practice, a uniform margin, typically two centimeters, is applied to account for microscopic spread of disease that is not directly assessable through imaging. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth, which arises from different factors: anatomical barriers such as the falx cerebri represent boundaries for migrating tumor cells. In addition, tumor cells primarily spread in white matter and infiltrate gray matter at lower rate. We investigate the use of a phenomenological tumor growth model for treatment planning. The model is based on the Fisher-Kolmogorov equation, which formalizes these growth characteristics and estimates the spatial distribution of tumor cells in normal appearing regions of the brain. The target volume for radiotherapy planning can be defined as an isoline of the simulated tumor cell density. This paper analyzes the model with respect to implications for target volume definition and identifies its most critical components. A retrospective study involving ten glioblastoma patients treated at our institution has been performed. To illustrate the main findings of the study, a detailed case study is presented for a glioblastoma located close to the falx. In this situation, the falx represents a boundary for migrating tumor cells, whereas the corpus callosum provides a route for the tumor to spread to the contralateral hemisphere. We further discuss the sensitivity of the model with respect to the input parameters. Correct segmentation of the brain appears to be the most

Radiotherapy planning for glioblastoma based on a tumor growth model: improving target volume delineation

NASA Astrophysics Data System (ADS)

Unkelbach, Jan; Menze, Bjoern H.; Konukoglu, Ender; Dittmann, Florian; Le, Matthieu; Ayache, Nicholas; Shih, Helen A.

2014-02-01

Glioblastoma differ from many other tumors in the sense that they grow infiltratively into the brain tissue instead of forming a solid tumor mass with a defined boundary. Only the part of the tumor with high tumor cell density can be localized through imaging directly. In contrast, brain tissue infiltrated by tumor cells at low density appears normal on current imaging modalities. In current clinical practice, a uniform margin, typically two centimeters, is applied to account for microscopic spread of disease that is not directly assessable through imaging. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth, which arises from different factors: anatomical barriers such as the falx cerebri represent boundaries for migrating tumor cells. In addition, tumor cells primarily spread in white matter and infiltrate gray matter at lower rate. We investigate the use of a phenomenological tumor growth model for treatment planning. The model is based on the Fisher-Kolmogorov equation, which formalizes these growth characteristics and estimates the spatial distribution of tumor cells in normal appearing regions of the brain. The target volume for radiotherapy planning can be defined as an isoline of the simulated tumor cell density. This paper analyzes the model with respect to implications for target volume definition and identifies its most critical components. A retrospective study involving ten glioblastoma patients treated at our institution has been performed. To illustrate the main findings of the study, a detailed case study is presented for a glioblastoma located close to the falx. In this situation, the falx represents a boundary for migrating tumor cells, whereas the corpus callosum provides a route for the tumor to spread to the contralateral hemisphere. We further discuss the sensitivity of the model with respect to the input parameters. Correct segmentation of the brain appears to be the most

Targeting tumor glycolysis by a mitotropic agent.

PubMed

Ganapathy-Kanniappan, Shanmugasundaram

2016-01-01

Metabolic reprogramming is one of the hallmarks of cancer. Altered metabolism in cancer cells is exemplified by enhanced glucose utilization, a biochemical signature that is clinically exploited for cancer diagnosis using positron-emission tomography and computed tomography imaging. Accordingly, disrupting the glucose metabolism of cancer cells has been contemplated as a potential therapeutic strategy against cancer. Experimental evidences indicate that targeting glucose metabolism by inhibition of glycolysis or oxidative phosphorylation promotes anticancer effects. Yet, successful clinical translation of antimetabolites or energy blockers to treat cancer remains a challenge, primarily due to lack of efficacy and/or systemic toxicity. Recently, using nanotechnology, Marrache and Dhar have documented the feasibility of delivering a glycolytic inhibitor through triphenylphosphonium (TPP), a mitotropic agent that selectively targets mitochondria based on membrane potential. Furthermore, by utilizing gold nanoparticles the investigators also demonstrated the potential for simultaneous induction of photothermal therapy, thus facilitating an additional line of attack on cancer cells. The report establishes that specific inhibition of tumor glycolysis is achievable through TPP-dependent selective targeting of cancer cells. This nanotechnological approach involving TPP-guided selective delivery of an antiglycolytic agent complemented with photothermal therapy provides a new window of opportunity for effective and specific targeting of tumor glycolysis.

Optoacoustic imaging of gold nanoparticles targeted to breast cancer cells

NASA Astrophysics Data System (ADS)

Eghtedari, Mohammad; Motamedi, Massoud; Popov, Vsevolod L.; Kotov, Nicholas A.; Oraevsky, Alexander A.

2004-07-01

Optoacoustic Tomography (OAT) is a rapidly growing technology that enables noninvasive deep imaging of biological tissues based on their light absorption. In OAT, the interaction of a pulsed laser with tissue increases the temperature of the absorbing components in a confined volume of tissue. Rapid perturbation of the temperature (<1°C) deep within tissue produces weak acoustic waves that easily travel to the surface of the tissue with minor attenuation. Abnormal angiogenesis in a malignant tumor, that increases its blood content, makes a native contrast for optoacoustic imaging; however, the application of OAT for early detection of malignant tumors requires the enhancement of optoacoustic signals originated from tumor by using an exogenous contrast agent. Due to their strong absorption, we have used gold nanoparticles (NP) as a contrast agent. 40nm spherical gold nanoparticles were attached to monoclonal antibody to target cell surface of breast cancer cells. The targeted cancer cells were implanted at depth of 5-6cm within a gelatinous object that optically resembles human breast. Experimental sensitivity measurements along with theoretical analysis showed that our optoacoustic imaging system is capable of detecting a phantom breast tumor with the volume of 0.15ml, which is composed of 25 million NP-targeted cancer cells, at a depth of 5 centimeters in vitro.

Synthesis and exploration of novel radiolabeled bombesin peptides for targeting receptor positive tumor.

PubMed

De, Kakali; Banerjee, Indranil; Sinha, Samarendu; Ganguly, Shantanu

2017-03-01

Increasing evidence of peptide receptor overexpression in various cancer cells, warrant the development of receptor specific radiolabeled peptides for molecular imaging and therapy in nuclear medicine. Gastrin-releasing-peptide (GRP) receptor, are overexpressed in a variety of human cancer cells. The present study report the synthesis and biological evaluation of new bombesin (BBN) analogs, HYNIC-Asp-[Phe 13 ]BBN(7-13)-NH-CH 2 -CH 2 -CH3:BA1, HYNIC-Pro-[Tyr 13 Met 14 ]BBN(7-14)NH 2 :BA2 as prospective tumor imaging agent with compare to BBN(7-14)NH 2 :BS as standard. The pharmacophores were radiolabeled in high yields with 99m Tc, characterized for their stability in serum and saline, cysteine/histidine and were found to be substantially stable. Internalization/externalization and receptor binding studies were assessed using MDA-MB-231 cells and showed high receptor binding-affinity and favourable internalization. Fluorescence studies revealed that BA1 changed the morphology of the cells and could localize in the nucleus more effectively than BA2/BS. Cell-viability studies displayed substantial antagonistic and nuclear-internalization effect of BA1. BA1 also exhibited antiproliferative effect on MDA-MB-231 cell by inducing apoptosis. In vivo behaviour of the radiopeptides was evaluated in GRP receptor positive tumor bearing mice. The 99m Tc-BA1/ 99m Tc-BA2 demonstrated rapid blood/urinary clearance through the renal pathway and comparatively more significant tumor uptake image and favourable tumor-to-non-target ratios provided by 99m Tc-BA1. The specificity of the in vivo uptake was confirmed by co-injection with BS. Moreover, 99m Tc-BA1 provided a much clearer tumor image in scintigraphic studies than others. Thus the combination of favourable in vitro and in vivo properties renders BA1 as more potential antagonist bombesin-peptide for targeting GRP-receptor positive tumor. These properties are encouraging to carry out further experiments for non-invasive receptor

Imaging cellularity in benign and malignant peripheral nerve sheath tumors: Utility of the "target sign" by diffusion weighted imaging.

PubMed

Ahlawat, Shivani; Fayad, Laura M

2018-05-01

To determine the utility of "target sign" on diffusion weighted imaging (DWI) and apparent diffusion coefficient (ADC) mapping for peripheral nerve sheath tumor (PNST) characterization. This IRB-approved, HIPAA-compliant study retrospectively reviewed the MR imaging (comprised of T2- FS, DWI (b-values 50, 400, 800 s/mm 2 and ADC mapping), and static contrast-enhanced (CE) T1-W imaging) of 42 patients (mean age: 40 years (range 8-68 years), 48% (20/42) females) with 15 malignant PNSTs (MPNSTs) and 33 benign PNSTs (BPNSTs). MPNSTs were histologically confirmed while BPNSTs were histologically-proven or with stable clinical and imaging appearance for at least 12 months. Two radiologists assessed imaging characteristics (size, signal intensity, heterogeneity, perilesional edema or enhancement) and the presence or absence of "target sign," on each sequence. A "target sign" was defined as a biphasic pattern of peripheral hyperintensity and homogeneous central hypointensity. Descriptive statistics are reported. Cohen's κ statistic or interclass correlation coefficient (ICC) were used to evaluate interobserver agreement between two observers. Univariate and multiple logistic regression analysis were performed to identify MRI features with predictive values. MPNSTs were larger than BPNSTs (6.3 ± 2.5 cm vs 3.5 ± -2.1 cm, p = 0.0002), had perilesional edema (87%(13/15) vs 18%(6/33), p < 0.0001), heterogeneous enhancement (71%(10/14) vs 13%(4/31), p = 0.0001) and perilesional enhancement (79%(11/14) vs 18%(6/31), p = 0.0001), respectively. The "target sign" was present in: 24%(8/33) BPNSTs vs 0/15 MPNST on T2-FS (p = 0.26); 39%(13/33) BPNSTs vs 20%(3/15) MPNST on DWI using b-value = 50 s/mm 2 (p = 0.5); 55%(18/33) BPNSTs vs 6%(1/15) MPNST on DWI using b-value = 400 s/mm 2 (p = 0.002); 48%(16/33) BPNSTs vs 6%(1/15) MPNST on DWI using b-value = 800 s/mm 2 (p = 0.005) and 64%(21/33) benign vs 0/15 MPNST on ADC

Functionalized Gold Nanorods for Tumor Imaging and Targeted Therapy

PubMed Central

Gui, Chen; Cui, Da-xiang

2012-01-01

Gold nanorods, as an emerging noble metal nanomaterial with unique properties, have become the new exciting focus of theoretical and experimental studies in the past few years. The structure and function of gold nanorods, especially their biocompatibility, optical property, and photothermal effects, have been attracting more and more attention. Gold nanorods exhibit great potential in applications such as tumor molecular imaging and photothermal therapy. In this article, we review some of the main advances made over the past few years in the application of gold nanorods in surface functionalization, molecular imaging, and photothermal therapy. We also explore other prospective applications and discuss the corresponding concepts, issues, approaches, and challenges, with the aim of stimulating broader interest in gold nanorod-based nanotechnology and improving its practical application. PMID:23691482

Selective tumor cell targeting by the disaccharide moiety of bleomycin.

PubMed

Yu, Zhiqiang; Schmaltz, Ryan M; Bozeman, Trevor C; Paul, Rakesh; Rishel, Michael J; Tsosie, Krystal S; Hecht, Sidney M

2013-02-27

In a recent study, the well-documented tumor targeting properties of the antitumor agent bleomycin (BLM) were studied in cell culture using microbubbles that had been derivatized with multiple copies of BLM. It was shown that BLM selectively targeted MCF-7 human breast carcinoma cells but not the "normal" breast cell line MCF-10A. Furthermore, it was found that the BLM analogue deglycobleomycin, which lacks the disaccharide moiety of BLM, did not target either cell line, indicating that the BLM disaccharide moiety is necessary for tumor selectivity. Not resolved in the earlier study were the issues of whether the BLM disaccharide moiety alone is sufficient for tumor cell targeting and the possible cellular uptake of the disaccharide. In the present study, we conjugated BLM, deglycoBLM, and BLM disaccharide to the cyanine dye Cy5**. It was found that the BLM and BLM disaccharide conjugates, but not the deglycoBLM conjugate, bound selectively to MCF-7 cells and were internalized. The same was also true for the prostate cancer cell line DU-145 (but not for normal PZ-HPV-7 prostate cells) and for the pancreatic cancer cell line BxPC-3 (but not for normal SVR A221a pancreas cells). The targeting efficiency of the disaccharide was only slightly less than that of BLM in MCF-7 and DU-145 cells and comparable to that of BLM in BxPC-3 cells. These results establish that the BLM disaccharide is both necessary and sufficient for tumor cell targeting, a finding with obvious implications for the design of novel tumor imaging and therapeutic agents.

Imaging-guided preclinical trials of vascular targeting in prostate cancer

NASA Astrophysics Data System (ADS)

Kalmuk, James

Purpose: Prostate cancer is the most common non-cutaneous malignancy in American men and is characterized by dependence on androgens (Testosterone/Dihydrotestosterone) for growth and survival. Although reduction of serum testosterone levels by surgical or chemical castration transiently inhibits neoplastic growth, tumor adaptation to castrate levels of androgens results in the generation of castration-resistant prostate cancer (CRPC). Progression to CRPC following androgen deprivation therapy (ADT) has been associated with changes in vascular morphology and increased angiogenesis. Based on this knowledge, we hypothesized that targeting tumor vasculature in combination with ADT would result in enhanced therapeutic efficacy against prostate cancer. Methods: To test this hypothesis, we examined the therapeutic activity of a tumor-vascular disrupting agent (tumor-VDA), EPC2407 (Crolibulin(TM)), alone and in combination with ADT in a murine model of prostate cancer (Myc-CaP). A non-invasive multimodality imaging approach based on magnetic resonance imaging (MRI), bioluminescence imaging (BLI), and ultrasound (US) was utilized to characterize tumor response to therapy and to guide preclinical trial design. Imaging results were correlated with histopathologic (H&E) and immunohistochemical (CD31) assessment as well as tumor growth inhibition and survival analyses. Results: Our imaging techniques were able to capture an acute reduction (within 24 hours) in tumor perfusion following castration and VDA monotherapy. BLI revealed onset of recurrent disease 5-7 days post castration prior to visible tumor regrowth suggestive of vascular recovery. Administration of VDA beginning 1 week post castration for 3 weeks resulted in sustained vascular suppression, inhibition of tumor regrowth, and conferred a more pronounced survival benefit compared to either monotherapy. Conclusion: The high mortality rate associated with CRPC underscores the need for investigating novel treatment

Improved tumor-targeting MRI contrast agents: Gd(DOTA) conjugates of a cycloalkane-based RGD peptide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Ji-Ae, E-mail: jpark@kirams.re.kr; Lee, Yong Jin; Ko, In Ok

2014-12-12

Highlights: • Development of improved tumor-targeting MRI contrast agents. • To increase the targeting ability of RGD, we developed cycloalkane-based RGD peptides. • Gd(DOTA) conjugates of cycloalkane-based RGD peptide show improved tumor signal enhancement in vivo MR images. - Abstract: Two new MRI contrast agents, Gd-DOTA-c(RGD-ACP-K) (1) and Gd-DOTA-c(RGD-ACH-K) (2), which were designed by incorporating aminocyclopentane (ACP)- or aminocyclohexane (ACH)-carboxylic acid into Gd-DOTA (gadolinium-tetraazacyclo dodecanetetraacetic acid) and cyclic RGDK peptides, were synthesized and evaluated for tumor-targeting ability in vitro and in vivo. Binding affinity studies showed that both 1 and 2 exhibited higher affinity for integrin receptors than cyclic RGDyKmore » peptides, which were used as a reference. These complexes showed high relaxivity and good stability in human serum and have the potential to improve target-specific signal enhancement in vivo MR images.« less

Multifunctional nanoparticles for upconversion luminescence/MR multimodal imaging and magnetically targeted photothermal therapy.

PubMed

Cheng, Liang; Yang, Kai; Li, Yonggang; Zeng, Xiao; Shao, Mingwang; Lee, Shuit-Tong; Liu, Zhuang

2012-03-01

Theranostics, the combination of diagnostics and therapies, has become a new concept in the battles with various major diseases such as cancer. Herein, we develop multifunctional nanoparticles (MFNPs) with highly integrated functionalities including upconversion luminescence, superparamagnetism, and strong optical absorption in the near-infrared (NIR) region with high photostability. In vivo dual modal optical/magnetic resonance imaging of mice uncovers that by placing a magnet nearby the tumor, MFNPs tend to migrate toward the tumor after intravenous injection and show high tumor accumulation, which is ~8 folds higher than that without magnetic targeting. NIR laser irradiation is then applied to the tumors grown on MFNP-injected mice under magnetic tumor-targeting, obtaining an outstanding photothermal therapeutic efficacy with 100% of tumor elimination in a murine breast cancer model. We present here a strategy for multimodal imaging-guided, magnetically targeted physical cancer therapy and highlight the promise of using multifunctional nanostructures for cancer theranostics. Copyright © 2011 Elsevier Ltd. All rights reserved.

Tumor-targeting delivery of herb-based drugs with cell-penetrating/tumor-targeting peptide-modified nanocarriers

PubMed Central

Kebebe, Dereje; Liu, Yuanyuan; Wu, Yumei; Vilakhamxay, Maikhone; Liu, Zhidong; Li, Jiawei

2018-01-01

Cancer has become one of the leading causes of mortality globally. The major challenges of conventional cancer therapy are the failure of most chemotherapeutic agents to accumulate selectively in tumor cells and their severe systemic side effects. In the past three decades, a number of drug delivery approaches have been discovered to overwhelm the obstacles. Among these, nanocarriers have gained much attention for their excellent and efficient drug delivery systems to improve specific tissue/organ/cell targeting. In order to enhance targeting efficiency further and reduce limitations of nanocarriers, nanoparticle surfaces are functionalized with different ligands. Several kinds of ligand-modified nanomedicines have been reported. Cell-penetrating peptides (CPPs) are promising ligands, attracting the attention of researchers due to their efficiency to transport bioactive molecules intracellularly. However, their lack of specificity and in vivo degradation led to the development of newer types of CPP. Currently, activable CPP and tumor-targeting peptide (TTP)-modified nanocarriers have shown dramatically superior cellular specific uptake, cytotoxicity, and tumor growth inhibition. In this review, we discuss recent advances in tumor-targeting strategies using CPPs and their limitations in tumor delivery systems. Special emphasis is given to activable CPPs and TTPs. Finally, we address the application of CPPs and/or TTPs in the delivery of plant-derived chemotherapeutic agents. PMID:29563797

Characterizing EPR-mediated passive drug targeting using contrast-enhanced functional ultrasound imaging.

PubMed

Theek, Benjamin; Gremse, Felix; Kunjachan, Sijumon; Fokong, Stanley; Pola, Robert; Pechar, Michal; Deckers, Roel; Storm, Gert; Ehling, Josef; Kiessling, Fabian; Lammers, Twan

2014-05-28

The Enhanced Permeability and Retention (EPR) effect is extensively used in drug delivery research. Taking into account that EPR is a highly variable phenomenon, we have here set out to evaluate if contrast-enhanced functional ultrasound (ceUS) imaging can be employed to characterize EPR-mediated passive drug targeting to tumors. Using standard fluorescence molecular tomography (FMT) and two different protocols for hybrid computed tomography-fluorescence molecular tomography (CT-FMT), the tumor accumulation of a ~10 nm-sized near-infrared-fluorophore-labeled polymeric drug carrier (pHPMA-Dy750) was evaluated in CT26 tumor-bearing mice. In the same set of animals, two different ceUS techniques (2D MIOT and 3D B-mode imaging) were employed to assess tumor vascularization. Subsequently, the degree of tumor vascularization was correlated with the degree of EPR-mediated drug targeting. Depending on the optical imaging protocol used, the tumor accumulation of the polymeric drug carrier ranged from 5 to 12% of the injected dose. The degree of tumor vascularization, determined using ceUS, varied from 4 to 11%. For both hybrid CT-FMT protocols, a good correlation between the degree of tumor vascularization and the degree of tumor accumulation was observed, within the case of reconstructed CT-FMT, correlation coefficients of ~0.8 and p-values of <0.02. These findings indicate that ceUS can be used to characterize and predict EPR, and potentially also to pre-select patients likely to respond to passively tumor-targeted nanomedicine treatments. Copyright © 2014 Elsevier B.V. All rights reserved.

Multimodal targeted high relaxivity thermosensitive liposome for in vivo imaging

NASA Astrophysics Data System (ADS)

Kuijten, Maayke M. P.; Hannah Degeling, M.; Chen, John W.; Wojtkiewicz, Gregory; Waterman, Peter; Weissleder, Ralph; Azzi, Jamil; Nicolay, Klaas; Tannous, Bakhos A.

2015-11-01

Liposomes are spherical, self-closed structures formed by lipid bilayers that can encapsulate drugs and/or imaging agents in their hydrophilic core or within their membrane moiety, making them suitable delivery vehicles. We have synthesized a new liposome containing gadolinium-DOTA lipid bilayer, as a targeting multimodal molecular imaging agent for magnetic resonance and optical imaging. We showed that this liposome has a much higher molar relaxivities r1 and r2 compared to a more conventional liposome containing gadolinium-DTPA-BSA lipid. By incorporating both gadolinium and rhodamine in the lipid bilayer as well as biotin on its surface, we used this agent for multimodal imaging and targeting of tumors through the strong biotin-streptavidin interaction. Since this new liposome is thermosensitive, it can be used for ultrasound-mediated drug delivery at specific sites, such as tumors, and can be guided by magnetic resonance imaging.

Functionalized near-infrared quantum dots for in vivo tumor vasculature imaging

NASA Astrophysics Data System (ADS)

Hu, Rui; Yong, Ken-Tye; Roy, Indrajit; Ding, Hong; Law, Wing-Cheung; Cai, Hongxing; Zhang, Xihe; Vathy, Lisa A.; Bergey, Earl J.; Prasad, Paras N.

2010-04-01

In this paper, we report the use of near-infrared (NIR)-emitting alloyed quantum dots (QDs) as efficient optical probes for high contrast in vivo imaging of tumors. Alloyed CdTe1 - xSex/CdS QDs were prepared in the non-aqueous phase using the hot colloidal synthesis approach. Water dispersion of the QDs were accomplished by their encapsulation within polyethyleneglycol (PEG)-grafted phospholipid micelles. For tumor-specific delivery in vivo, the micelle-encapsulated QDs were conjugated with the cyclic arginine-glycine-aspartic acid (cRGD) peptide, which targets the αvβ3 integrins overexpressed in the angiogenic tumor vasculatures. Using in vivo NIR optical imaging of mice bearing pancreatic cancer xenografts, implanted both subcutaneously and orthotopically, we have demonstrated that systemically delivered cRGD-conjugated QDs, but not the unconjugated ones, can efficiently target and label the tumors with high signal-to-noise ratio. Histopathological analysis of major organs of the treated mice showed no evidence of systemic toxicity associated with these QDs. These experiments suggest that cRGD-conjugated NIR QDs can serve as safe and efficient probes for optical bioimaging of tumors in vivo. Furthermore, by co-encapsulating these QDs and anticancer drugs within these micelles, we have demonstrated a promising theranostic, nanosized platform for both cancer imaging and therapy.

Targeted imaging of cancer by fluorocoxib C, a near-infrared cyclooxygenase-2 probe

NASA Astrophysics Data System (ADS)

Uddin, Md. Jashim; Crews, Brenda C.; Ghebreselasie, Kebreab; Daniel, Cristina K.; Kingsley, Philip J.; Xu, Shu; Marnett, Lawrence J.

2015-05-01

Cyclooxygenase-2 (COX-2) is a promising target for the imaging of cancer in a range of diagnostic and therapeutic settings. We report a near-infrared COX-2-targeted probe, fluorocoxib C (FC), for visualization of solid tumors by optical imaging. FC exhibits selective and potent COX-2 inhibition in both purified protein and human cancer cell lines. In vivo optical imaging shows selective accumulation of FC in COX-2-overexpressing human tumor xenografts [1483 head and neck squamous cell carcinoma (HNSCC)] implanted in nude mice, while minimal uptake is detectable in COX-2-negative tumor xenografts (HCT116) or 1483 HNSCC xenografts preblocked with the COX-2-selective inhibitor celecoxib. Time course imaging studies conducted from 3 h to 7-day post-FC injection revealed a marked reduction in nonspecific fluorescent signals with retention of fluorescence in 1483 HNSCC tumors. Thus, use of FC in a delayed imaging protocol offers an approach to improve imaging signal-to-noise that should improve cancer detection in multiple preclinical and clinical settings.

Tumor Targeting and Pharmacokinetics of a Near-Infrared Fluorescent-Labeled δ-Opioid Receptor Antagonist Agent, Dmt-Tic-Cy5.

PubMed

Huynh, Amanda Shanks; Estrella, Veronica; Stark, Valerie E; Cohen, Allison S; Chen, Tingan; Casagni, Todd J; Josan, Jatinder S; Lloyd, Mark C; Johnson, Joseph; Kim, Jongphil; Hruby, Victor J; Vagner, Josef; Morse, David L

2016-02-01

Fluorescence molecular imaging can be employed for the development of novel cancer targeting agents. Herein, we investigated the pharmacokinetics (PK) and cellular uptake of Dmt-Tic-Cy5, a delta-opioid receptor (δOR) antagonist-fluorescent dye conjugate, as a tumor-targeting molecular imaging agent. δOR expression is observed normally in the CNS, and pathologically in some tumors, including lung liver and breast cancers. In vitro, in vivo, and ex vivo experiments were conducted to image and quantify the fluorescence signal associated with Dmt-Tic-Cy5 over time using in vitro and intravital fluorescence microscopy and small animal fluorescence imaging of tumor-bearing mice. We observed specific retention of Dmt-Tic-Cy5 in tumors with maximum uptake in δOR-expressing positive tumors at 3 h and observable persistence for >96 h; clearance from δOR nonexpressing negative tumors by 6 h; and systemic clearance from normal organs by 24 h. Live-cell and intravital fluorescence microscopy demonstrated that Dmt-Tic-Cy5 had sustained cell-surface binding lasting at least 24 h with gradual internalization over the initial 6 h following administration. Dmt-Tic-Cy5 is a δOR-targeted agent that exhibits long-lasting and specific signal in δOR-expressing tumors, is rapidly cleared from systemic circulation, and is not retained in non-δOR-expressing tissues. Hence, Dmt-Tic-Cy5 has potential as a fluorescent tumor imaging agent.

CT-guided automated detection of lung tumors on PET images

NASA Astrophysics Data System (ADS)

Cui, Yunfeng; Zhao, Binsheng; Akhurst, Timothy J.; Yan, Jiayong; Schwartz, Lawrence H.

2008-03-01

The calculation of standardized uptake values (SUVs) in tumors on serial [ 18F]2-fluoro-2-deoxy-D-glucose ( 18F-FDG) positron emission tomography (PET) images is often used for the assessment of therapy response. We present a computerized method that automatically detects lung tumors on 18F-FDG PET/Computed Tomography (CT) images using both anatomic and metabolic information. First, on CT images, relevant organs, including lung, bone, liver and spleen, are automatically identified and segmented based on their locations and intensity distributions. Hot spots (SUV >= 1.5) on 18F-FDG PET images are then labeled using the connected component analysis. The resultant "hot objects" (geometrically connected hot spots in three dimensions) that fall into, reside at the edges or are in the vicinity of the lungs are considered as tumor candidates. To determine true lesions, further analyses are conducted, including reduction of tumor candidates by the masking out of hot objects within CT-determined normal organs, and analysis of candidate tumors' locations, intensity distributions and shapes on both CT and PET. The method was applied to 18F-FDG-PET/CT scans from 9 patients, on which 31 target lesions had been identified by a nuclear medicine radiologist during a Phase II lung cancer clinical trial. Out of 31 target lesions, 30 (97%) were detected by the computer method. However, sensitivity and specificity were not estimated because not all lesions had been marked up in the clinical trial. The method effectively excluded the hot spots caused by mediastinum, liver, spleen, skeletal muscle and bone metastasis.

Cholesterol-modified poly(lactide-co-glycolide) nanoparticles for tumor-targeted drug delivery.

PubMed

Lee, Jeong-Jun; Lee, Song Yi; Park, Ju-Hwan; Kim, Dae-Duk; Cho, Hyun-Jong

2016-07-25

Poly(lactide-co-glycolide)-cholesterol (PLGA-C)-based nanoparticles (NPs) were developed for the tumor-targeted delivery of curcumin (CUR). PLGA-C/CUR NPs with ∼200nm mean diameter, narrow size distribution, and neutral zeta potential were fabricated by a modified emulsification-solvent evaporation method. The existence of cholesterol moiety in PLGA-C copolymer was confirmed by proton nuclear magnetic resonance ((1)H NMR) analysis. In vitro stability of developed NPs after 24h incubation was confirmed in phosphate buffered saline (PBS) and serum media. Sustained (∼6days) and pH-responsive drug release profiles from PLGA-C NPs were presented. Blank PLGA and PLGA-C NPs exhibited a negligible cytotoxicity in Hep-2 (human laryngeal carcinoma) cells in the tested concentration range. According to the results of flow cytometry and confocal laser scanning microscopy (CLSM) studies, PLGA-C NPs presented an improved cellular accumulation efficiency, compared to PLGA NPs, in Hep-2 cells. Enhanced in vivo tumor targetability of PLGA-C NPs, compared to PLGA NPs, in Hep-2 tumor-xenografted mouse model was also verified by a real-time near-infrared fluorescence (NIRF) imaging study. Developed PLGA-C NPs may be a candidate of efficient and biocompatible nanosystems for tumor-targeted drug delivery and cancer imaging. Copyright © 2016 Elsevier B.V. All rights reserved.

The Application of Heptamethine Cyanine Dye DZ-1 and Indocyanine Green for Imaging and Targeting in Xenograft Models of Hepatocellular Carcinoma

PubMed Central

Zhang, Caiqin; Zhao, Yong; Zhang, He; Chen, Xue; Zhao, Ningning; Tan, Dengxu; Zhang, Hai; Shi, Changhong

2017-01-01

Near infrared fluorescence (NIRF) imaging has strong potential for widespread use in noninvasive tumor imaging. Indocyanine green (ICG) is the only Food and Drug Administration (FDA) -approved NIRF dye for clinical diagnosis; however, it is unstable and poorly targets tumors. DZ-1 is a novel heptamethine cyanine NIRF dye, suitable for imaging and tumor targeting. Here, we compared the fluorescence intensity and metabolism of DZ-1 and ICG. Additionally, we assayed their specificities and abilities to target tumor cells, using cultured hepatocellular carcinoma (HCC) cell lines, a nude mouse subcutaneous xenograft model of liver cancer, and a rabbit orthotopic transplantation model. We found that DZ-1 accumulates in tumor tissue and specifically recognizes HCC in subcutaneous and orthotopic models. The NIRF intensity of DZ-1 was one order of magnitude stronger than that of ICG, and DZ-1 showed excellent intraoperative tumor targeting in the rabbit model. Importantly, ICG accumulated at tumor sites, as well as in the liver and kidney. Furthermore, DZ-1 analog-gemcitabine conjugate (NIRG) exhibited similar tumor-specific targeting and imaging properties, including inhibition of tumor growth, in HCC patient-derived xenograft (PDX) mice. DZ-1 and NIRG demonstrated superior tumor-targeting specificity, compared to ICG. We show that DZ-1 is an effective molecular probe for specific imaging, targeting, and therapy in HCC. PMID:28635650

The Application of Heptamethine Cyanine Dye DZ-1 and Indocyanine Green for Imaging and Targeting in Xenograft Models of Hepatocellular Carcinoma.

PubMed

Zhang, Caiqin; Zhao, Yong; Zhang, He; Chen, Xue; Zhao, Ningning; Tan, Dengxu; Zhang, Hai; Shi, Changhong

2017-06-21

Near infrared fluorescence (NIRF) imaging has strong potential for widespread use in noninvasive tumor imaging. Indocyanine green (ICG) is the only Food and Drug Administration (FDA) -approved NIRF dye for clinical diagnosis; however, it is unstable and poorly targets tumors. DZ-1 is a novel heptamethine cyanine NIRF dye, suitable for imaging and tumor targeting. Here, we compared the fluorescence intensity and metabolism of DZ-1 and ICG. Additionally, we assayed their specificities and abilities to target tumor cells, using cultured hepatocellular carcinoma (HCC) cell lines, a nude mouse subcutaneous xenograft model of liver cancer, and a rabbit orthotopic transplantation model. We found that DZ-1 accumulates in tumor tissue and specifically recognizes HCC in subcutaneous and orthotopic models. The NIRF intensity of DZ-1 was one order of magnitude stronger than that of ICG, and DZ-1 showed excellent intraoperative tumor targeting in the rabbit model. Importantly, ICG accumulated at tumor sites, as well as in the liver and kidney. Furthermore, DZ-1 analog-gemcitabine conjugate (NIRG) exhibited similar tumor-specific targeting and imaging properties, including inhibition of tumor growth, in HCC patient-derived xenograft (PDX) mice. DZ-1 and NIRG demonstrated superior tumor-targeting specificity, compared to ICG. We show that DZ-1 is an effective molecular probe for specific imaging, targeting, and therapy in HCC.

Physiological Imaging-Defined, Response-Driven Subvolumes of a Tumor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farjam, Reza; Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan; Tsien, Christina I.

2013-04-01

Purpose: To develop an image analysis framework to delineate the physiological imaging-defined subvolumes of a tumor in relating to treatment response and outcome. Methods and Materials: Our proposed approach delineates the subvolumes of a tumor based on its heterogeneous distributions of physiological imaging parameters. The method assigns each voxel a probabilistic membership function belonging to the physiological parameter classes defined in a sample of tumors, and then calculates the related subvolumes in each tumor. We applied our approach to regional cerebral blood volume (rCBV) and Gd-DTPA transfer constant (K{sup trans}) images of patients who had brain metastases and were treatedmore » by whole-brain radiation therapy (WBRT). A total of 45 lesions were included in the analysis. Changes in the rCBV (or K{sup trans})–defined subvolumes of the tumors from pre-RT to 2 weeks after the start of WBRT (2W) were evaluated for differentiation of responsive, stable, and progressive tumors using the Mann-Whitney U test. Performance of the newly developed metrics for predicting tumor response to WBRT was evaluated by receiver operating characteristic (ROC) curve analysis. Results: The percentage decrease in the high-CBV-defined subvolumes of the tumors from pre-RT to 2W was significantly greater in the group of responsive tumors than in the group of stable and progressive tumors (P<.007). The change in the high-CBV-defined subvolumes of the tumors from pre-RT to 2W was a predictor for post-RT response significantly better than change in the gross tumor volume observed during the same time interval (P=.012), suggesting that the physiological change occurs before the volumetric change. Also, K{sup trans} did not add significant discriminatory information for assessing response with respect to rCBV. Conclusion: The physiological imaging-defined subvolumes of the tumors delineated by our method could be candidates for boost target, for which further development and

Y1-receptor-ligand-functionalized ultrasmall upconversion nanoparticles for tumor-targeted trimodality imaging and photodynamic therapy with low toxicity.

PubMed

Yu, Zhangsen; Xia, Yuanzhi; Xing, Jie; Li, Zihou; Zhen, Jianjun; Jin, Yinhua; Tian, Yuchen; Liu, Chuang; Jiang, Zhenqi; Li, Juan; Wu, Aiguo

2018-05-31

Achieving efficient photodynamic therapy (PDT) in deeper biological tissue is still the biggest bottleneck that limits its widespread application in clinic. Although deeper biological tissue PDT could be realized through a combination of upconversion nanoparticles with a photosensitizer, issues with particle-size-induced upconversion fluorescence (UF) reduction and the related in vivo toxicity still cannot be solved properly. In this study, we synthesized Y1Rs-ligand [Pro30, Nle31, Bpa32, Leu34]NPY(28-36) (NPY)-modified and photosensitizer MC540-loaded LiLuF4:Yb,Er@nLiGdF4@mSiO2 multifunctional nanocomposites (MNPs) with a core-multishell structure and ultrasmall size. Their in vitro and in vivo breast tumor targeting, trimodality imaging performance, PDT therapeutic efficacy, and acute toxicity were evaluated. Our results demonstrated that the core-multishell MNPs(MC540) could achieve excellent UF imaging, and that doping with Gd3+ and Lu3+ rare earth ions could enhance the MR and CT imaging performance. In addition, the mSiO2 shell provided a higher loading rate for the photosensitizer MC540, and the DSPE-PEG thin layer coating outside the MNPs(MC540) further improved the water solubility and biocompatibility, reducing the acute toxicity of the nanocomposites. Finally, the NPY modification enhanced the targetability of MNPs(MC540)/DSPE-PEG-NPY to breast tumors, improving the trimodality UF, CT, and MR imaging performance and PDT efficacy for Y1-receptor-overexpressed breast cancer. In general, our developed multifunctional nanocomposites can serve as a theranostic agent with low toxicity, providing great potential for their use in clinical breast cancer diagnosis and therapy.

Focused US system for MR imaging-guided tumor ablation.

PubMed

Cline, H E; Hynynen, K; Watkins, R D; Adams, W J; Schenck, J F; Ettinger, R H; Freund, W R; Vetro, J P; Jolesz, F A

1995-03-01

To measure the performance characteristics of a focused ultrasound (US) system for magnetic resonance (MR) imaging-guided tumor ablation. The authors constructed a focused US system for MR imaging-guided tumor ablation. The location of the heated region and thermal dose were monitored with temperature-sensitive MR images obtained in phantoms and rabbit skeletal muscle after application of each sonic pulse. The region heated by the focused ultrasound beam was within 1 mm of that observed on temperature-sensitive fast gradient-echo MR images of in vivo rabbit skeletal muscle. Analysis of heat flow and the rate of coagulation necrosis provided an estimate of the size of the ablated region that was in agreement with experimental findings. MR imaging provides target definition and control for thermal therapy in regions of variable perfusion or in tissues that are not well characterized.

Detection limits of intraoperative near infrared imaging for tumor resection.

PubMed

Thurber, Greg M; Figueiredo, Jose-Luiz; Weissleder, Ralph

2010-12-01

The application of fluorescent molecular imaging to surgical oncology is a developing field with the potential to reduce morbidity and mortality. However, the detection thresholds and other requirements for successful intervention remain poorly understood. Here we modeled and experimentally validated depth and size of detection of tumor deposits, trade-offs in coverage and resolution of areas of interest, and required pharmacokinetics of probes based on differing levels of tumor target presentation. Three orthotopic tumor models were imaged by widefield epifluorescence and confocal microscopes, and the experimental results were compared with pharmacokinetic models and light scattering simulations to determine detection thresholds. Widefield epifluorescence imaging can provide sufficient contrast to visualize tumor margins and detect tumor deposits 3-5  mm deep based on labeled monoclonal antibodies at low objective magnification. At higher magnification, surface tumor deposits at cellular resolution are detectable at TBR ratios achieved with highly expressed antigens. A widefield illumination system with the capability for macroscopic surveying and microscopic imaging provides the greatest utility for varying surgical goals. These results have implications for system and agent designs, which ultimately should aid complete resection in most surgical beds and provide real-time feedback to obtain clean margins. © 2010 Wiley-Liss, Inc.

A method for deriving a 4D-interpolated balanced planning target for mobile tumor radiotherapy.

PubMed

Roland, Teboh; Hales, Russell; McNutt, Todd; Wong, John; Simari, Patricio; Tryggestad, Erik

2012-01-01

Tumor control and normal tissue toxicity are strongly correlated to the tumor and normal tissue volumes receiving high prescribed dose levels in the course of radiotherapy. Planning target definition is, therefore, crucial to ensure favorable clinical outcomes. This is especially important for stereotactic body radiation therapy of lung cancers, characterized by high fractional doses and steep dose gradients. The shift in recent years from population-based to patient-specific treatment margins, as facilitated by the emergence of 4D medical imaging capabilities, is a major improvement. The commonly used motion-encompassing, or internal-target volume (ITV), target definition approach provides a high likelihood of coverage for the mobile tumor but inevitably exposes healthy tissue to high prescribed dose levels. The goal of this work was to generate an interpolated balanced planning target that takes into account both tumor coverage and normal tissue sparing from high prescribed dose levels, thereby improving on the ITV approach. For each 4DCT dataset, 4D deformable image registration was used to derive two bounding targets, namely, a 4D-intersection and a 4D-composite target which minimized normal tissue exposure to high prescribed dose levels and maximized tumor coverage, respectively. Through definition of an "effective overlap volume histogram" the authors derived an "interpolated balanced planning target" intended to balance normal tissue sparing from prescribed doses with tumor coverage. To demonstrate the dosimetric efficacy of the interpolated balanced planning target, the authors performed 4D treatment planning based on deformable image registration of 4D-CT data for five previously treated lung cancer patients. Two 4D plans were generated per patient, one based on the interpolated balanced planning target and the other based on the conventional ITV target. Plans were compared for tumor coverage and the degree of normal tissue sparing resulting from the new

In Vivo Evaluation of Magnetic Targeting in Mice Colon Tumors with Ultra-Magnetic Liposomes Monitored by MRI.

PubMed

Thébault, Caroline J; Ramniceanu, Grégory; Michel, Aude; Beauvineau, Claire; Girard, Christian; Seguin, Johanne; Mignet, Nathalie; Ménager, Christine; Doan, Bich-Thuy

2018-06-25

The development of theranostic nanocarriers as an innovative therapy against cancer has been improved by targeting properties in order to optimize the drug delivery to safely achieve its desired therapeutic effect. The aim of this paper is to evaluate the magnetic targeting (MT) efficiency of ultra-magnetic liposomes (UML) into CT26 murine colon tumor by magnetic resonance imaging (MRI). Dynamic susceptibility contrast MRI was applied to assess the bloodstream circulation time. A novel semi-quantitative method called %I 0.25 , based on the intensity distribution in T 2 * -weighted MRI images was developed to compare the accumulation of T 2 contrast agent in tumors with or without MT. To evaluate the efficiency of magnetic targeting, the percentage of pixels under the intensity value I 0.25 (I 0.25  = 0.25(I max  - I min )) was calculated on the intensity distribution histogram. This innovative method of processing MRI images showed the MT efficiency by a %I 0.25 that was significantly higher in tumors using MT compared to passive accumulation, from 15.3 to 28.6 %. This methodology was validated by ex vivo methods with an iron concentration that is 3-fold higher in tumors using MT. We have developed a method that allows a semi-quantitative evaluation of targeting efficiency in tumors, which could be applied to different T 2 contrast agents.

Drug-induced amplification of nanoparticle targeting to tumors

PubMed Central

Lin, Kevin Y.; Kwon, Ester J.; Lo, Justin H.; Bhatia, Sangeeta N.

2018-01-01

Summary Nanomedicines have the potential to significantly impact cancer therapy by improving drug efficacy and decreasing off-target effects, yet our ability to efficiently home nanoparticles to disease sites remains limited. One frequently overlooked constraint of current active targeting schemes is the relative dearth of targetable antigens within tumors, which restricts the amount of cargo that can be delivered in a tumor-specific manner. To address this limitation, we exploit tumor-specific responses to drugs to construct a cooperative targeting system where a small molecule therapeutic modulates the disease microenvironment to amplify nanoparticle recruitment in vivo. We first administer a vascular disrupting agent, ombrabulin, which selectively affects tumors and leads to locally elevated presentation of the stress-related protein, p32. This increase in p32 levels provides more binding sites for circulating p32-targeted nanoparticles, enhancing their delivery of diagnostic or therapeutic cargos to tumors. We show that this cooperative targeting system recruits over five times higher doses of nanoparticles to tumors and decreases tumor burden when compared with non-cooperative controls. These results suggest that using nanomedicine in conjunction with drugs that enhance the presentation of target antigens in the tumor environment may be an effective strategy for improving the diagnosis and treatment of cancer. PMID:29731806

Nanomedicine Strategies to Target Tumor-Associated Macrophages

PubMed Central

Binnemars-Postma, Karin; Storm, Gert; Prakash, Jai

2017-01-01

In recent years, the influence of the tumor microenvironment (TME) on cancer progression has been better understood. Macrophages, one of the most important cell types in the TME, exist in different subtypes, each of which has a different function. While classically activated M1 macrophages are involved in inflammatory and malignant processes, activated M2 macrophages are more involved in the wound-healing processes occurring in tumors. Tumor-associated macrophages (TAM) display M2 macrophage characteristics and support tumor growth and metastasis by matrix remodeling, neo-angiogenesis, and suppressing local immunity. Due to their detrimental role in tumor growth and metastasis, selective targeting of TAM for the treatment of cancer may prove to be beneficial in the treatment of cancer. Due to the plastic nature of macrophages, their activities may be altered to inhibit tumor growth. In this review, we will discuss the therapeutic options for the modulation and targeting of TAM. Different therapeutic strategies to deplete, inhibit recruitment of, or re-educate TAM will be discussed. Current strategies for the targeting of TAM using nanomedicine are reviewed. Passive targeting using different nanoparticle systems is described. Since TAM display a number of upregulated surface proteins compared to non-TAM, specific targeting using targeting ligands coupled to nanoparticles is discussed in detail. PMID:28471401

Multi-functional liposomes showing radiofrequency-triggered release and magnetic resonance imaging for tumor multi-mechanism therapy.

PubMed

Du, Bin; Han, Shuping; Li, Hongyan; Zhao, Feifei; Su, Xiangjie; Cao, Xiaohui; Zhang, Zhenzhong

2015-03-12

Recently, nanoplatforms with multiple functions, such as tumor-targeting drug carriers, MRI, optical imaging, thermal therapy etc., have become popular in the field of cancer research. The present study reports a novel multi-functional liposome for cancer theranostics. A dual targeted drug delivery with radiofrequency-triggered drug release and imaging based on the magnetic field influence was used advantageously for tumor multi-mechanism therapy. In this system, the surface of fullerene (C60) was decorated with iron oxide nanoparticles, and PEGylation formed a hybrid nanosystem (C60-Fe3O4-PEG2000). Thermosensitive liposomes (dipalmitoylphosphatidylcholine, DPPC) with DSPE-PEG2000-folate wrapped up the hybrid nanosystem and docetaxel (DTX), which were designed to combine features of biological and physical (magnetic) drug targeting for fullerene radiofrequency-triggered drug release. The magnetic liposomes not only served as powerful tumor diagnostic magnetic resonance imaging (MRI) contrast agents, but also as powerful agents for photothermal ablation of tumors. Furthermore, a remarkable thermal therapy combined chemotherapy multi-functional liposome nanoplatform converted radiofrequency energy into thermal energy to release drugs from thermosensitive liposomes, which was also observed during both in vitro and in vivo treatment. The multi-functional liposomes also could selectively kill cancer cells in highly localized regions via their excellent active tumor targeting and magnetic targeted abilities.

Phthalocyanine-labeled LDL for tumor imaging and photodynamic therapy

NASA Astrophysics Data System (ADS)

Li, Hui; Marotta, Diane; Kim, Soungkyoo; Chance, Britton; Glickson, Jerry D.; Busch, Theresa M.; Zheng, Gang

2005-01-01

Current limitation of both near-infrared (NIR) tumor imaging and photodynamic therapy (PDT) is their lack of sufficient tumor-to-tissue contrast due to the relatively non-specific nature of delivering dye to the tumor, which has led to false negatives for NIR imaging and inadequate therapeutic ratio for PDT. Hence, agents targeting "cancer signatures", i.e. molecules that accumulate selectively in cancer cells, are particular attractive. One of these signatures is low-density-lipoprotein receptor (LDLR), which is overexpressed in many tumors. We have developed pyropheophorbide cholesterol oleate reconstituted LDL as a LDLR-targeting photosensitizer (PS) and demonstrated its LDLR-mediated uptake in vitro and in vivo. To improve the labeling efficiency for achieving high probe/protein ratio, tetra-t-butyl silicon phthalocyanine bearing two oleate moieties at its axial positions, (tBu)4SiPcBOA, was designed and synthesized. This compound was designed to 1) prevent the PS aggregation; 2) improve the PS solubility in non-polar solvent; and 3) maximize the PS binding to LDL phospholipid monolayer. Using this novel strategy, (tBu)4SiPcBOA was reconstituted into LDL (r-SiPcBOA-LDL) with a very high payload (500:1 molar ratio). In addition, (tBu)4SiPcBOA reconstituted acetylated LDL (r-SiPcBOA)-AcLDL with similar payload was also prepared. Since Ac-LDL cannot bind to LDLR, (r-SiPcBOA)-AcLDL can serve as the negative control to evaluate LDLR targeting specificity. For biological evaluation of these new agents, confocal microscopy and in vitro PDT protocols were performed using LDLR-overexpressing human hepatoblastoma G2 (HepG2) tumor model. These studies suggest that LDL serves as a delivery vehicle to bring large amount of the NIR/PDT agents selectively to tumor cells overexpressing LDLR.

Synthesis and evaluation of novel Tc-99m labeled NGR-containing hexapeptides as tumor imaging agents.

PubMed

Kim, Dae-Weung; Kim, Woo Hyoung; Kim, Myoung Hyoun; Kim, Chang Guhn

2015-02-01

Asparagine-glycine-arginine (NGR)-containing peptides targeting aminopeptidase N (APN)/CD13 can be an excellent candidate for targeting ligands in molecular tumor imaging. In this study, we developed two NGR-containing hexapeptides, and evaluated the diagnostic performance of Tc-99m labeled hexapeptides as molecular imaging agents in an HT-1080 fibrosarcoma-bearing murine model. Peptides were synthesized using Fmoc solid-phase peptide synthesis. Radiochemical purity of Tc-99m was evaluated using instant thin-layer chromatography. The uptake of two NGR-containing hexapeptides within HT-1080 cells was evaluated in vitro. In HT-1080 fibrosarcoma tumor-bearing mice, gamma images were acquired. A biodistribution study was performed to calculate percentage of the injected dose per gram of tissue (%ID/g). Two hexapeptides, glutamic acid-cysteine-glycine (ECG)-NGR and NGR-ECG were successfully synthesized. After radiolabeling procedures with Tc-99m, the complexes Tc-99m hexapeptides were prepared in high yield. The uptake of Tc-99m ECG-NGR within the tumor cells had been assured by in vitro studies. The gamma camera imaging in the murine model showed that Tc-99m ECG-NGR was accumulated substantially in the subcutaneously engrafted tumor. However, Tc-99m NGR-ECG was accumulated minimally in the tumor. Two NGR-containing hexapeptides, ECG-NGR and NGR-ECG were developed as molecular imaging agents to target APN/CD13 in HT-1080 fibrosarcoma. Tc-99m ECG-NGR showed a significant uptake in the tumor, and it is a good candidate for tumor imaging. Copyright © 2015 John Wiley & Sons, Ltd.

Alpha-fetoprotein-targeted reporter gene expression imaging in hepatocellular carcinoma.

PubMed

Kim, Kwang Il; Chung, Hye Kyung; Park, Ju Hui; Lee, Yong Jin; Kang, Joo Hyun

2016-07-21

Hepatocellular carcinoma (HCC) is one of the most common cancers in Eastern Asia, and its incidence is increasing globally. Numerous experimental models have been developed to better our understanding of the pathogenic mechanism of HCC and to evaluate novel therapeutic approaches. Molecular imaging is a convenient and up-to-date biomedical tool that enables the visualization, characterization and quantification of biologic processes in a living subject. Molecular imaging based on reporter gene expression, in particular, can elucidate tumor-specific events or processes by acquiring images of a reporter gene's expression driven by tumor-specific enhancers/promoters. In this review, we discuss the advantages and disadvantages of various experimental HCC mouse models and we present in vivo images of tumor-specific reporter gene expression driven by an alpha-fetoprotein (AFP) enhancer/promoter system in a mouse model of HCC. The current mouse models of HCC development are established by xenograft, carcinogen induction and genetic engineering, representing the spectrum of tumor-inducing factors and tumor locations. The imaging analysis approach of reporter genes driven by AFP enhancer/promoter is presented for these different HCC mouse models. Such molecular imaging can provide longitudinal information about carcinogenesis and tumor progression. We expect that clinical application of AFP-targeted reporter gene expression imaging systems will be useful for the detection of AFP-expressing HCC tumors and screening of increased/decreased AFP levels due to disease or drug treatment.

Alpha-fetoprotein-targeted reporter gene expression imaging in hepatocellular carcinoma

PubMed Central

Kim, Kwang Il; Chung, Hye Kyung; Park, Ju Hui; Lee, Yong Jin; Kang, Joo Hyun

2016-01-01

Hepatocellular carcinoma (HCC) is one of the most common cancers in Eastern Asia, and its incidence is increasing globally. Numerous experimental models have been developed to better our understanding of the pathogenic mechanism of HCC and to evaluate novel therapeutic approaches. Molecular imaging is a convenient and up-to-date biomedical tool that enables the visualization, characterization and quantification of biologic processes in a living subject. Molecular imaging based on reporter gene expression, in particular, can elucidate tumor-specific events or processes by acquiring images of a reporter gene’s expression driven by tumor-specific enhancers/promoters. In this review, we discuss the advantages and disadvantages of various experimental HCC mouse models and we present in vivo images of tumor-specific reporter gene expression driven by an alpha-fetoprotein (AFP) enhancer/promoter system in a mouse model of HCC. The current mouse models of HCC development are established by xenograft, carcinogen induction and genetic engineering, representing the spectrum of tumor-inducing factors and tumor locations. The imaging analysis approach of reporter genes driven by AFP enhancer/promoter is presented for these different HCC mouse models. Such molecular imaging can provide longitudinal information about carcinogenesis and tumor progression. We expect that clinical application of AFP-targeted reporter gene expression imaging systems will be useful for the detection of AFP-expressing HCC tumors and screening of increased/decreased AFP levels due to disease or drug treatment. PMID:27468205

Targeted two-photon PDT photo-sensitizers for the treatment of subcutaneous tumors

NASA Astrophysics Data System (ADS)

Spangler, C. W.; Rebane, A.; Starkey, J.; Drobizhev, M.

2009-06-01

New porphyrin-based photo-sensitizers have been designed, synthesized and characterized that exhibit greatly enhanced intrinsic two-photon absorption. These new photo-sensitizers have been incorporated into triad formulations that also incorporate Near-infrared (NIR) imaging agents, and small-molecule targeting agents that direct the triads to cancerous tumors' over-expressed receptor sites. PDT can be initiated deep into the tissue transparency window at 780-800 nm utilizing a regeneratively amplified Ti:sapphire laser using 100-150 fs pulses of 600-800 mW. Human tumor xenografts of human breast cancer (MDA-MB-231) and both small SCLC (NCI-H69) and NSCLC (A-459) have been successfully treated using octreotate targeting of over-expressed SST2 receptors. In particular, the lung cancer xenografts can be successfully treated by irradiating from the side of the mouse opposite the implanted tumor, thereby passing through ca. 2 cm of mouse skin, tissue and organs with no discernible damage to healthy tissue while causing regression in the tumors. These results suggest a new PDT paradigm for the noninvasive treatment of subcutaneous tumors, including the possibility that the targeting moiety could be matched to individual patient genetic profiles (patient-specific therapeutics).

[The development of novel tumor targeting delivery strategy].

PubMed

Gao, Hui-le; Jiang, Xin-guo

2016-02-01

Tumor is one of the most serious threats for human being. Although many anti-tumor drugs are approved for clinical use, the treatment outcome is still modest because of the poor tumor targeting efficiency and low accumulation in tumor. Therefore, it is important to deliver anti-tumor drug into tumor efficiently, elevate drug concentration in tumor tissues and reduce the drug distribution in normal tissues. And it has been one of the most attractive directions of pharmaceutical academy and industry. Many kinds of strategies, especially various nanoparticulated drug delivery systems, have been developed to address the critical points of complex tumor microenvironment, which are partially or mostly satisfied for tumor treatment. In this paper, we carefully reviewed the novel targeting delivery strategies developed in recent years. The most powerful method is passive targeting delivery based on the enhanced permeability and retention(EPR) effect, and most commercial nanomedicines are based on the EPR effect. However, the high permeability and retention require different particle sizes, thus several kinds of size-changeable nanoparticles are developed, such as size reducible particles and assemble particles, to satisfy the controversial requirement for particle size and enhance both tumor retention and penetration. Surface charge reversible nanoparticles also shows a high efficiency because the anionic charge in blood circulation and normal organs decrease the unintended internalization. The charge can change into positive in tumor microenvironment, facilitating drug uptake by tumor cells. Additionally, tumor microenvironment responsive drug release is important to decrease drug side effect, and many strategies are developed, such as p H sensitive release and enzyme sensitive release. Except the responsive nanoparticles, shaping tumor microenvironment could attenuate the barriers in drug delivery, for example, decreasing tumor collagen intensity and normalizing tumor

Improving oncoplastic breast tumor bed localization for radiotherapy planning using image registration algorithms

NASA Astrophysics Data System (ADS)

Wodzinski, Marek; Skalski, Andrzej; Ciepiela, Izabela; Kuszewski, Tomasz; Kedzierawski, Piotr; Gajda, Janusz

2018-02-01

Knowledge about tumor bed localization and its shape analysis is a crucial factor for preventing irradiation of healthy tissues during supportive radiotherapy and as a result, cancer recurrence. The localization process is especially hard for tumors placed nearby soft tissues, which undergo complex, nonrigid deformations. Among them, breast cancer can be considered as the most representative example. A natural approach to improving tumor bed localization is the use of image registration algorithms. However, this involves two unusual aspects which are not common in typical medical image registration: the real deformation field is discontinuous, and there is no direct correspondence between the cancer and its bed in the source and the target 3D images respectively. The tumor no longer exists during radiotherapy planning. Therefore, a traditional evaluation approach based on known, smooth deformations and target registration error are not directly applicable. In this work, we propose alternative artificial deformations which model the tumor bed creation process. We perform a comprehensive evaluation of the most commonly used deformable registration algorithms: B-Splines free form deformations (B-Splines FFD), different variants of the Demons and TV-L1 optical flow. The evaluation procedure includes quantitative assessment of the dedicated artificial deformations, target registration error calculation, 3D contour propagation and medical experts visual judgment. The results demonstrate that the currently, practically applied image registration (rigid registration and B-Splines FFD) are not able to correctly reconstruct discontinuous deformation fields. We show that the symmetric Demons provide the most accurate soft tissues alignment in terms of the ability to reconstruct the deformation field, target registration error and relative tumor volume change, while B-Splines FFD and TV-L1 optical flow are not an appropriate choice for the breast tumor bed localization problem

GPER-targeted, 99mTc-labeled, nonsteroidal ligands demonstrate selective tumor imaging and in vivo estrogen binding

PubMed Central

Nayak, Tapan K.; Ramesh, Chinnasamy; Hathaway, Helen J.; Norenberg, Jeffrey P.; Arterburn, Jeffrey B.; Prossnitz, Eric R.

2014-01-01

Our understanding of estrogen (E2) receptor biology has evolved in recent years with the discovery and characterization of a 7-transmembrane-spanning G protein-coupled estrogen receptor (GPER1/GPER/GPR30) and the development of GPER-selective functional chemical probes. GPER is highly expressed in certain breast, endometrial and ovarian cancers, establishing the importance of non-invasive methods to evaluate GPER expression in vivo. Herein, we developed 99mTc-labeled GPER ligands to demonstrate the in vivo status of GPER as an estrogen receptor and for GPER visualization in whole animals. A series of 99mTc(I)-labeled non-steroidal tetrahydro-3H-cyclopenta[c]quinolone derivatives was synthesized utilizing pyridin-2-yl hydrazine and picolylamine chelates. Radioligand receptor binding studies revealed binding affinities in the 10–30 nM range. Cell signaling assays previously demonstrated that derivatives retaining a ketone functionality displayed agonist properties whereas those lacking such a hydrogen bond acceptor were antagonists. In vivo biodistribution and imaging studies performed on mice bearing human endometrial and breast cancer cell xenografts yielded significant tumor uptake (0.4–1.1 %ID/g). Blocking studies revealed specific uptake in multiple organs (adrenals, uterus, mammary tissue) as well as tumor uptake with similar levels of competition by E2 and G-1, a GPER-selective agonist. In conclusion, we synthesized and evaluated a series of first generation 99mTc-labeled GPER-specific radioligands, demonstrating GPER as an estrogen-binding receptor for the first time in vivo using competitive binding principles, and establishing the utility of such ligands as tumor imaging agents. These results warrant further investigation into the role of GPER in estrogen-mediated carcinogenesis and as a target for diagnostic/therapeutic/ image-guided drug delivery. PMID:25030373

Facilitating in vivo tumor localization by principal component analysis based on dynamic fluorescence molecular imaging

NASA Astrophysics Data System (ADS)

Gao, Yang; Chen, Maomao; Wu, Junyu; Zhou, Yuan; Cai, Chuangjian; Wang, Daliang; Luo, Jianwen

2017-09-01

Fluorescence molecular imaging has been used to target tumors in mice with xenograft tumors. However, tumor imaging is largely distorted by the aggregation of fluorescent probes in the liver. A principal component analysis (PCA)-based strategy was applied on the in vivo dynamic fluorescence imaging results of three mice with xenograft tumors to facilitate tumor imaging, with the help of a tumor-specific fluorescent probe. Tumor-relevant features were extracted from the original images by PCA and represented by the principal component (PC) maps. The second principal component (PC2) map represented the tumor-related features, and the first principal component (PC1) map retained the original pharmacokinetic profiles, especially of the liver. The distribution patterns of the PC2 map of the tumor-bearing mice were in good agreement with the actual tumor location. The tumor-to-liver ratio and contrast-to-noise ratio were significantly higher on the PC2 map than on the original images, thus distinguishing the tumor from its nearby fluorescence noise of liver. The results suggest that the PC2 map could serve as a bioimaging marker to facilitate in vivo tumor localization, and dynamic fluorescence molecular imaging with PCA could be a valuable tool for future studies of in vivo tumor metabolism and progression.

Markerless EPID image guided dynamic multi-leaf collimator tracking for lung tumors

NASA Astrophysics Data System (ADS)

Rottmann, J.; Keall, P.; Berbeco, R.

2013-06-01

Compensation of target motion during the delivery of radiotherapy has the potential to improve treatment accuracy, dose conformity and sparing of healthy tissue. We implement an online image guided therapy system based on soft tissue localization (STiL) of the target from electronic portal images and treatment aperture adaptation with a dynamic multi-leaf collimator (DMLC). The treatment aperture is moved synchronously and in real time with the tumor during the entire breathing cycle. The system is implemented and tested on a Varian TX clinical linear accelerator featuring an AS-1000 electronic portal imaging device (EPID) acquiring images at a frame rate of 12.86 Hz throughout the treatment. A position update cycle for the treatment aperture consists of four steps: in the first step at time t = t0 a frame is grabbed, in the second step the frame is processed with the STiL algorithm to get the tumor position at t = t0, in a third step the tumor position at t = ti + δt is predicted to overcome system latencies and in the fourth step, the DMLC control software calculates the required leaf motions and applies them at time t = ti + δt. The prediction model is trained before the start of the treatment with data representing the tumor motion. We analyze the system latency with a dynamic chest phantom (4D motion phantom, Washington University). We estimate the average planar position deviation between target and treatment aperture in a clinical setting by driving the phantom with several lung tumor trajectories (recorded from fiducial tracking during radiotherapy delivery to the lung). DMLC tracking for lung stereotactic body radiation therapy without fiducial markers was successfully demonstrated. The inherent system latency is found to be δt = (230 ± 11) ms for a MV portal image acquisition frame rate of 12.86 Hz. The root mean square deviation between tumor and aperture position is smaller than 1 mm. We demonstrate the feasibility of real-time markerless DMLC

A novel solid lipid nanoparticle formulation for active targeting to tumor α(v) β(3) integrin receptors reveals cyclic RGD as a double-edged sword.

PubMed

Shuhendler, Adam J; Prasad, Preethy; Leung, Michael; Rauth, Andrew M; Dacosta, Ralph S; Wu, Xiao Yu

2012-09-01

The overexpression of α(v) β(3) integrin receptors on tumor cells and tumor vascular endothelium makes it a useful target for imaging, chemotherapy and anti-angiogenic therapy. However integrin-targeted delivery of therapeutics by nanoparticles have provided only marginal, if any, enhancement of therapeutic effect. This work was thus focused on the development of novel α(v) β(3) -targeted near infrared light-emitting solid lipid nanoparticles (SLN) through conjugation to the α(v) β(3) integrin-specific ligand cyclic Arg-Gly-Asp (cRGD), and the assessment of the effects of α(v) β(3) targeting on nanoparticle biodistribution. Since our previously developed non-targeted "stealth" SLN showed little hepatic accumulation, unlike most reported liposomes and micelles, they served as a reference for quantifying the effects of cRGD-conjugation on tumor uptake and whole animal biodistribution of SLN. Non-targeted SLN, actively targeted (RGD-SLN) and blocked RGD-SLN were prepared to contain near infrared quantum dots for live animal imaging. They were injected intravenously to nude mice bearing xenograft orthotopic human breast tumors or dorsal window chamber breast tumors. Tumor micropharmacokinetics of various SLN formulations were determined using intravital microscopy, and whole animal biodistribution was followed over time by optical imaging. The active tumor targeting with cRGD was found to be a "double-edged sword": while the specificity of RGD-SLN accumulation in tumor blood vessels and their tumor residence time increased, their distribution in the liver, spleen, and kidneys was significantly greater than the non-targeted SLN, leaving a smaller amount of nanoparticles in the tumor tissue. Nevertheless the enhanced specificity and retention of RGD-SLN in tumor neovasculature could make this novel formulation useful for tumor neovascular-specific therapies and imaging applications. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

GPER-targeted, 99mTc-labeled, nonsteroidal ligands demonstrate selective tumor imaging and in vivo estrogen binding.

PubMed

Nayak, Tapan K; Ramesh, Chinnasamy; Hathaway, Helen J; Norenberg, Jeffrey P; Arterburn, Jeffrey B; Prossnitz, Eric R

2014-11-01

Our understanding of estrogen (17β-estradiol, E2) receptor biology has evolved in recent years with the discovery and characterization of a 7-transmembrane-spanning G protein-coupled estrogen receptor (GPER/GPR30) and the development of GPER-selective functional chemical probes. GPER is highly expressed in certain breast, endometrial, and ovarian cancers, establishing the importance of noninvasive methods to evaluate GPER expression in vivo. Here, we developed (99m)Tc-labeled GPER ligands to demonstrate the in vivo status of GPER as an estrogen receptor (ER) and for GPER visualization in whole animals. A series of (99m)Tc(I)-labeled nonsteroidal tetrahydro-3H-cyclopenta[c]quinolone derivatives was synthesized utilizing pyridin-2-yl hydrazine and picolylamine chelates. Radioligand receptor binding studies revealed binding affinities in the 10 to 30 nmol/L range. Cell signaling assays previously demonstrated that derivatives retaining a ketone functionality displayed agonist properties, whereas those lacking such a hydrogen bond acceptor were antagonists. In vivo biodistribution and imaging studies performed on mice bearing human endometrial and breast cancer cell xenografts yielded significant tumor uptake (0.4-1.1%ID/g). Blocking studies revealed specific uptake in multiple organs (adrenals, uterus, and mammary tissue), as well as tumor uptake with similar levels of competition by E2 and G-1, a GPER-selective agonist. In conclusion, we synthesized and evaluated a series of first-generation (99m)Tc-labeled GPER-specific radioligands, demonstrating GPER as an estrogen-binding receptor for the first time in vivo using competitive binding principles, and establishing the utility of such ligands as tumor imaging agents. These results warrant further investigation into the role of GPER in estrogen-mediated carcinogenesis and as a target for diagnostic/therapeutic/image-guided drug delivery. These studies provide a molecular basis to evaluate GPER expression and function

Targeting Tumor Oct4 to Deplete Prostate Tumor and Metastasis Initiating Cells

DTIC Science & Technology

2016-10-01

Award Number: W81XWH-13-1-0461 TITLE: Targeting Tumor Oct4 to Deplete Prostate Tumor- and Metastasis-Initiating Cells PRINCIPAL INVESTIGATOR: Daotai...29 2016 4. TITLE AND SUBTILE Targeting Tumor Oct4 to Deplete Prostate Tumor- and Metastasis-Initiating Cells 5a. CONTRACT NUMBER 5b. GRANT NUMBER...the c-MYC oncogene. POU5F1B is a pseudogene of embryonic Oct4 (POU5F1). A recent study found that tumor Oct4 found in prostate cancer cells is due

Instrumentation of Molecular Imaging on Site-Specific Targeting Fluorescent Peptide for Early Detection of Breast Cancer

NASA Astrophysics Data System (ADS)

Yu, Ping; Ma, Lixin

2012-02-01

In this work we developed two biomedical imaging techniques for early detection of breast cancer. Both image modalities provide molecular imaging capability to probe site-specific targeting dyes. The first technique, heterodyne CCD fluorescence mediated tomography, is a non-invasive biomedical imaging that uses fluorescent photons from the targeted dye on the tumor cells inside human breast tissue. The technique detects a large volume of tissue (20 cm) with a moderate resolution (1 mm) and provides the high sensitivity. The second technique, dual-band spectral-domain optical coherence tomography, is a high-resolution tissue imaging modality. It uses a low coherence interferometer to detect coherent photons hidden in the incoherent background. Due to the coherence detection, a high resolution (20 microns) is possible. We have finished prototype imaging systems for the development of both image modalities and performed imaging experiments on tumor tissues. The spectroscopic/tomographic images show contrasts of dense tumor tissues and tumor necrotic regions. In order to correlate the findings from our results, a diffusion-weighted magnetic resonance imaging (MRI) of the tumors was performed using a small animal 7-Telsa MRI and demonstrated excellent agreement.

Molecular imaging with targeted contrast ultrasound.

PubMed

Piedra, Mark; Allroggen, Achim; Lindner, Jonathan R

2009-01-01

Molecular imaging with contrast-enhanced ultrasound uses targeted microbubbles that are retained in diseased tissue. The resonant properties of these microbubbles produce acoustic signals in an ultrasound field. The microbubbles are targeted to diseased tissue by using certain chemical constituents in the microbubble shell or by attaching disease-specific ligands such as antibodies to the microbubble. In this review, we discuss the applications of this technique to pathological states in the cerebrovascular system including atherosclerosis, tumor angiogenesis, ischemia, intravascular thrombus, and inflammation. Copyright 2009 S. Karger AG, Basel.

Assessment of α-fetoprotein targeted HSV1-tk expression in hepatocellular carcinoma with in vivo imaging.

PubMed

Park, Ju Hui; Kim, Kwang Il; Lee, Kyo Chul; Lee, Yong Jin; Lee, Tae Sup; Chung, Wee Sup; Lim, Sang Moo; Kang, Joo Hyun

2015-02-01

Tumor-specific enhancer/promoter is applicable for targeting gene expression in tumors and helpful for tumor-targeting imaging and therapy. We aimed to acquire α-fetoprotein (AFP)-producing hepatocellular carcinoma (HCC) specific images using adenovirus containing HSV1-tk gene controlled by AFP enhancer/promoter and evaluate in vivo ganciclovir (GCV)-medicated therapeutic effects on AFP-targeted HSV1-tk expression with (18)F-FDG positron emission tomography (PET). Recombinant adenovirus expressing HSV1-tk under AFP enhancer/promoter was produced (AdAFP-TK) and the expression levels were evaluated by RT-PCR and (125)I-IVDU uptake. GCV-mediated HSV1-tk cytotoxicity was determined by MTT assay. After the mixture of AdAFP-fLuc and AdAFP-TK was administrated, bioluminescent images (BLIs) and (18)F-FHBG PET images were obtained in tumor-bearing mice. In vivo therapeutic effects of AdAFP-TK and GCV in the HuH-7 xenograft model were monitored by (18)F-FDG PET. When infected with AdAFP-TK, cell viability in HuH-7 was reduced, but those in HT-29 and SK-Hep-1 were not significantly decreased at any GCV concentration less than 100 μM. AFP-targeted fLuc and HSV1-tk expression were clearly visualized by BLI and (18)F-FHBG PET images in AFP-producing HCC, respectively. In vivo GCV-mediated tumor growth inhibition by AFP-targeted HSV1-tk expression was monitored by (18)F-FDG PET. Recombinant AdAFP-TK could be applied for AFP-targeted HCC gene therapy and imaging in AFP-producing HCC.

Tumor Endothelial Marker Imaging in Melanomas Using Dual-Tracer Fluorescence Molecular Imaging

PubMed Central

Tichauer, Kenneth M.; Deharvengt, Sophie J.; Samkoe, Kimberley S.; Gunn, Jason R.; Bosenberg, Marcus W.; Turk, Mary-Jo; Hasan, Tayyaba; Stan, Radu V.; Pogue, Brian W.

2014-01-01

Purpose Cancer-specific endothelial markers available for intravascular binding are promising targets for new molecular therapies. In this study, a molecular imaging approach of quantifying endothelial marker concentrations (EMCI) is developed and tested in highly light-absorbing melanomas. The approach involves injection of targeted imaging tracer in conjunction with an untargeted tracer, which is used to account for nonspecific uptake and tissue optical property effects on measured targeted tracer concentrations. Procedures Theoretical simulations and a mouse melanoma model experiment were used to test out the EMCI approach. The tracers used in the melanoma experiments were fluorescently labeled anti-Plvap/PV1 antibody (plasmalemma vesicle associated protein Plvap/PV1 is a transmembrane protein marker exposed on the luminal surface of endothelial cells in tumor vasculature) and a fluorescent isotype control antibody, the uptakes of which were measured on a planar fluorescence imaging system. Results The EMCI model was found to be robust to experimental noise under reversible and irreversible binding conditions and was capable of predicting expected overexpression of PV1 in melanomas compared to healthy skin despite a 5-time higher measured fluorescence in healthy skin compared to melanoma: attributable to substantial light attenuation from melanin in the tumors. Conclusions This study demonstrates the potential of EMCI to quantify endothelial marker concentrations in vivo, an accomplishment that is currently unavailable through any other methods, either in vivo or ex vivo. PMID:24217944

Tumor-targeting Salmonella typhimurium A1-R Inhibits Osteosarcoma Angiogenesis in the In Vivo Gelfoam® Assay Visualized by Color-coded Imaging.

PubMed

Kiyuna, Tasuku; Tome, Yasunori; Uehara, Fuminari; Murakami, Takashi; Zhang, Yong; Zhao, Ming; Kanaya, Fuminori; Hoffman, Robert M

2018-01-01

We previously developed a color-coded imaging model that can quantify the length of nascent blood vessels using Gelfoam® implanted in nestin-driven green fluorescent protein (ND-GFP) nude mice. In this model, nascent blood vessels selectively express GFP. We also previously showed that osteosarcoma cells promote angiogenesis in this assay. We have also previously demonstrated the tumor-targeting bacteria Salmonella typhimurium A1-R (S. typhimurium A1-R) can inhibit or regress all tested tumor types in mouse models. The aim of the present study was to determine if S. typhimurium A1-R could inhibit osteosarcoma angiogenesis in the in vivo Gelfoam® color-coded imaging assay. Gelfoam® was implanted subcutaneously in ND-GFP nude mice. Skin flaps were made 7 days after implantation and 143B-RFP human osteosarcoma cells expressing red fluorescent protein (RFP) were injected into the implanted Gelfoam. After establishment of tumors in the Gelfoam®, control-group mice were treated with phosphate buffered saline via tail-vein injection (iv) and the experimental group was treated with S. typhimurium A1-R iv Skin flaps were made at day 7, 14, 21, and 28 after implantation of the Gelfoam® to allow imaging of vascularization in the Gelfoam® using a variable-magnification small-animal imaging system and confocal fluorescence microscopy. Nascent blood vessels expressing ND-GFP extended into the Gelfoam® over time in both groups. However, the extent of nascent blood-vessel growth was significantly inhibited by S. typhimurium A1-R treatment by day 28. The present results indicate S. typhimurium A1-R has potential for anti-angiogenic targeted therapy of osteosarcoma. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

FDG-PET/CT imaging for tumor staging and definition of tumor volumes in radiation treatment planning in non-small cell lung cancer.

PubMed

Zheng, Yuanda; Sun, Xiaojiang; Wang, Jian; Zhang, Lingnan; DI, Xiaoyun; Xu, Yaping

2014-04-01

18 F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) has the potential to improve the staging and radiation treatment (RT) planning of various tumor sites. However, from a clinical standpoint, questions remain with regard to what extent PET/CT changes the target volume and whether PET/CT reduces interobserver variability in target volume delineation. The present study analyzed the use of FDG-PET/CT images for staging and evaluated the impact of FDG-PET/CT on the radiotherapy volume delineation compared with CT in patients with non-small cell lung cancer (NSCLC) who were candidates for radiotherapy. Intraobserver variation in delineating tumor volumes was also observed. In total, 23 patients with stage I-III NSCLC were enrolled and treated with fractionated RT-based therapy with or without chemotherapy. FDG-PET/CT scans were acquired within two weeks prior to RT. PET and CT data sets were sent to the treatment planning system, Pinnacle, through compact discs. The CT and PET images were subsequently fused by means of a dedicated RT planning system. Gross tumor volume (GTV) was contoured by four radiation oncologists on CT (GTV-CT) and PET/CT images (GTV-PET/CT). The resulting volumes were analyzed and compared. For the first phase, two radiation oncologists outlined the contours together, achieving a final consensus. Based on PET/CT, changes in tumor-node-metastasis categories occurred in 8/23 cases (35%). Radiation targeting with fused FDG-PET and CT images resulted in alterations in radiation therapy planning in 12/20 patients (60%) in comparison with CT targeting. The most prominent changes in GTV were observed in cases with atelectasis. For the second phase, the variation in delineating tumor volumes was assessed by four observers. The mean ratio of largest to smallest CT-based GTV was 2.31 (range, 1.01-5.96). The addition of the PET results reduced the mean ratio to 1.46 (range, 1.02-2.27). PET/CT fusion images may have a

Development of PLGA-lipid nanoparticles with covalently conjugated indocyanine green as a versatile nanoplatform for tumor-targeted imaging and drug delivery.

PubMed

Xin, Yu; Liu, Tie; Yang, Chenlong

We have prepared novel poly(d,l-lactide- co -glycolide) (PLGA) lipid nanoparticles (PNPs) that covalently conjugate folic acid (FA) and indocyanine green (ICG), in addition to encapsulating resveratrol (RSV) (FA-RSV/ICG-PLGA-lipid NPs, abbreviated as FA-RIPNPs); these nanoparticles have been developed for simultaneous targeted delivery of anticancer drug and fluorescence imaging. The FA-RIPNPs, with an average particle size of 92.8±2.1 nm, were prepared by a facile self-assembly-and-nanoprecipitation method, and they showed excellent stability and biocompatibility characteristics. The FA-RIPNPs exhibited an RSV encapsulation efficiency of approximately 65.6%±4.7% and a maximum release ratio of 78.2%±4.1% at pH 5.0 and 37°C. Confocal fluorescence images showed that FA-RIPNPs may facilitate a high cellular uptake via FA receptor-mediated endocytosis. Furthermore, FA-RIPNPs (containing 50 μg/mL RSV) induced a 81.4%±2.1% U87 cell inhibition rate via apoptosis, a value that proved to be higher than what has been shown for free RSV (53.1%±1.1%, equivalent RSV concentration). With a formulated polyethylene glycol (PEG) shell around the PLGA core, FA-RIPNPs prolonged the blood circulation of both free RSV and ICG, which approximately increased 6.96- and 39.4-fold ( t 1/2 ), respectively. Regarding FA-RIPNP use as a near-infrared probe, in vivo fluorescence images indicated a highly efficient accumulation of FA-RIPNPs in the tumor tissue, which proved to be approximately 2.8- and 12.6-fold higher than the RIPNPs and free ICG, respectively. Intravenous injection of FA-RIPNPs into U87 tumor-bearing mice demonstrated the best tumor inhibition effect for all tested drugs, including free RSV and RIPNPs, with no relapse, showing high biocompatibility and with no significant systemic in vivo toxicity over the course of the treatment (1 month). The results obtained demonstrate the versatility of the NPs, featuring stable fluorescence and tumor-targeting characteristics, with

Development of PLGA-lipid nanoparticles with covalently conjugated indocyanine green as a versatile nanoplatform for tumor-targeted imaging and drug delivery

PubMed Central

Xin, Yu; Liu, Tie; Yang, Chenlong

2016-01-01

We have prepared novel poly(d,l-lactide-co-glycolide) (PLGA) lipid nanoparticles (PNPs) that covalently conjugate folic acid (FA) and indocyanine green (ICG), in addition to encapsulating resveratrol (RSV) (FA-RSV/ICG-PLGA-lipid NPs, abbreviated as FA-RIPNPs); these nanoparticles have been developed for simultaneous targeted delivery of anticancer drug and fluorescence imaging. The FA-RIPNPs, with an average particle size of 92.8±2.1 nm, were prepared by a facile self-assembly-and-nanoprecipitation method, and they showed excellent stability and biocompatibility characteristics. The FA-RIPNPs exhibited an RSV encapsulation efficiency of approximately 65.6%±4.7% and a maximum release ratio of 78.2%±4.1% at pH 5.0 and 37°C. Confocal fluorescence images showed that FA-RIPNPs may facilitate a high cellular uptake via FA receptor-mediated endocytosis. Furthermore, FA-RIPNPs (containing 50 μg/mL RSV) induced a 81.4%±2.1% U87 cell inhibition rate via apoptosis, a value that proved to be higher than what has been shown for free RSV (53.1%±1.1%, equivalent RSV concentration). With a formulated polyethylene glycol (PEG) shell around the PLGA core, FA-RIPNPs prolonged the blood circulation of both free RSV and ICG, which approximately increased 6.96- and 39.4-fold (t1/2), respectively. Regarding FA-RIPNP use as a near-infrared probe, in vivo fluorescence images indicated a highly efficient accumulation of FA-RIPNPs in the tumor tissue, which proved to be approximately 2.8- and 12.6-fold higher than the RIPNPs and free ICG, respectively. Intravenous injection of FA-RIPNPs into U87 tumor-bearing mice demonstrated the best tumor inhibition effect for all tested drugs, including free RSV and RIPNPs, with no relapse, showing high biocompatibility and with no significant systemic in vivo toxicity over the course of the treatment (1 month). The results obtained demonstrate the versatility of the NPs, featuring stable fluorescence and tumor-targeting characteristics, with

Transferrin-mediated rapid targeting, isolation, and detection of circulating tumor cells by multifunctional magneto-dendritic nanosystem.

PubMed

Banerjee, Shashwat S; Jalota-Badhwar, Archana; Satavalekar, Sneha D; Bhansali, Sujit G; Aher, Naval D; Mascarenhas, Russel R; Paul, Debjani; Sharma, Somesh; Khandare, Jayant J

2013-06-01

A multicomponent magneto-dendritic nanosystem (MDNS) is designed for rapid tumor cell targeting, isolation, and high-resolution imaging by a facile bioconjugation approach. The highly efficient and rapid-acting MDNS provides a convenient platform for simultaneous isolation and high-resolution imaging of tumor cells, potentially leading towards an early diagnosis of cancer. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Nonclinical Profile of BLZ-100, a Tumor-Targeting Fluorescent Imaging Agent.

PubMed

Parrish-Novak, Julia; Byrnes-Blake, Kelly; Lalayeva, Narine; Burleson, Stefanie; Fidel, Janean; Gilmore, Rhonda; Gayheart-Walsten, Pamela; Bricker, Gregory A; Crumb, William J; Tarlo, K S; Hansen, Stacey; Wiss, Valorie; Malta, Errol; Dernell, William S; Olson, James M; Miller, Dennis M

BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. BLZ-100 is in clinical development for intraoperative visualization of human tumors. The nonclinical safety and pharmacokinetic (PK) profile of BLZ-100 was evaluated in mice, rats, canines, and nonhuman primates (NHP). Single bolus intravenous administration of BLZ-100 was well tolerated, and no adverse changes were observed in cardiovascular safety pharmacology, PK, and toxicology studies in rats and NHP. The single-dose no-observed-adverse-effect-levels (NOAELs) were 7 mg (28 mg/kg) in rats and 60 mg (20 mg/kg) in NHP, corresponding to peak concentration values of 89 400 and 436 000 ng/mL and area-under-the-curve exposure values of 130 000 and 1 240 000 h·ng/mL, respectively. Based on a human imaging dose of 3 mg, dose safety margins are >100 for rat and monkey. BLZ-100 produced hypersensitivity reactions in canine imaging studies (lethargy, pruritus, swollen muzzle, etc). The severity of the reactions was not dose related. In a follow-up study in dogs, plasma histamine concentrations were increased 5 to 60 minutes after BLZ-100 injection; this coincided with signs of hypersensitivity, supporting the conclusion that the reactions were histamine based. Hypersensitivity reactions were not observed in other species or in BLZ-100 human clinical studies conducted to date. The combined imaging, safety pharmacology, PK, and toxicology studies contributed to an extensive initial nonclinical profile for BLZ-100, supporting first-in-human clinical trials.

A new target ligand Ser-Glu for PEPT1-overexpressing cancer imaging.

PubMed

Dai, Tongcheng; Li, Na; Zhang, Lingzhi; Zhang, Yuanxing; Liu, Qin

2016-01-01

Nanoparticles functionalized with active target ligands have been widely used for tumor-specific diagnosis and therapy. The target ligands include antibodies, peptides, proteins, small molecules, and nucleic acid aptamers. Here, we utilize dipeptide Ser-Glu (DIP) as a new ligand to functionalize polymer-based fluorescent nanoparticles (NPs) for pancreatic cancer target imaging. We demonstrate that in the first step, Ser-Glu-conjugated NPs (NPs-DIP) efficiently bind to AsPC-1 and in the following NPs-DIP are internalized into AsPC-1 in vitro. The peptide transporter 1 inhibition experiment reveals that the targeting effects mainly depend on the specific binding of DIP to peptide transporter 1, which is remarkably upregulated in pancreatic cancer cells compared with varied normal cells. Furthermore, NPs-DIP specifically accumulate in the site of pancreatic tumor xenograft and are further internalized into the tumor cells in vivo after intravenous administration, indicating that DIP successfully enhanced nanoparticles internalization efficacy into tumor cells in vivo. This work establishes Ser-Glu to be a new tumor-targeting ligand and provides a promising tool for future tumor diagnostic or therapeutic applications.

IGF-1 receptor targeted nanoparticles for image-guided therapy of stroma-rich and drug resistant human cancer

NASA Astrophysics Data System (ADS)

Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M.; Zhou, Zhiyang; Wang, Liya; Wang, Andrew; Mao, Hui; Yang, Lily

2016-05-01

Low drug delivery efficiency and drug resistance from highly heterogeneous cancer cells and tumor microenvironment represent major challenges in clinical oncology. Growth factor receptor, IGF-1R, is overexpressed in both human tumor cells and tumor associated stromal cells. The level of IGF-1R expression is further up-regulated in drug resistant tumor cells. We have developed IGF-1R targeted magnetic iron oxide nanoparticles (IONPs) carrying multiple anticancer drugs into human tumors. This IGF-1R targeted theranostic nanoparticle delivery system has an iron core for non-invasive MR imaging, amphiphilic polymer coating to ensure the biocompatibility as well as for drug loading and conjugation of recombinant human IGF-1 as targeting molecules. Chemotherapy drugs, Doxorubicin (Dox), was encapsulated into the polymer coating and/or conjugated to the IONP surface by coupling with the carboxyl groups. The ability of IGF1R targeted theranostic nanoparticles to penetrate tumor stromal barrier and enhance tumor cell killing has been demonstrated in human pancreatic cancer patient tissue derived xenograft (PDX) models. Repeated systemic administrations of those IGF-1R targeted theranostic IONP carrying Dox led to breaking the tumor stromal barrier and improved therapeutic effect. Near infrared (NIR) optical and MR imaging enabled noninvasive monitoring of nanoparticle-drug delivery and therapeutic responses. Our results demonstrated that IGF-1R targeted nanoparticles carrying multiple drugs are promising combination therapy approaches for image-guided therapy of stroma-rich and drug resistant human cancer, such as pancreatic cancer.

Nanobiotechnology-based delivery strategies: New frontiers in brain tumor targeted therapies.

PubMed

Mangraviti, Antonella; Gullotti, David; Tyler, Betty; Brem, Henry

2016-10-28

Despite recent technological advancements and promising preclinical experiments, brain tumor patients are still met with limited treatment options. Some of the barriers to clinical improvements include the systemic toxicity of cytotoxic compounds, the impedance of the blood brain barrier (BBB), and the lack of therapeutic agents that can selectively target the intracranial tumor environment. To overcome such barriers, a number of chemotherapeutic agents and nucleic acid-based therapies are rapidly being synthesized and tested as new brain tumor-targeted delivery strategies. Novel carriers include liposomal and polymeric nanoparticles, wafers, microchips, microparticle-based nanoplatforms and cells-based vectors. Strong preclinical results suggest that these nanotechnologies are set to transform the therapeutic paradigm for brain tumor treatment. In addition to new tumoricidal agents, parallel work is also being conducted on the BBB front. Preclinical testing of chemical and physical modulation strategies is yielding improved intracranial concentrations. New diagnostic and therapeutic imaging techniques, such as high-intensity focused ultrasound and MRI-guided focused ultrasound, are being used to modulate the BBB in a more precise and non-invasive manner. This review details some of the tremendous advances that are being explored in current brain tumor targeted therapies, including local implant development, nanobiotechnology-based delivery strategies, and techniques of BBB manipulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Imaging Tumor Necrosis with Ferumoxytol

PubMed Central

Aghighi, Maryam; Golovko, Daniel; Ansari, Celina; Marina, Neyssa M.; Pisani, Laura; Kurlander, Lonnie; Klenk, Christopher; Bhaumik, Srabani; Wendland, Michael; Daldrup-Link, Heike E.

2015-01-01

Objective Ultra-small superparamagnetic iron oxide nanoparticles (USPIO) are promising contrast agents for magnetic resonance imaging (MRI). USPIO mediated proton relaxation rate enhancement is strongly dependent on compartmentalization of the agent and can vary depending on their intracellular or extracellular location in the tumor microenvironment. We compared the T1- and T2-enhancement pattern of intracellular and extracellular USPIO in mouse models of cancer and pilot data from patients. A better understanding of these MR signal effects will enable non-invasive characterizations of the composition of the tumor microenvironment. Materials and Methods Six 4T1 and six MMTV-PyMT mammary tumors were grown in mice and imaged with ferumoxytol-enhanced MRI. R1 relaxation rates were calculated for different tumor types and different tumor areas and compared with histology. The transendothelial leakage rate of ferumoxytol was obtained by our measured relaxivity of ferumoxytol and compared between different tumor types, using a t-test. Additionally, 3 patients with malignant sarcomas were imaged with ferumoxytol-enhanced MRI. T1- and T2-enhancement patterns were compared with histopathology in a descriptive manner as a proof of concept for clinical translation of our observations. Results 4T1 tumors showed central areas of high signal on T1 and low signal on T2 weighted MR images, which corresponded to extracellular nanoparticles in a necrotic core on histopathology. MMTV-PyMT tumors showed little change on T1 but decreased signal on T2 weighted images, which correlated to compartmentalized nanoparticles in tumor associated macrophages. Only 4T1 tumors demonstrated significantly increased R1 relaxation rates of the tumor core compared to the tumor periphery (p<0.001). Transendothelial USPIO leakage was significantly higher for 4T1 tumors (3.4±0.9x10-3 mL/min/100cm3) compared to MMTV-PyMT tumors (1.0±0.9x10-3 mL/min/100 cm3). Likewise, ferumoxytol imaging in patients

N-(2-Hydroxypropyl)methacrylamide polymer conjugated pyropheophorbide-a, a promising tumor-targeted theranostic probe for photodynamic therapy and imaging.

PubMed

Fang, Jun; Šubr, Vladimír; Md Islam, Waliul; Hackbarth, Steffen; Md Islam, Rayhanul; Etrych, Tomáš; Ulbrich, Karel; Maeda, Hiroshi

2018-06-07

Tumor-targeted photodynamic therapy (PDT) using polymeric photosensitizers is a promising therapeutic strategy for cancer treatment. In this study, we synthesized a pHPMA conjugated pyropheophorbide-a (P-PyF) as a cancer theranostic agent for PDT and photodynamic diagnostics (PDD). Pyropheophorbide-a has one carboxyl group which was conjugated to pHPMA via amide bond yielding the intended product with high purity. In aqueous solutions, P-PyF showed a mean particle size of ∼200 nm as it forms micelle which exhibited fluorescence quenching and thus very little singlet oxygen ( 1 O 2 ) production. In contrast, upon disruption of micelle strong fluorescence and 1 O 2 production were observed. In vitro study clearly showed the PDT effect of P-PyF. More potent 1 O 2 production and PDT effect were observed during irradiation at ∼420 nm, the maximal absorbance of pyropheophorbide-a, than irradiation at longer wavelength (i.e., ∼ 680 nm), suggesting selection of proper absorption light is essential for successful PDT. In vivo study showed high tumor accumulation of P-PyF compared with most of normal tissues due to the enhanced permeability and retention (EPR) effect, which resulting in superior antitumor effect under irradiation using normal xenon light source of endoscope, and clear tumor imaging profiles even in the metastatic lung cancer at 28 days after administration of P-PyF. On the contrary irradiation using long wavelength (i.e., ∼ 680 nm), the lowest Q-Band, exhibited remarkable tumor imaging effect with little autofluorescence of background. These findings strongly suggested P-PyF may be a potential candidate-drug for PDT/PDD, particularly using two different wavelength for treatment and detection/imaging, respectively. Copyright © 2018. Published by Elsevier B.V.

Arginine-glycine-aspartic acid-conjugated dendrimer-modified quantum dots for targeting and imaging melanoma.

PubMed

Li, Zhiming; Huang, Peng; Lin, Jing; He, Rong; Liu, Bing; Zhang, Xiaomin; Yang, Sen; Xi, Peng; Zhang, Xuejun; Ren, Qiushi; Cui, Daxiang

2010-08-01

Angiogenesis is essential for the development of malignant tumors and provides important targets for tumor diagnosis and therapy. Quantum dots have been broadly investigated for their potential application in cancer molecular imaging. In present work, CdSe quantum dots were synthesized, polyamidoamine dendrimers were used to modify surface of quantum dots and improve their solubility in water solution. Then, dendrimer-modified CdSe quantum dots were conjugated with arginine-glycine-aspartic acid (RGD) peptides. These prepared nanoprobes were injected into nude mice loaded with melanoma (A375) tumor xenografts via tail vessels, IVIS imaging system was used to image the targeting and bio-distribution of as-prepared nanoprobes. The dendrimer-modified quantum dots exhibit water-soluble, high quantum yield, and good biocompatibility. RGD-conjugated quantum dots can specifically target human umbilical vein endothelial cells (HUVEC) and A375 melanoma cells, as well as nude mice loaded with A735 melanoma cells. High-performance RGD-conjugated dendrimers modified quantum dot-based nanoprobes have great potential in application such as tumor diagnosis and therapy.

In vivo tumor targeting of gold nanoparticles: effect of particle type and dosing strategy.

PubMed

Puvanakrishnan, Priyaveena; Park, Jaesook; Chatterjee, Deyali; Krishnan, Sunil; Tunnell, James W

2012-01-01

Gold nanoparticles (GNPs) have gained significant interest as nanovectors for combined imaging and photothermal therapy of tumors. Delivered systemically, GNPs preferentially accumulate at the tumor site via the enhanced permeability and retention effect, and when irradiated with near infrared light, produce sufficient heat to treat tumor tissue. The efficacy of this process strongly depends on the targeting ability of the GNPs, which is a function of the particle's geometric properties (eg, size) and dosing strategy (eg, number and amount of injections). The purpose of this study was to investigate the effect of GNP type and dosing strategy on in vivo tumor targeting. Specifically, we investigated the in vivo tumor-targeting efficiency of pegylated gold nanoshells (GNSs) and gold nanorods (GNRs) for single and multiple dosing. We used Swiss nu/nu mice with a subcutaneous tumor xenograft model that received intravenous administration for a single and multiple doses of GNS and GNR. We performed neutron activation analysis to quantify the gold present in the tumor and liver. We performed histology to determine if there was acute toxicity as a result of multiple dosing. Neutron activation analysis results showed that the smaller GNRs accumulated in higher concentrations in the tumor compared to the larger GNSs. We observed a significant increase in GNS and GNR accumulation in the liver for higher doses. However, multiple doses increased targeting efficiency with minimal effect beyond three doses of GNPs. These results suggest a significant effect of particle type and multiple doses on increasing particle accumulation and on tumor targeting ability.

A targeted nanoglobular contrast agent from host-guest self-assembly for MR cancer molecular imaging

PubMed Central

Zhou, Zhuxian; Han, Zhen; Lu, Zheng-Rong

2016-01-01

The clinical application of nanoparticular Gd(III) based contrast agents for tumor molecular MRI has been hindered by safety concerns associated with prolonged tissue retention, although they can produce strong tumor enhancement. In this study, a targeted well-defined cyclodextrin-based nanoglobular contrast agent was developed through self-assembly driven by host-guest interactions for safe and effective cancer molecular MRI. Multiple β-cyclodextrins attached POSS (polyhedral oligomeric silsesquioxane) nanoglobule was used as host molecule. Adamantane–modified macrocyclic Gd(III) contrast agent, cRGD (cyclic RGDfK peptide) targeting ligand and fluorescent probe was used as guest molecules. The targeted host-guest nanoglobular contrast agent cRGD-POSS-βCD-(DOTA-Gd) specifically bond to αvβ3 integrin in malignant 4T1 breast tumor and provided greater contrast enhancement than the corresponding non-targeted agent. The agent also provided significant fluorescence signal in tumor tissue. The histological analysis of the tumor tissue confirmed its specific and effective targeting to αvβ3 integrin. The targeted imaging agent has a potential for specific cancer molecular MR and fluorescent imaging. PMID:26874280

A targeted nanoglobular contrast agent from host-guest self-assembly for MR cancer molecular imaging.

PubMed

Zhou, Zhuxian; Han, Zhen; Lu, Zheng-Rong

2016-04-01

The clinical application of nanoparticular Gd(III) based contrast agents for tumor molecular MRI has been hindered by safety concerns associated with prolonged tissue retention, although they can produce strong tumor enhancement. In this study, a targeted well-defined cyclodextrin-based nanoglobular contrast agent was developed through self-assembly driven by host-guest interactions for safe and effective cancer molecular MRI. Multiple β-cyclodextrins attached POSS (polyhedral oligomeric silsesquioxane) nanoglobule was used as host molecule. Adamantane-modified macrocyclic Gd(III) contrast agent, cRGD (cyclic RGDfK peptide) targeting ligand and fluorescent probe was used as guest molecules. The targeted host-guest nanoglobular contrast agent cRGD-POSS-βCD-(DOTA-Gd) specifically bond to αvβ3 integrin in malignant 4T1 breast tumor and provided greater contrast enhancement than the corresponding non-targeted agent. The agent also provided significant fluorescence signal in tumor tissue. The histological analysis of the tumor tissue confirmed its specific and effective targeting to αvβ3 integrin. The targeted imaging agent has a potential for specific cancer molecular MR and fluorescent imaging. Copyright © 2016 Elsevier Ltd. All rights reserved.

Targeting tumor-associated macrophages by anti-tumor Chinese materia medica.

PubMed

Pu, Wei-Ling; Sun, Li-Kang; Gao, Xiu-Mei; Rüegg, Curzio; Cuendet, Muriel; Hottiger, Micheal O; Zhou, Kun; Miao, Lin; Zhang, Yun-Sha; Gebauer, Margaret

2017-10-01

Tumor-associated macrophages (TAMs) play a key role in all stages of tumorigenesis and tumor progression. TAMs secrete different kinds of cytokines, chemokines, and enzymes to affect the progression, metastasis, and resistance to therapy depending on their state of reprogramming. Therapeutic benefit in targeting TAMs suggests that macrophages are attractive targets for cancer treatment. Chinese materia medica (CMM) is an important approach for treating cancer in China and in the Asian region. According to the theory of Chinese medicine (CM) and its practice, some prescriptions of CM regulate the body's internal environment possibly including the remodeling the tumor microenvironment (TME). Here we briefly summarize the pivotal effects of TAMs in shaping the TME and promoting tumorigenesis, invasion, metastasis and immunosuppression. Furthermore, we illustrate the effects and mechanisms of CMM targeting TAMs in antitumor therapy. Finally, we reveal the CMM's dual-regulatory and multi-targeting functions on regulating TAMs, and hopefully, provide the theoretical basis for CMM clinical practice related to cancer therapy.

A tissue factor-cascade-targeted strategy to tumor vasculature: a combination of EGFP-EGF1 conjugation nanoparticles with photodynamic therapy.

PubMed

Shi, Wei; Yin, Yanxue; Wang, Yao; Zhang, Bo; Tan, Pei; Jiang, Ting; Mei, Heng; Deng, Jun; Wang, Huafang; Guo, Tao; Pang, Zhiqing; Hu, Yu

2017-05-09

Tumor requires tumor vasculature to supply oxygen and nutrients so as to support its continued growth, as well as provide a main route for metastatic spread. In this study, a TF-cascade-targeted strategy aiming to disrupt tumor blood vessels was developed by combination of TF-targeted HMME-loaded drug delivery system and PDT. PDT is a promising new modality in the treatment of cancers, which employs the interaction between a tumor-localizing photosensitizer and light of an appropriate wavelength to bring about ROS-induced cell death. In vitro results showed that protein EGFP-EGF1modification could significantly contribute to the uptake of nanoparticles by TF over-expressed BCECs. In vivo multispectral fluorescent imaging, the EGFP-EGF1 conjugated nanoparticles showed significantly higher accumulation in tumor tissues than non-conjugated ones. Tumor tissue slides further presented that EGFP-EGF1 conjugated nanoparticles showed significantly higher accumulation in tumor vasculature than non-conjugated ones. In vitro study demonstrated that PDT increased TF expression of BCECs. In vivo imaging, ex vivo imaging and tumor tissue slides showed that PDT further contribute EGFP-EGF1-NP accumulation in tumor. These promising results indicated that PDT enhanced EGFP-EGF1modified PEG-PLGA nanoparticle accumulation in tumor vaculature. Considering that EGFP-EGF1 conjugation enhanced nanoparticles uptake by TF over-expressed endothelium and PDT increased endothelium TF expression. We conclude that PDT triggered a TF cascade targeted effect. A combination of both EGFP-EGF1 modification and PDT provided a positive feed-back target effect to tumor vessels and might have a great potential for tumor therapy.

Time-Adjusted Internal Target Volume: A Novel Approach Focusing on Heterogeneity of Tumor Motion Based on 4-Dimensional Computed Tomography Imaging for Radiation Therapy Planning of Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nishibuchi, Ikuno; Department of Radiation Oncology, Hiroshima Prefectural Hospital, Hiroshima; Kimura, Tomoki, E-mail: tkkimura@hiroshima-u.ac.jp

2014-08-01

Purpose: To consider nonuniform tumor motion within the internal target volume (ITV) by defining time-adjusted ITV (TTV), a volume designed to include heterogeneity of tumor existence on the basis of 4-dimensional computed tomography (4D-CT). Methods and Materials: We evaluated 30 lung cancer patients. Breath-hold CT (BH-CT) and free-breathing 4D-CT scans were acquired for each patient. The tumors were manually delineated using a lung CT window setting (window, 1600 HU; level, −300 HU). Tumor in BH-CT images was defined as gross tumor volume (GTV), and the sum of tumors in 4D-CT images was defined as ITV-4D. The TTV images were generatedmore » from the 4D-CT datasets, and the tumor existence probability within ITV-4D was calculated. We calculated the TTV{sub 80} value, which is the percentage of the volume with a tumor existence probability that exceeded 80% on ITV-4D. Several factors that affected the TTV{sub 80} value, such as the ITV-4D/GTV ratio or tumor centroid deviation, were evaluated. Results: Time-adjusted ITV images were acquired for all patients, and tumor respiratory motion heterogeneity was visualized. The median (range) ITV-4D/GTV ratio and median tumor centroid deviation were 1.6 (1.0-4.1) and 6.3 mm (0.1-30.3 mm), respectively. The median TTV{sub 80} value was 43.3% (2.9-98.7%). Strong correlations were observed between the TTV{sub 80} value and the ITV-4D/GTV ratio (R=−0.71) and tumor centroid deviation (R=−0.72). The TTV images revealed the tumor motion pattern features within ITV. Conclusions: The TTV images reflected nonuniform tumor motion, and they revealed the tumor motion pattern features, suggesting that the TTV concept may facilitate various aspects of radiation therapy planning of lung cancer while incorporating respiratory motion in the future.« less

Biodegradable double-targeted PTX-mPEG-PLGA nanoparticles for ultrasound contrast enhanced imaging and antitumor therapy in vitro.

PubMed

Ma, Jing; Shen, Ming; Xu, Chang Song; Sun, Ying; Duan, You Rong; Du, Lian Fang

2016-11-29

A porous-structure nano-scale ultrasound contrast agent (UCA) was made of monomethoxypoly (ethylene glycol)-poly (lactic-co-glycolic acid) (mPEG-PLGA), and modified by double-targeted antibody: anti-carcinoembryonic antigen (CEA) and anti-carbohydrate antigen 19-9 (CA19-9), as a double-targeted nanoparticles (NPs). Anti-tumor drug paclitaxel (PTX) was encapsulated in the double-targeted nanoparticles (NPs). The morphor and release curve were characterized. We verified a certain anticancer effect of PTX-NPs through cytotoxicity experiments. The cell uptake result showed much more NPs may be facilitated to ingress the cells or tissues with ultrasound (US) or ultrasound targeted microbubble destruction (UTMD) transient sonoporation in vitro. Ultrasound contrast-enhanced images in vitro and in vivo were investigated. Compared with SonoVue, the NPs prolonged imaging time in rabbit kidneys and tumor of nude mice, which make it possible to further enhance anti-tumor effects by extending retention time in the tumor region. The novel double-targeted NPs with the function of ultrasound contrast enhanced imaging and anti-tumor therapy can be a promising way in clinic.

Radiotherapy treatment planning: benefits of CT-MR image registration and fusion in tumor volume delineation.

PubMed

Djan, Igor; Petrović, Borislava; Erak, Marko; Nikolić, Ivan; Lucić, Silvija

2013-08-01

Development of imaging techniques, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), made great impact on radiotherapy treatment planning by improving the localization of target volumes. Improved localization allows better local control of tumor volumes, but also minimizes geographical misses. Mutual information is obtained by registration and fusion of images achieved manually or automatically. The aim of this study was to validate the CT-MRI image fusion method and compare delineation obtained by CT versus CT-MRI image fusion. The image fusion software (XIO CMS 4.50.0) was applied to delineate 16 patients. The patients were scanned on CT and MRI in the treatment position within an immobilization device before the initial treatment. The gross tumor volume (GTV) and clinical target volume (CTV) were delineated on CT alone and on CT+MRI images consecutively and image fusion was obtained. Image fusion showed that CTV delineated on a CT image study set is mainly inadequate for treatment planning, in comparison with CTV delineated on CT-MRI fused image study set. Fusion of different modalities enables the most accurate target volume delineation. This study shows that registration and image fusion allows precise target localization in terms of GTV and CTV and local disease control.

Brain Tumor Image Segmentation in MRI Image

NASA Astrophysics Data System (ADS)

Peni Agustin Tjahyaningtijas, Hapsari

2018-04-01

Brain tumor segmentation plays an important role in medical image processing. Treatment of patients with brain tumors is highly dependent on early detection of these tumors. Early detection of brain tumors will improve the patient’s life chances. Diagnosis of brain tumors by experts usually use a manual segmentation that is difficult and time consuming because of the necessary automatic segmentation. Nowadays automatic segmentation is very populer and can be a solution to the problem of tumor brain segmentation with better performance. The purpose of this paper is to provide a review of MRI-based brain tumor segmentation methods. There are number of existing review papers, focusing on traditional methods for MRI-based brain tumor image segmentation. this paper, we focus on the recent trend of automatic segmentation in this field. First, an introduction to brain tumors and methods for brain tumor segmentation is given. Then, the state-of-the-art algorithms with a focus on recent trend of full automatic segmentaion are discussed. Finally, an assessment of the current state is presented and future developments to standardize MRI-based brain tumor segmentation methods into daily clinical routine are addressed.

Programmed near-infrared light-responsive drug delivery system for combined magnetic tumor-targeting magnetic resonance imaging and chemo-phototherapy.

PubMed

Feng, Qianhua; Zhang, Yuanyuan; Zhang, Wanxia; Hao, Yongwei; Wang, Yongchao; Zhang, Hongling; Hou, Lin; Zhang, Zhenzhong

2017-02-01

In this study, an intelligent drug delivery system was developed by capping doxorubicin (DOX)-loaded hollow mesoporous CuS nanoparticles (HMCuS NPs) with superparamagnetic iron oxide nanoparticles (IONPs). Under near infrared (NIR) light irradiation, the versatile HMCuS NPs could exploit the merits of both photothermal therapy (PTT) and photodynamic therapy (PDT) simultaneously. Herein, the multifunctional IONPs as gatekeeper with the enhanced capping efficiency were supposed to realize "zero premature release" and minimize the adverse side effects during the drug delivery in vivo. More importantly, the hybrid metal nanoplatform (HMCuS/DOX@IONP-PEG) allowed several emerging exceptional characteristics. Our studies have substantiated the hybrid nanoparticles possessed an enhanced PTT effect due to coupled plasmonic resonances with an elevated heat-generating capacity. Notably, an effective removal of IONP-caps occurred after NIR-induced photo-hyperthermia via weakening of the coordination interactions between HMCuS-NH 2 and IONPs, which suggested the feasibility of sophisticated controlled on-demand drug release upon exposing to NIR stimulus with spatial/temporal resolution. Benefiting from the favorable magnetic tumor targeting efficacy, the in vitro and in vivo experiments indicated a remarkable anti-tumor therapeutic efficacy under NIR irradiation, resulting from the synergistic combination of chemo-phototherapy. In addition, T 2 -weighted magnetic resonance imaging (MRI) contrast performance of IONPs provided the identification of cancerous lesions. Based on these findings, the well-designed drug delivery system via integration of programmed functions will provide knowledge for advancing multimodality theranostic strategy. As we all know, a series of shortcomings of conventional chemotherapy such as limited stability, rapid clearing and non-specific tumor targeting ability remain a significant challenge to achieve successful clinical therapeutic efficiency in

T1-Weighted MR imaging of liver tumor by gadolinium-encapsulated glycol chitosan nanoparticles without non-specific toxicity in normal tissues

NASA Astrophysics Data System (ADS)

Na, Jin Hee; Lee, Sangmin; Koo, Heebeom; Han, Hyounkoo; Lee, Kyung Eun; Han, Seung Jin; Choi, Seung Hong; Kim, Hyuncheol; Lee, Seulki; Kwon, Ick Chan; Choi, Kuiwon; Kim, Kwangmeyung

2016-05-01

Herein, we have synthesized Gd(iii)-encapsulated glycol chitosan nanoparticles (Gd(iii)-CNPs) for tumor-targeted T1-weighted magnetic resonance (MR) imaging. The T1 contrast agent, Gd(iii), was successfully encapsulated into 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-modified CNPs to form stable Gd(iii)-encapsulated CNPs (Gd(iii)-CNPs) with an average particle size of approximately 280 nm. The stable nanoparticle structure of Gd(iii)-CNPs is beneficial for liver tumor accumulation by the enhanced permeation and retention (EPR) effect. Moreover, the amine groups on the surface of Gd(iii)-CNPs could be protonated and could induce fast cellular uptake at acidic pH in tumor tissue. To assay the tumor-targeting ability of Cy5.5-labeled Gd(iii)-CNPs, near-infrared fluorescence (NIRF) imaging and MR imaging were used in a liver tumor model as well as a subcutaneous tumor model. Cy5.5-labeled Gd(iii)-CNPs generated highly intense fluorescence and T1 MR signals in tumor tissues after intravenous injection, while DOTAREM®, the commercialized control MR contrast agent, showed very low tumor-targeting efficiency on MR images. Furthermore, damaged tissues were found in the livers and kidneys of mice injected with DOTAREM®, but there were no obvious adverse effects with Gd(iii)-CNPs. Taken together, these results demonstrate the superiority of Gd(iii)-CNPs as a tumor-targeting T1 MR agent.Herein, we have synthesized Gd(iii)-encapsulated glycol chitosan nanoparticles (Gd(iii)-CNPs) for tumor-targeted T1-weighted magnetic resonance (MR) imaging. The T1 contrast agent, Gd(iii), was successfully encapsulated into 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-modified CNPs to form stable Gd(iii)-encapsulated CNPs (Gd(iii)-CNPs) with an average particle size of approximately 280 nm. The stable nanoparticle structure of Gd(iii)-CNPs is beneficial for liver tumor accumulation by the enhanced permeation and retention (EPR) effect. Moreover, the

In vivo near-infrared fluorescence imaging of CD105 expression during tumor angiogenesis.

PubMed

Yang, Yunan; Zhang, Yin; Hong, Hao; Liu, Glenn; Leigh, Bryan R; Cai, Weibo

2011-11-01

Angiogenesis is an indispensable process during tumor development. The currently accepted standard method for quantifying tumor angiogenesis is to assess microvessel density (MVD) based on CD105 staining, which is an independent prognostic factor for survival in patients with most solid tumor types. The goal of this study is to evaluate tumor angiogenesis in a mouse model by near-infrared fluorescence (NIRF) imaging of CD105 expression. TRC105, a human/murine chimeric anti-CD105 monoclonal antibody, was conjugated to an NIRF dye (IRDye 800CW; Ex: 778 nm; Em: 806 nm). FACS analysis and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and 800CW-TRC105. In vivo/ex vivo NIRF imaging, blocking studies, and ex vivo histology were performed on 4T1 murine breast tumor-bearing mice to evaluate the ability of 800CW-TRC105 to target tumor angiogenesis. Another chimeric antibody, cetuximab, was used as an isotype-matched control. FACS analysis of human umbilical vein endothelial cells (HUVECs) revealed no difference in CD105 binding affinity between TRC105 and 800CW-TRC105, which was further validated by fluorescence microscopy. 800CW conjugation of TRC105 was achieved in excellent yield (> 85%), with an average of 0.4 800CW molecules per TRC105. Serial NIRF imaging after intravenous injection of 800CW-TRC105 revealed that the 4T1 tumor could be clearly visualized as early as 30 min post-injection. Quantitative region of interest (ROI) analysis showed that the tumor uptake peaked at about 16 h post-injection. Based on ex vivo NIRF imaging at 48 h post-injection, tumor uptake of 800CW-TRC105 was higher than most organs, thus providing excellent tumor contrast. Blocking experiments, control studies with 800CW-cetuximab and 800CW, as well as ex vivo histology all confirmed the in vivo target specificity of 800CW-TRC105. This is the first successful NIRF imaging study of CD105 expression in vivo. Fast, prominent, persistent, and CD105-specific

Development of a novel folate-modified nanobubbles with improved targeting ability to tumor cells.

PubMed

Duan, Sujuan; Guo, Lu; Shi, Dandan; Shang, Mengmeng; Meng, Dong; Li, Jie

2017-07-01

Conjugation of folate (FOL) to nanobubbles could enhance the selective targeting to tumors expressing high levels of folate receptor (FR). To further improve the selective targeting ability of FOL-modified nanobubbles, a novel FOL-targeted nanobubble ((FOL) 2 -NB) with increasing FOL content (accomplished by linking two FOL molecules per DSPE-PEG2000 chain) was synthesized, through the methods of mechanical shaking and low-speed centrifugation based on lipid-stabilized perfluoropropane. The bubble size and distribution range were measured by dynamic light scattering (DLS). Enhanced imaging ability was evaluated using a custom-made agarose mold with a clinical US imaging system at mechanical indices of up to 0.12 at a center frequency of 9.0MHz. Targeted ability was also carried out in human breast cancer MCF-7 cells, which over-express the FR, by fluorescence activated cell sorting (FACS) and fluorescence microscopy, respectively. (FOL) 2 -NB with a particle size of 286.87±22.96nm were successfully prepared, and they exhibited superior contrast imaging effect. FACS and fluorescence microscopy studies showed greater cellular targeting ability in the group of (FOL) 2 -NB than in their control group of Non-targeted-NB (no FOL targeted nanobubbles) and FOL-NB (one FOL molecule per DSPE-PEG2000 chain). These results suggest that a new type of stronger targeted nanobubble was successfully prepared by increasing the FOL content per DSPE-PEG2000 chain. This novel (FOL) 2 -NBs are potentially useful for ultrasound molecular imaging and treatment of FR-positive tumors and are worthy for further investigation. Copyright © 2017 Elsevier B.V. All rights reserved.

Optical imaging of tumor cells in hollow fibers: evaluation of the antitumor activities of anticancer drugs and target validation.

PubMed

Zhang, Guo-Jun; Chen, Tsing-Bau; Bednar, Bohumil; Connolly, Brett M; Hargreaves, Richard; Sur, Cyrille; Williams, David L

2007-08-01

The in vivo hollow fiber assay, in which semipermeable hollow fibers filled with tumor cells, are implanted into animals, was originally developed to screen for anticancer compounds before assessment in more complex tumor models. To enhance screening and evaluation of anticancer drugs, we have applied optical imaging technology to this assay. To demonstrate that tumor cells inside hollow fibers can communicate with the host mice, we have used fluorescence imaging in vivo and CD31 immunostaining ex vivo to show that angiogenesis occurs around cell-filled hollow fibers by 2 weeks after subcutaneous implantation. Bioluminescence imaging has been used to follow the number of luciferase-expressing tumor cells within implanted hollow fibers; proliferation of those cells was found to be significantly inhibited by docetaxel or irinotecan. We also used bioluminescence imaging of hollow fibers to monitor the nuclear factor kappaB (NFkappaB) pathway in vivo; NFkappaB activation by lipopolysaccharide and tumor necrosis factor-alpha was evaluated in tumor cell lines genetically engineered to express luciferase controlled by an NFkappaB-responsive element. These results demonstrate that optical imaging of hollow fibers containing reporter tumor cells can be used for the rapid and accurate evaluation of antitumor activities of anticancer drugs and for measurement of molecular pathways.

Tumor resistance to vascular disrupting agents: mechanisms, imaging, and solutions

PubMed Central

Liang, Wenjie; Ni, Yicheng; Chen, Feng

2016-01-01

The emergence of vascular disrupting agents (VDAs) is a significant advance in the treatment of solid tumors. VDAs induce rapid and selective shutdown of tumor blood flow resulting in massive necrosis. However, a viable marginal tumor rim always remains after VDA treatment and is a major cause of recurrence. In this review, we discuss the mechanisms involved in the resistance of solid tumors to VDAs. Hypoxia, tumor-associated macrophages, and bone marrow-derived circulating endothelial progenitor cells all may contribute to resistance. Resistance can be monitored using magnetic resonance imaging markers. The various solutions proposed to manage tumor resistance to VDAs emphasize combining these agents with other approaches including antiangiogenic agents, chemotherapy, radiotherapy, radioimmunotherapy, and sequential dual-targeting internal radiotherapy. PMID:26812886

Tumor Specific Detection of an Optically Targeted Antibody Combined with a Quencher-conjugated Neutravidin “Quencher-Chaser”: A Dual “Quench and Chase” Strategy to Improve Target to Non-target Ratios for Molecular Imaging of Cancer

PubMed Central

Ogawa, Mikako; Kosaka, Nobuyuki; Choyke, Peter L; Kobayashi, Hisataka

2009-01-01

In vivo molecular cancer imaging with monoclonal antibodies has great potential not only for cancer detection but also for cancer characterization. However, the prolonged retention of intravenously injected antibody in the blood causes low target tumor-to-background ratio (TBR). Avidin has been used as a “chase” to clear the unbound, circulating biotinylated antibody and decrease the background signal. Here, we utilize a combined approach of a Fluorescence Resonance Energy Transfer (FRET) quenched antibody with an “avidin chase” to increase TBR. Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor type 2 (HER2), was biotinylated and conjugated with the near-infrared (NIR) fluorophore Alexa680 to synthesize Tra-Alexa680-biotin. Next, the FRET quencher, QSY-21, was conjugated to avidin, neutravidin (nAv) or streptavidin (sAv), thus creating Av-QSY21, nAv-QSY21 or sAv-QSY21 as “chasers”. The fluorescence was quenched in vitro by binding Tra-Alexa680-biotin to Av-QSY21, nAv-QSY21 or sAv-QSY21. To evaluate if the injection of quencher-conjugated avidin-derivatives can improve target TBR by using a dual “quench and chase” strategy, both target (3T3/HER2+) and non-target (Balb3T3/ZsGreen) tumor bearing mice were employed. The “FRET quench” effect induced by all the QSY21 avidin-based conjugates reduced but did not totally eliminate background signal from the blood pool. The addition of nAv-QSY21 administration increased target TBR mainly due to the “chase” effect where unbound conjugated antibody was preferentially cleared to the liver. The relatively slow clearance of unbound nAv-QSY21 leads to further reductions in background signal by leaking out of the vascular space and binding to unbound antibodies in the extravascular space of tumors resulting in decreased non-target tumor-to-background ratios but increased target TBR due to the “FRET quench” effect because target-bound antibodies were internalized

Analysis of image heterogeneity using 2D Minkowski functionals detects tumor responses to treatment.

PubMed

Larkin, Timothy J; Canuto, Holly C; Kettunen, Mikko I; Booth, Thomas C; Hu, De-En; Krishnan, Anant S; Bohndiek, Sarah E; Neves, André A; McLachlan, Charles; Hobson, Michael P; Brindle, Kevin M

2014-01-01

The acquisition of ever increasing volumes of high resolution magnetic resonance imaging (MRI) data has created an urgent need to develop automated and objective image analysis algorithms that can assist in determining tumor margins, diagnosing tumor stage, and detecting treatment response. We have shown previously that Minkowski functionals, which are precise morphological and structural descriptors of image heterogeneity, can be used to enhance the detection, in T1 -weighted images, of a targeted Gd(3+) -chelate-based contrast agent for detecting tumor cell death. We have used Minkowski functionals here to characterize heterogeneity in T2 -weighted images acquired before and after drug treatment, and obtained without contrast agent administration. We show that Minkowski functionals can be used to characterize the changes in image heterogeneity that accompany treatment of tumors with a vascular disrupting agent, combretastatin A4-phosphate, and with a cytotoxic drug, etoposide. Parameterizing changes in the heterogeneity of T2 -weighted images can be used to detect early responses of tumors to drug treatment, even when there is no change in tumor size. The approach provides a quantitative and therefore objective assessment of treatment response that could be used with other types of MR image and also with other imaging modalities. Copyright © 2013 Wiley Periodicals, Inc.

Long residence time of ultrasound microbubbles targeted to integrin in murine tumor model.

PubMed

Jun, Hong Young; Park, Seong Hoon; Kim, Hun Soo; Yoon, Kwon-Ha

2010-01-01

The aim of this study was to evaluate the intratumoral residence time of microbubbles (MBs) targeted to alpha(v)beta(3) integrin expressed in the endothelial cells of mice during the process of tumor angiogenesis. For the preparation of MBs, decafluorobutane gas was sonically dispersed in phosphate buffer saline containing L-A-phosphatidylcholine-distearoyl, polyethylene glycol 40 stearate, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[biotinyl(polyethylene glycol)2000] in a 77:15:8 molar ratio. Avidin-fluorescein isothiocyanate and biotin-cyclic arginine-glycine-aspartate-D-tyrosine-lysine (cRGD) or biotin-alanine-glycine-aspartate (AGD) conjugates were added to the reaction mixture. Adhesion testing of the targeting MBs was performed for the MS-1 cell line expressing alpha(v)beta(3) integrin in vitro. The in vivo acoustic properties of the MBs were assessed by clinical ultrasound on the HT1080 fibrosarcoma model (n = 8) for 1 hour. Cryosections were stained with hematoxylin and eosin and by immunohistochemical staining to identify expression of alpha(v)beta(3) integrin in the HT1080 tumor. The adherence of the MBs conjugated to cRGD was significantly greater than the adherence of the MBs conjugated to biotin-AGD (P < .01) for the MS-1 endothelial cell line. The acoustic enhancement on ultrasound was observed as a stable imaging window until 1 hour after injection of the MB conjugates in the mice. The MBs targeted via cRGD preferentially adhered to the vascular endothelium of the HT-1080 tumors. The findings of ultrasound imaging were correlated with immunohistochemical findings for the expression of alpha(v)beta(3) integrin on the vascular endothelium of the tumors. The prepared MBs conjugated with cRGD demonstrated a sufficient residence time to attach to the target integrin of tumor tissues. This finding suggests that the MBs are a potential molecular contrast agent that enables characterization of tumor angiogenesis and the monitoring of antitumor and

Targeting tumor cell motility to prevent metastasis

PubMed Central

Palmer, Trenis D.; Ashby, William J.; Lewis, John D.; Zijlstra, Andries

2011-01-01

Mortality and morbidity in patients with solid tumors invariably results from the disruption of normal biological function caused by disseminating tumor cells. Tumor cell migration is under intense investigation as the underlying cause of cancer metastasis. The need for tumor cell motility in the progression of metastasis has been established experimentally and is supported empirically by basic and clinical research implicating a large collection of migration-related genes. However, there are few clinical interventions designed to specifically target the motility of tumor cells and adjuvant therapy to specifically prevent cancer cell dissemination is severely limited. In an attempt to define motility targets suitable for treating metastasis, we have parsed the molecular determinants of tumor cell motility into five underlying principles including cell autonomous ability, soluble communication, cell-cell adhesion, cell-matrix adhesion, and integrating these determinants of migration on molecular scaffolds. The current challenge is to implement meaningful and sustainable inhibition of metastasis by developing clinically viable disruption of molecular targets that control these fundamental capabilities. PMID:21664937

Artificial Chemical Reporter Targeting Strategy Using Bioorthogonal Click Reaction for Improving Active-Targeting Efficiency of Tumor.

PubMed

Yoon, Hong Yeol; Shin, Min Lee; Shim, Man Kyu; Lee, Sangmin; Na, Jin Hee; Koo, Heebeom; Lee, Hyukjin; Kim, Jong-Ho; Lee, Kuen Yong; Kim, Kwangmeyung; Kwon, Ick Chan

2017-05-01

Biological ligands such as aptamer, antibody, glucose, and peptide have been widely used to bind specific surface molecules or receptors in tumor cells or subcellular structures to improve tumor-targeting efficiency of nanoparticles. However, this active-targeting strategy has limitations for tumor targeting due to inter- and intraheterogeneity of tumors. In this study, we demonstrated an alternative active-targeting strategy using metabolic engineering and bioorthogonal click reaction to improve tumor-targeting efficiency of nanoparticles. We observed that azide-containing chemical reporters were successfully generated onto surface glycans of various tumor cells such as lung cancer (A549), brain cancer (U87), and breast cancer (BT-474, MDA-MB231, MCF-7) via metabolic engineering in vitro. In addition, we compared tumor targeting of artificial azide reporter with bicyclononyne (BCN)-conjugated glycol chitosan nanoparticles (BCN-CNPs) and integrin α v β 3 with cyclic RGD-conjugated CNPs (cRGD-CNPs) in vitro and in vivo. Fluorescence intensity of azide-reporter-targeted BCN-CNPs in tumor tissues was 1.6-fold higher and with a more uniform distribution compared to that of cRGD-CNPs. Moreover, even in the isolated heterogeneous U87 cells, BCN-CNPs could bind artificial azide reporters on tumor cells more uniformly (∼92.9%) compared to cRGD-CNPs. Therefore, the artificial azide-reporter-targeting strategy can be utilized for targeting heterogeneous tumor cells via bioorthogonal click reaction and may provide an alternative method of tumor targeting for further investigation in cancer therapy.

Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model.

PubMed

MacDiarmid, Jennifer A; Langova, Veronika; Bailey, Dale; Pattison, Scott T; Pattison, Stacey L; Christensen, Neil; Armstrong, Luke R; Brahmbhatt, Vatsala N; Smolarczyk, Katarzyna; Harrison, Matthew T; Costa, Marylia; Mugridge, Nancy B; Sedliarou, Ilya; Grimes, Nicholas A; Kiss, Debra L; Stillman, Bruce; Hann, Christine L; Gallia, Gary L; Graham, Robert M; Brahmbhatt, Himanshu

2016-01-01

Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On this basis, we have designed a Phase 1 clinical study of EGFR-targeted

Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model

PubMed Central

MacDiarmid, Jennifer A.; Langova, Veronika; Bailey, Dale; Pattison, Scott T.; Pattison, Stacey L.; Christensen, Neil; Armstrong, Luke R.; Brahmbhatt, Vatsala N.; Smolarczyk, Katarzyna; Harrison, Matthew T.; Costa, Marylia; Mugridge, Nancy B.; Sedliarou, Ilya; Grimes, Nicholas A.; Kiss, Debra L.; Stillman, Bruce; Hann, Christine L.; Gallia, Gary L.; Graham, Robert M.; Brahmbhatt, Himanshu

2016-01-01

Background Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. Methodology/Principle Findings EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). Conclusions/Significance Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On

Molecularly-Targeted Gold-Based Nanoparticles for Cancer Imaging and Near-Infrared Photothermal Therapy

NASA Astrophysics Data System (ADS)

Day, Emily Shannon

2011-12-01

This thesis advances the use of nanoparticles as multifunctional agents for molecularly-targeted cancer imaging and photothermal therapy. Cancer mortality has remained relatively unchanged for several decades, indicating a significant need for improvements in care. Researchers are evaluating strategies incorporating nanoparticles as exogenous energy absorbers to deliver heat capable of inducing cell death selectively to tumors, sparing normal tissue. Molecular targeting of nanoparticles is predicted to improve photothermal therapy by enhancing tumor retention. This hypothesis is evaluated with two types of nanoparticles. The nanoparticles utilized, silica-gold nanoshells and gold-gold sulfide nanoparticles, can convert light energy into heat to damage cancerous cells. For in vivo applications nanoparticles are usually coated with poly(ethylene glycol) (PEG) to increase blood circulation time. Here, heterobifunctional PEG links nanoparticles to targeting agents (antibodies and growth factors) to provide cell-specific binding. This approach is evaluated through a series of experiments. In vitro, antibody-coated nanoparticles can bind breast carcinoma cells expressing the targeted receptor and act as contrast agents for multiphoton microscopy prior to inducing cell death via photoablation. Furthermore, antibody-coated nanoparticles can bind tissue ex vivo at levels corresponding to receptor expression, suggesting they should bind their target even in the complex biological milieu. This is evaluated by comparing the accumulation of antibody-coated and PEG-coated nanoparticles in subcutaneous glioma tumors in mice. Contrary to expectations, antibody targeting did not yield more nanoparticles within tumors. Nevertheless, these studies established the sensitivity of glioma to photothermal therapy; mice treated with PEG-coated nanoshells experienced 57% complete tumor regression versus no regression in control mice. Subsequent experiments employed intracranial tumors to

Targeting of drugs and nanoparticles to tumors

PubMed Central

Bhatia, Sangeeta N.; Sailor, Michael J.

2010-01-01

The various types of cells that comprise the tumor mass all carry molecular markers that are not expressed or are expressed at much lower levels in normal cells. These differentially expressed molecules can be used as docking sites to concentrate drug conjugates and nanoparticles at tumors. Specific markers in tumor vessels are particularly well suited for targeting because molecules at the surface of blood vessels are readily accessible to circulating compounds. The increased concentration of a drug in the site of disease made possible by targeted delivery can be used to increase efficacy, reduce side effects, or achieve some of both. We review the recent advances in this delivery approach with a focus on the use of molecular markers of tumor vasculature as the primary target and nanoparticles as the delivery vehicle. PMID:20231381

EGFR Targeted Theranostic Nanoemulsion For Image-Guided Ovarian Cancer Therapy

PubMed Central

Ganta, Srinivas; Singh, Amit; Kulkarni, Praveen; Keeler, Amanda W.; Piroyan, Aleksandr; Sawant, Rupa R.; Patel, Niravkumar R.; Davis, Barbara; Ferris, Craig; O’Neal, Sara; Zamboni, William; Amiji, Mansoor M.; Coleman, Timothy P.

2015-01-01

Purpose Platinum-based therapies are the first line treatments for most types of cancer including ovarian cancer. However, their use is associated with dose-limiting toxicities and resistance. We report initial translational studies of a theranostic nanoemulsion loaded with a cisplatin derivative, myrisplatin and pro-apoptotic agent, C6-ceramide. Methods The surface of the nanoemulsion is annotated with an endothelial growth factor receptor (EGFR) binding peptide to improve targeting ability and gadolinium to provide diagnostic capability for image-guided therapy of EGFR overexpressing ovarian cancers. A high shear microfludization process was employed to produce the formulation with particle size below 150 nm. Results Pharmacokinetic study showed a prolonged blood platinum and gadolinium levels with nanoemulsions in nu/nu mice. The theranostic nanoemulsions also exhibited less toxicity and enhanced the survival time of mice as compared to an equivalent cisplatin treatment. Conclusions Magnetic resonance imaging (MRI) studies indicate the theranostic nanoemulsions were effective contrast agents and could be used to track accumulation in a tumor. The MRI study additionally indicate that significantly more EGFR-targeted theranostic nanoemulsion accumulated in a tumor than non-targeted nanoemulsuion providing the feasibility of using a targeted theranostic agent in conjunction with MRI to image disease loci and quantify the disease progression. PMID:25732960

Intraoperative Molecular Imaging of Lung Adenocarcinoma Can Identify Residual Tumor Cells at the Surgical Margins

PubMed Central

Keating, Jane J.; Okusanya, Olugbenga T.; De Jesus, Elizabeth; Judy, Ryan; Jiang, Jack; Deshpande, Charuhas; Nie, Shuming; Low, Philip; Singhal, Sunil

2017-01-01

Purpose During lung surgery, identification of surgical margins is challenging. We hypothesized that molecular imaging with a fluorescent probe to pulmonary adenocarcinomas could enhance residual tumor during resection. Procedures Mice with flank tumors received a contrast agent targeting folate receptor alpha. Optimal dose and time of injection was established. Margin detection was compared using traditional methods versus molecular imaging. A pilot study was then performed in 3 humans with lung adenocarcinoma. Results The peak tumor-to background ratio (TBR) of murine tumors was 3.9. Fluorescence peaked at 2 hours and was not improved beyond 0.1 mg/kg. Traditional inspection identified 30% of mice with positive margins. Molecular imaging identified an additional 50% of residual tumor deposits (P<0.05). The fluorescent probe visually enhanced all human tumors with a mean TBR of 3.5. Conclusions Molecular imaging is an important adjunct to traditional inspection to identify surgical margins after tumor resection. PMID:26228697

Early tumor detection afforded by in vivo imaging of near-infrared II fluorescence.

PubMed

Tao, Zhimin; Dang, Xiangnan; Huang, Xing; Muzumdar, Mandar D; Xu, Eric S; Bardhan, Neelkanth Manoj; Song, Haiqin; Qi, Ruogu; Yu, Yingjie; Li, Ting; Wei, Wei; Wyckoff, Jeffrey; Birrer, Michael J; Belcher, Angela M; Ghoroghchian, P Peter

2017-07-01

Cell-intrinsic reporters such as luciferase (LUC) and red fluorescent protein (RFP) have been commonly utilized in preclinical studies to image tumor growth and to monitor therapeutic responses. While extrinsic reporters that emit near infrared I (NIR-I: 650-950 nm) or near-infrared II (NIR-II: 1000-1700 nm) optical signals have enabled minimization of tissue autofluorescence and light scattering, it has remained unclear as to whether their use has afforded more accurate tumor imaging in small animals. Here, we developed a novel optical imaging construct comprised of rare earth lanthanide nanoparticles coated with biodegradable diblock copolymers and doped with organic fluorophores, generating NIR-I and NIR-II emissive bands upon optical excitation. Simultaneous injection of multiple spectrally-unique nanoparticles into mice bearing tumor implants established via intraperitoneal dissemination of LUC + /RFP + OVCAR-8 ovarian cancer cells enabled direct comparisons of imaging with extrinsic vs. intrinsic reporters, NIR-II vs. NIR-I signals, as well as targeted vs. untargeted exogenous contrast agents in the same animal and over time. We discovered that in vivo optical imaging at NIR-II wavelengths facilitates more accurate detection of smaller and earlier tumor deposits, offering enhanced sensitivity, improved spatial contrast, and increased depths of tissue penetration as compared to imaging with visible or NIR-I fluorescent agents. Our work further highlights the hitherto underappreciated enhancements in tumor accumulation that may be achieved with intraperitoneal as opposed to intravenous administration of nanoparticles. Lastly, we found discrepancies in the fidelity of tumor uptake that could be obtained by utilizing small molecules for in vivo as opposed to in vitro targeting of nanoparticles to disseminated tumors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Neuroendocrine Tumor-Targeted Upconversion Nanoparticle-Based Micelles for Simultaneous NIR-Controlled Combination Chemotherapy and Photodynamic Therapy, and Fluorescence Imaging

PubMed Central

Chen, Guojun; Jaskula-Sztul, Renata; Esquibel, Corinne R.; Lou, Irene; Zheng, Qifeng; Dammalapati, Ajitha; Harrison, April; Eliceiri, Kevin W.; Tang, Weiping

2017-01-01

Although neuroendocrine tumors (NETs) are slow growing, they are frequently metastatic at the time of discovery and no longer amenable to curative surgery, emphasizing the need for the development of other treatments. In this study, multifunctional upconversion nanoparticle (UCNP)-based theranostic micelles are developed for NET-targeted and near-infrared (NIR)-controlled combination chemotherapy and photodynamic therapy (PDT), and bioimaging. The theranostic micelle is formed by individual UCNP functionalized with light-sensitive amphiphilic block copolymers poly(4,5-dimethoxy-2-nitrobenzyl methacrylate)-polyethylene glycol (PNBMA-PEG) and Rose Bengal (RB) photosensitizers. A hydrophobic anticancer drug, AB3, is loaded into the micelles. The NIR-activated UCNPs emit multiple luminescence bands, including UV, 540 nm, and 650 nm. The UV peaks overlap with the absorption peak of photocleavable hydrophobic PNBMA segments, triggering a rapid drug release due to the NIR-induced hydrophobic-to-hydrophilic transition of the micelle core and thus enabling NIR-controlled chemotherapy. RB molecules are activated via luminescence resonance energy transfer to generate 1O2 for NIR-induced PDT. Meanwhile, the 650 nm emission allows for efficient fluorescence imaging. KE108, a true pansomatostatin nonapeptide, as an NET-targeting ligand, drastically increases the tumoral uptake of the micelles. Intravenously injected AB3-loaded UCNP-based micelles conjugated with RB and KE108—enabling NET-targeted combination chemotherapy and PDT—induce the best antitumor efficacy. PMID:28989337

Neuroendocrine Tumor-Targeted Upconversion Nanoparticle-Based Micelles for Simultaneous NIR-Controlled Combination Chemotherapy and Photodynamic Therapy, and Fluorescence Imaging.

PubMed

Chen, Guojun; Jaskula-Sztul, Renata; Esquibel, Corinne R; Lou, Irene; Zheng, Qifeng; Dammalapati, Ajitha; Harrison, April; Eliceiri, Kevin W; Tang, Weiping; Chen, Herbert; Gong, Shaoqin

2017-02-23

Although neuroendocrine tumors (NETs) are slow growing, they are frequently metastatic at the time of discovery and no longer amenable to curative surgery, emphasizing the need for the development of other treatments. In this study, multifunctional upconversion nanoparticle (UCNP)-based theranostic micelles are developed for NET-targeted and near-infrared (NIR)-controlled combination chemotherapy and photodynamic therapy (PDT), and bioimaging. The theranostic micelle is formed by individual UCNP functionalized with light-sensitive amphiphilic block copolymers poly(4,5-dimethoxy-2-nitrobenzyl methacrylate)-polyethylene glycol (PNBMA-PEG) and Rose Bengal (RB) photosensitizers. A hydrophobic anticancer drug, AB3, is loaded into the micelles. The NIR-activated UCNPs emit multiple luminescence bands, including UV, 540 nm, and 650 nm. The UV peaks overlap with the absorption peak of photocleavable hydrophobic PNBMA segments, triggering a rapid drug release due to the NIR-induced hydrophobic-to-hydrophilic transition of the micelle core and thus enabling NIR-controlled chemotherapy. RB molecules are activated via luminescence resonance energy transfer to generate 1 O 2 for NIR-induced PDT. Meanwhile, the 650 nm emission allows for efficient fluorescence imaging. KE108, a true pansomatostatin nonapeptide, as an NET-targeting ligand, drastically increases the tumoral uptake of the micelles. Intravenously injected AB3-loaded UCNP-based micelles conjugated with RB and KE108-enabling NET-targeted combination chemotherapy and PDT-induce the best antitumor efficacy.

Predictive value of magnetic resonance imaging determined tumor contact length for extracapsular extension of prostate cancer.

PubMed

Baco, Eduard; Rud, Erik; Vlatkovic, Ljiljana; Svindland, Aud; Eggesbø, Heidi B; Hung, Andrew J; Matsugasumi, Toru; Bernhard, Jean-Christophe; Gill, Inderbir S; Ukimura, Osamu

2015-02-01

Tumor contact length is defined as the amount of prostate cancer in contact with the prostatic capsule. We evaluated the ability of magnetic resonance imaging determined tumor contact length to predict microscopic extracapsular extension compared to existing predictors of extracapsular extension. We retrospectively analyzed the records of 111 consecutive patients with magnetic resonance imaging/ultrasound fusion targeted, biopsy proven prostate cancer who underwent radical prostatectomy from January 2010 to July 2013. Median patient age was 64 years and median prostate specific antigen was 8.9 ng/ml. Clinical stage was cT1 in 93 cases (84%) and cT2 in 18 (16%). Postoperative pathological analysis confirmed pT2 in 71 patients (64%) and pT3 in 40 (36%). We evaluated 1) in the radical prostatectomy specimen the correlation of microscopic extracapsular extension with pathological cancer volume, pathological tumor contact length and Gleason score, 2) the correlation between microscopic extracapsular extension and magnetic resonance imaging tumor contact length, and 3) the ability of preoperative variables to predict microscopic extracapsular extension. Logistic regression analysis revealed that pathological tumor contact length correlated better with microscopic extracapsular extension than the predictive power of pathological cancer volume (0.821 vs 0.685). The Spearman correlation between pathological and magnetic resonance imaging tumor contact length was r = 0.839 (p <0.0001). ROC AUC analysis revealed that magnetic resonance imaging tumor contact length outperformed cancer core involvement on targeted biopsy and the Partin tables to predict microscopic extracapsular extension (0.88 vs 0.70 and 0.63, respectively). At a magnetic resonance imaging tumor contact length threshold of 20 mm the accuracy for diagnosing microscopic extracapsular extension was superior to that of conventional magnetic resonance imaging criteria (82% vs 67%, p = 0.015). We developed a

Multichannel imaging to quantify four classes of pharmacokinetic distribution in tumors.

PubMed

Bhatnagar, Sumit; Deschenes, Emily; Liao, Jianshan; Cilliers, Cornelius; Thurber, Greg M

2014-10-01

Low and heterogeneous delivery of drugs and imaging agents to tumors results in decreased efficacy and poor imaging results. Systemic delivery involves a complex interplay of drug properties and physiological factors, and heterogeneity in the tumor microenvironment makes predicting and overcoming these limitations exceptionally difficult. Theoretical models have indicated that there are four different classes of pharmacokinetic behavior in tissue, depending on the fundamental steps in distribution. In order to study these limiting behaviors, we used multichannel fluorescence microscopy and stitching of high-resolution images to examine the distribution of four agents in the same tumor microenvironment. A validated generic partial differential equation model with a graphical user interface was used to select fluorescent agents exhibiting these four classes of behavior, and the imaging results agreed with predictions. BODIPY-FL exhibited higher concentrations in tissue with high blood flow, cetuximab gave perivascular distribution limited by permeability, high plasma protein and target binding resulted in diffusion-limited distribution for Hoechst 33342, and Integrisense 680 was limited by the number of binding sites in the tissue. Together, the probes and simulations can be used to investigate distribution in other tumor models, predict tumor drug distribution profiles, and design and interpret in vivo experiments. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Multichannel imaging to quantify four classes of pharmacokinetic distribution in tumors

PubMed Central

Bhatnagar, Sumit; Deschenes, Emily; Liao, Jianshan; Cilliers, Cornelius; Thurber, Greg M.

2014-01-01

Low and heterogeneous delivery of drugs and imaging agents to tumors results in decreased efficacy and poor imaging results. Systemic delivery involves a complex interplay of drug properties and physiological factors, and heterogeneity in the tumor microenvironment makes predicting and overcoming these limitations exceptionally difficult. Theoretical models have indicated that there are four different classes of pharmacokinetic behavior in tissue, depending on the fundamental steps in distribution. In order to study these limiting behaviors, we used multichannel fluorescence microscopy and stitching of high-resolution images to examine the distribution of four agents in the same tumor microenvironment. A validated generic partial differential equation model with a graphical user interface was used to select fluorescent agents exhibiting these four classes of behavior, and the imaging results agreed with predictions. BODIPY-FL exhibited higher concentrations in tissue with high blood flow, cetuximab gave perivascular distribution limited by permeability, high plasma protein and target binding resulted in diffusion-limited distribution for Hoechst 33342, and Integrisense 680 was limited by the number of binding sites in the tissue. Together, the probes and simulations can be used to investigate distribution in other tumor models, predict tumor drug distribution profiles, and design and interpret in vivo experiments. PMID:25048378

Overexpression of miRNA-497 inhibits tumor angiogenesis by targeting VEGFR2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tu, Yingfeng; Liu, Li; Zhao, Dongliang

Recent studies reported miR-497 exhibited inhibitory effects in various cancers. However, whether miR-497 is involved in inhibiting angiogenesis, which is critical for tumor growth and metastasis, is still unknown. The purpose of this study was to investigate the potential role of miR-497 in tumor angiogenesis. In this work, cell proliferation and apoptosis analyses were conducted to explore the potential function of miR-497 in HUVECs by using MTT and TUNEL assays. Western blotting (WB) was employed to validate the downstream targets of miR-497. Furthermore, in order to disclose the role of miR-497 on angiogenesis, VEGFR2-luc transgenic mice were treated with miR-497more » mimic and applied to monitor tumor angiogenesis and growth by in vivo bioluminescent imaging (BLI). The results demonstrated that overexpression of miR-497 showed inhibitory effects on VEGFR2 activation and downstream Raf/MEK/ERK signal pathways in vitro and in vivo. Moreover, overexpression of miR-497 effectively induced HUVECs apoptosis by targeting VEGFR2 and downstream PI3K/AKT signaling pathway. Furthermore, miR-497 exhibited anti-angiogenesis and anti-tumor effects in the VEGFR2-luc breast tumor model proven by BLI, WB and immunohistochemistry analysis. In summary, miR-497 inhibits tumor angiogenesis and growth via targeting VEGFR2, indicating miR-497 can be explored as a potential drug candidate for cancer therapy.« less

Overexpression of miRNA-497 inhibits tumor angiogenesis by targeting VEGFR2

DOE PAGES

Tu, Yingfeng; Liu, Li; Zhao, Dongliang; ...

2015-09-08

Recent studies reported miR-497 exhibited inhibitory effects in various cancers. However, whether miR-497 is involved in inhibiting angiogenesis, which is critical for tumor growth and metastasis, is still unknown. The purpose of this study was to investigate the potential role of miR-497 in tumor angiogenesis. In this work, cell proliferation and apoptosis analyses were conducted to explore the potential function of miR-497 in HUVECs by using MTT and TUNEL assays. Western blotting (WB) was employed to validate the downstream targets of miR-497. Furthermore, in order to disclose the role of miR-497 on angiogenesis, VEGFR2-luc transgenic mice were treated with miR-497more » mimic and applied to monitor tumor angiogenesis and growth by in vivo bioluminescent imaging (BLI). The results demonstrated that overexpression of miR-497 showed inhibitory effects on VEGFR2 activation and downstream Raf/MEK/ERK signal pathways in vitro and in vivo. Moreover, overexpression of miR-497 effectively induced HUVECs apoptosis by targeting VEGFR2 and downstream PI3K/AKT signaling pathway. Furthermore, miR-497 exhibited anti-angiogenesis and anti-tumor effects in the VEGFR2-luc breast tumor model proven by BLI, WB and immunohistochemistry analysis. In summary, miR-497 inhibits tumor angiogenesis and growth via targeting VEGFR2, indicating miR-497 can be explored as a potential drug candidate for cancer therapy.« less

Radiolabeled Cyclic RGD Peptides as Radiotracers for Imaging Tumors and Thrombosis by SPECT

PubMed Central

Zhou, Yang; Chakraborty, Sudipta; Liu, Shuang

2011-01-01

The integrin family is a group of transmembrane glycoprotein comprised of 19 α- and 8 β-subunits that are expressed in 25 different α/β heterodimeric combinations on the cell surface. Integrins play critical roles in many physiological processes, including cell attachment, proliferation, bone remodeling, and wound healing. Integrins also contribute to pathological events such as thrombosis, atherosclerosis, tumor invasion, angiogenesis and metastasis, infection by pathogenic microorganisms, and immune dysfunction. Among 25 members of the integrin family, the αvβ3 is studied most extensively for its role of tumor growth, progression and angiogenesis. In contrast, the αIIbβ3 is expressed exclusively on platelets, facilitates the intercellular bidirectional signaling (“inside-out” and “outside-in”) and allows the aggregation of platelets during vascular injury. The αIIbβ3 plays an important role in thrombosis by its activation and binding to fibrinogen especially in arterial thrombosis due to the high blood flow rate. In the resting state, the αIIbβ3 on platelets does not bind to fibrinogen; on activation, the conformation of platelet is altered and the binding sites of αIIbβ3 are exposed for fibrinogen to crosslink platelets. Over the last two decades, integrins have been proposed as the molecular targets for diagnosis and therapy of cancer, thrombosis and other diseases. Several excellent review articles have appeared recently to cover a broad range of topics related to the integrin-targeted radiotracers and their nuclear medicine applications in tumor imaging by single photon emission computed tomography (SPECT) or a positron-emitting radionuclide for positron emission tomography (PET). This review will focus on recent developments of αvβ3-targeted radiotracers for imaging tumors and the use of αIIbβ3-targeted radiotracers for thrombosis imaging, and discuss different approaches to maximize the targeting capability of cyclic RGD peptides

Boronic acid-tethered amphiphilic hyaluronic acid derivative-based nanoassemblies for tumor targeting and penetration.

PubMed

Jeong, Jae Young; Hong, Eun-Hye; Lee, Song Yi; Lee, Jae-Young; Song, Jae-Hyoung; Ko, Seung-Hak; Shim, Jae-Seong; Choe, Sunghwa; Kim, Dae-Duk; Ko, Hyun-Jeong; Cho, Hyun-Jong

2017-04-15

of HACE-AMPB/MB NPs (in the aqueous milieu) may react with the sialic acid over-expressed in cancer cells and intramolecular B‒O bond can be formed. This phenylboronic acid-sialic acid interaction may provide additional tumor targeting and penetration potentials together with an enhanced permeability and retention (EPR) effect (passive tumor targeting) and HA-CD44 receptor interaction (active tumor targeting). Developed HACE-AMPB NP may be one of promising nanocarriers for the imaging and therapy of CD44 receptor-expressed cancers. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Efficacy of NGR peptide-modified PEGylated quantum dots for crossing the blood-brain barrier and targeted fluorescence imaging of glioma and tumor vasculature.

PubMed

Huang, Ning; Cheng, Si; Zhang, Xiang; Tian, Qi; Pi, Jiangli; Tang, Jun; Huang, Qing; Wang, Feng; Chen, Jin; Xie, Zongyi; Xu, Zhongye; Chen, Weifu; Zheng, Huzhi; Cheng, Yuan

2017-01-01

Delivery of imaging agents to brain glioma is challenging because the blood-brain barrier (BBB) functions as a physiological checkpoint guarding the central nervous system from circulating large molecules. Moreover, the ability of existing probes to target glioma has been insufficient and needs to be improved. In present study, PEG-based long circulation, CdSe/ZnS quantum dots (QDs)-based nanoscale and fluorescence, asparagines-glycine-arginine peptides (NGR)-based specific CD13 recognition were integrated to design and synthesize a novel nanoprobe by conjugating biotinylated NGR peptides to avidin-PEG-coated QDs. Our data showed that the NGR-PEG-QDs were nanoscale with less than 100 nm and were stable in various pH (4.0~8.0). These nanomaterials with non-toxic concentrations could cross the BBB and target CD13-overexpressing glioma and tumor vasculature in vitro and in vivo, contributing to fluorescence imaging of this brain malignancy. These achievements allowed groundbreaking technological advances in targeted fluorescence imaging for the diagnosis and surgical removal of glioma, facilitating potential transformation toward clinical nanomedicine. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluation of potential internal target volume of liver tumors using cine-MRI

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akino, Yuichi, E-mail: akino@radonc.med.osaka-u.ac.jp; Oh, Ryoong-Jin; Masai, Norihisa

2014-11-01

Purpose: Four-dimensional computed tomography (4DCT) is widely used for evaluating moving tumors, including lung and liver cancers. For patients with unstable respiration, however, the 4DCT may not visualize tumor motion properly. High-speed magnetic resonance imaging (MRI) sequences (cine-MRI) permit direct visualization of respiratory motion of liver tumors without considering radiation dose exposure to patients. Here, the authors demonstrated a technique for evaluating internal target volume (ITV) with consideration of respiratory variation using cine-MRI. Methods: The authors retrospectively evaluated six patients who received stereotactic body radiotherapy (SBRT) to hepatocellular carcinoma. Before acquiring planning CT, sagittal and coronal cine-MRI images were acquiredmore » for 30 s with a frame rate of 2 frames/s. The patient immobilization was conducted under the same condition as SBRT. Planning CT images were then acquired within 15 min from cine-MRI image acquisitions, followed by a 4DCT scan. To calculate tumor motion, the motion vectors between two continuous frames of cine-MRI images were calculated for each frame using the pyramidal Lucas–Kanade method. The target contour was delineated on one frame, and each vertex of the contour was shifted and copied onto the following frame using neighboring motion vectors. 3D trajectory data were generated with the centroid of the contours on sagittal and coronal images. To evaluate the accuracy of the tracking method, the motion of clearly visible blood vessel was analyzed with the motion tracking and manual detection techniques. The target volume delineated on the 50% (end-exhale) phase of 4DCT was translated with the trajectory data, and the distribution of the occupancy probability of target volume was calculated as potential ITV (ITV {sub Potential}). The concordance between ITV {sub Potential} and ITV estimated with 4DCT (ITV {sub 4DCT}) was evaluated using the Dice’s similarity coefficient (DSC

Molecular photoacoustic imaging of breast cancer using an actively targeted conjugated polymer

PubMed Central

Balasundaram, Ghayathri; Ho, Chris Jun Hui; Li, Kai; Driessen, Wouter; Dinish, US; Wong, Chi Lok; Ntziachristos, Vasilis; Liu, Bin; Olivo, Malini

2015-01-01

Conjugated polymers (CPs) are upcoming optical contrast agents in view of their unique optical properties and versatile synthetic chemistry. Biofunctionalization of these polymer-based nanoparticles enables molecular imaging of biological processes. In this work, we propose the concept of using a biofunctionalized CP for noninvasive photoacoustic (PA) molecular imaging of breast cancer. In particular, after verifying the PA activity of a CP nanoparticle (CP dots) in phantoms and the targeting efficacy of a folate-functionalized version of the same (folate-CP dots) in vitro, we systemically administered the probe into a folate receptor-positive (FR+ve) MCF-7 breast cancer xenograft model to demonstrate the possible application of folate-CP dots for imaging FR+ve breast cancers in comparison to CP dots with no folate moieties. We observed a strong PA signal at the tumor site of folate-CP dots-administered mice as early as 1 hour after administration as a result of the active targeting of the folate-CP dots to the FR+ve tumor cells but a weak PA signal at the tumor site of CP-dots-administered mice as a result of the passive accumulation of the probe by enhanced permeability and retention effect. We also observed that folate-CP dots produced ~4-fold enhancement in the PA signal in the tumor, when compared to CP dots. These observations demonstrate the great potential of this active-targeting CP to be used as a contrast agent for molecular PA diagnostic imaging in various biomedical applications. PMID:25609951

Folic acid modified Pluronic F127 coating Ag2S quantum dot for photoacoustic imaging of tumor cell-targeting

NASA Astrophysics Data System (ADS)

Zhang, Ruo-Yun; Wang, Zhao-Yang; Yang, Xiao-Quan; Xuan, Yang; Cheng, Kai; Li, Cheng; Song, Xian-Lin; An, Jie; Hou, Xiao-Lin; Zhao, Yuan-Di

2018-02-01

In this study, an oil-soluble Ag2S quantum dot (QD) was synthesized through thermal decomposition using the single-source precursor method, and Pluronic F127 (PF127), a triblock copolymer functionalized with folic acid (FA), was deposited on the surface of the QD, then a water-soluble PF127-FA@Ag2S nanoprobe with targeting ability was fabricated. The as-prepared PF127-FA@Ag2S exhibited spheroidal morphology and high dispersibility, with average diameters of 115 ± 20.7 nm (as observed by transmission electron microscopy). No obvious toxicity of the PF127-FA@Ag2S nanoprobe was found in standard 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay and colony-formation assay, indicating good biocompatibility and safety. The resulting PF127-FA@Ag2S exhibited excellent stability between 4 °C-40 °C. Additionally, the capacity of the tumor cell-targeting high contrast enhanced photoacoustic imaging of PF127-FA@Ag2S was verified in comparison with A547 and HeLa cells. In other words, the excellent properties of PF127-FA@Ag2S show great potential in further research for targeting and photoacoustic imaging.

Development of Novel Tumor-Targeted Theranostic Nanoparticles Activated by Membrane-Type Matrix Metalloproteinases for Combined Cancer Magnetic Resonance Imaging and Therapy

PubMed Central

Ansari, Celina; Tikhomirov, Grigory A.; Hong, Su Hyun; Falconer, Robert A.; Loadman, Paul M.; Gill, Jason H.; Castaneda, Rosalinda; Hazard, Florette K.; Tong, Ling; Lenkov, Olga D.; Felsher, Dean W.; Rao, Jianghong; Daldrup-Link, Heike E.

2013-01-01

A major drawback with current cancer therapy is the prevalence of unrequired dose-limiting toxicity to non-cancerous tissues and organs, which is further compounded by a limited ability to rapidly and easily monitor drug delivery, pharmacodynamics and therapeutic response. In this report, we describe the design and characterization of novel multifunctional “theranostic” nanoparticles (TNPs) for enzyme-specific drug activation at tumor sites and simultaneous in vivo magnetic resonance imaging (MRI) of drug delivery. TNPs were synthesized by conjugation of FDA-approved iron oxide nanoparticles ferumoxytol to an MMP-activatable peptide conjugate of azademethylcolchicine (ICT), creating CLIO-ICTs (TNPs). Significant cell death was observed in TNP-treated MMP-14 positive MMTV-PyMT breast cancer cells in vitro, but not MMP-14 negative fibroblasts or cells treated with ferumoxytol alone. Intravenous administration of TNPs to MMTV-PyMT tumor-bearing mice and subsequent MRI demonstrated significant tumor selective accumulation of the TNP, an observation confirmed by histopathology. Treatment with CLIO-ICTs induced a significant antitumor effect and tumor necrosis, a response not observed with ferumoxytol. Furthermore, no toxicity or cell death was observed in normal tissues following treatment with CLIO-ICTs, ICT, or ferumoxytol. Our findings demonstrate proof of concept for a new nanotemplate that integrates tumor specificity, drug delivery and in vivo imaging into a single TNP entity through attachment of enzyme-activated prodrugs onto magnetic nanoparticles. This novel approach holds the potential to significantly improve targeted cancer therapies, and ultimately enable personalized therapy regimens. PMID:24038954

In Vivo Bio-distribution and Efficient Tumor Targeting of Gelatin/Silica Nanoparticles for Gene Delivery

NASA Astrophysics Data System (ADS)

Zhao, Xueqin; Wang, Jun; Tao, SiJie; Ye, Ting; Kong, Xiangdong; Ren, Lei

2016-04-01

The non-viral gene delivery system is an attractive alternative to cancer therapy. The clinical success of non-viral gene delivery is hampered by transfection efficiency and tumor targeting, which can be individually overcome by addition of functional modules such as cell penetration or targeting. Here, we first engineered the multifunctional gelatin/silica (GS) nanovectors with separately controllable modules, including tumor-targeting aptamer AGRO100, membrane-destabilizing peptide HA2, and polyethylene glycol (PEG), and then studied their bio-distribution and in vivo transfection efficiencies by contrast resonance imaging (CRI). The results suggest that the sizes and zeta potentials of multifunctional gelatin/silica nanovectors were 203-217 nm and 2-8 mV, respectively. Functional GS-PEG nanoparticles mainly accumulated in the liver and tumor, with the lowest uptake by the heart and brain. Moreover, the synergistic effects of tumor-targeting aptamer AGRO100 and fusogenic peptide HA2 promoted the efficient cellular internalization in the tumor site. More importantly, the combined use of AGRO100 and PEG enhanced tumor gene expression specificity and effectively reduced toxicity in reticuloendothelial system (RES) organs after intravenous injection. Additionally, low accumulation of GS-PEG was observed in the heart tissues with high gene expression levels, which could provide opportunities for non-invasive gene therapy.

Visualization of Tumor-Immune Interaction - Target-Specific Imaging of S100A8/A9 Reveals Pre-Metastatic Niche Establishment.

PubMed

Eisenblaetter, Michel; Flores-Borja, Fabian; Lee, Jae Jin; Wefers, Christina; Smith, Hannah; Hueting, Rebekka; Cooper, Margaret S; Blower, Philip J; Patel, Dominic; Rodriguez-Justo, Manuel; Milewicz, Hanna; Vogl, Thomas; Roth, Johannes; Tutt, Andrew; Schaeffter, Tobias; Ng, Tony

2017-01-01

Background Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis - the premetastatic niche. As crucial players in establishment of the pre-metastatic niche, myeloid derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression. We report the application of antibody-based single-photon emission computed tomography (SPECT) for detection of S100A8/A9 in vivo as an imaging marker for pre-metastatic tissue priming. Methods A syngeneic model system for invasive breast cancer with (4T1.2) or without (67NR) the tendency to form lung metastasis was established in BALB/c mice. A SPECT-probe has been generated and tested for visualization of S100A9 release. Tumor-associated changes in numbers and fuction of immune cells in pre-metastatic tissue were evaluated by flow cytometry and confocal microscopy. Results S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in pre-metastatic lung tissue (activity 4T1.2 vs. healthy control: 0.95 vs. 0.45 %ID; p<0.001). The S100A8/A9 imaging signal in the pre-metastatic lung correlated with the subsequent metastatic tumor burden in the same organ (r 2 =0.788; p<0.0001). CCL2 blockade and the consecutive inhibition of premetastatic niche establishment was clearly depicted by S100A9-SPECT (lung activity untreated vs. treated: 2 vs, 1.4 %ID). Conclusion We report S100A8/A9 as a potent imaging biomarker for tumor-mediated immune remodeling with potential applications in basic research and clinical oncology.

Visualization of Tumor-Immune Interaction - Target-Specific Imaging of S100A8/A9 Reveals Pre-Metastatic Niche Establishment

PubMed Central

Eisenblaetter, Michel; Flores-Borja, Fabian; Lee, Jae Jin; Wefers, Christina; Smith, Hannah; Hueting, Rebekka; Cooper, Margaret S; Blower, Philip J; Patel, Dominic; Rodriguez-Justo, Manuel; Milewicz, Hanna; Vogl, Thomas; Roth, Johannes; Tutt, Andrew; Schaeffter, Tobias; Ng, Tony

2017-01-01

Background Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis - the premetastatic niche. As crucial players in establishment of the pre-metastatic niche, myeloid derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression. We report the application of antibody-based single-photon emission computed tomography (SPECT) for detection of S100A8/A9 in vivo as an imaging marker for pre-metastatic tissue priming. Methods A syngeneic model system for invasive breast cancer with (4T1.2) or without (67NR) the tendency to form lung metastasis was established in BALB/c mice. A SPECT-probe has been generated and tested for visualization of S100A9 release. Tumor-associated changes in numbers and fuction of immune cells in pre-metastatic tissue were evaluated by flow cytometry and confocal microscopy. Results S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in pre-metastatic lung tissue (activity 4T1.2 vs. healthy control: 0.95 vs. 0.45 %ID; p<0.001). The S100A8/A9 imaging signal in the pre-metastatic lung correlated with the subsequent metastatic tumor burden in the same organ (r2=0.788; p<0.0001). CCL2 blockade and the consecutive inhibition of premetastatic niche establishment was clearly depicted by S100A9-SPECT (lung activity untreated vs. treated: 2 vs, 1.4 %ID). Conclusion We report S100A8/A9 as a potent imaging biomarker for tumor-mediated immune remodeling with potential applications in basic research and clinical oncology. PMID:28744322

Experimental Drug Metarrestin Targets Metastatic Tumors

Cancer.gov

An experimental drug called metarrestin appears to selectively target tumors that have spread to other parts of the body. As this Cancer Currents blog post reports, the drug shrank metastatic tumors and extended survival in in mouse models of pancreatic cancer.

Fusion Protein Vaccines Targeting Two Tumor Antigens Generate Synergistic Anti-Tumor Effects

PubMed Central

Cheng, Wen-Fang; Chang, Ming-Cheng; Sun, Wei-Zen; Jen, Yu-Wei; Liao, Chao-Wei; Chen, Yun-Yuan; Chen, Chi-An

2013-01-01

Introduction Human papillomavirus (HPV) has been consistently implicated in causing several kinds of malignancies, and two HPV oncogenes, E6 and E7, represent two potential target antigens for cancer vaccines. We developed two fusion protein vaccines, PE(ΔIII)/E6 and PE(ΔIII)/E7 by targeting these two tumor antigens to test whether a combination of two fusion proteins can generate more potent anti-tumor effects than a single fusion protein. Materials and Methods In vivo antitumor effects including preventive, therapeutic, and antibody depletion experiments were performed. In vitro assays including intracellular cytokine staining and ELISA for Ab responses were also performed. Results PE(ΔIII)/E6+PE(ΔIII)/E7 generated both stronger E6 and E7-specific immunity. Only 60% of the tumor protective effect was observed in the PE(ΔIII)/E6 group compared to 100% in the PE(ΔIII)/E7 and PE(ΔIII)/E6+PE(ΔIII)/E7 groups. Mice vaccinated with the PE(ΔIII)/E6+PE(ΔIII)/E7 fusion proteins had a smaller subcutaneous tumor size than those vaccinated with PE(ΔIII)/E6 or PE(ΔIII)/E7 fusion proteins alone. Conclusion Fusion protein vaccines targeting both E6 and E7 tumor antigens generated more potent immunotherapeutic effects than E6 or E7 tumor antigens alone. This novel strategy of targeting two tumor antigens together can promote the development of cancer vaccines and immunotherapy in HPV-related malignancies. PMID:24058440

Near-infrared fluorescent peptide probes for imaging of tumor in vivo and their biotoxicity evaluation.

PubMed

Liu, Liwei; Lin, Guimiao; Yin, Feng; Law, Wing-Cheung; Yong, Ken-Tye

2016-04-01

Optical imaging techniques are becoming increasingly urgent for the early detection and monitoring the progression of tumor development. However, tumor vasculature imaging has so far been largely unexplored because of the lack of suitable optical probes. In this study, we demonstrated the preparation of near-infrared (NIR) fluorescent RGD peptide probes for noninvasive imaging of tumor vasculature during tumor angiogenesis. The peptide optical probes combined the advantages of NIR emission and RGD peptide, which possesses minimal biological absorption and specially targets the integrin, which highly expressed on activated tumor endothelial cells. In vivo optical imaging of nude mice bearing pancreatic tumor showed that systemically delivered NIR probes enabled us to visualize the tumors at 24 hours post-injection. In addition, we have performed in vivo toxicity study on the prepared fluorescent RGD peptide probes formulation. The blood test results and histological analysis demonstrated that no obvious toxicity was found for the mice treated with RGD peptide probes for two weeks. These studies suggest that the NIR fluorescent peptide probes can be further designed and employed for ultrasensitive fluorescence imaging of angiogenic tumor vasculature, as well as imaging of other pathophysiological processes accompanied by activation of endothelial cells. © 2016 Wiley Periodicals, Inc.

A theranostic nanoplatform: magneto-gold@fluorescence polymer nanoparticles for tumor targeting T1&T2-MRI/CT/NIR fluorescence imaging and induction of genuine autophagy mediated chemotherapy.

PubMed

Wang, Guannan; Qian, Kun; Mei, Xifan

2018-06-14

Multifunctional nanoparticles, bearing low toxicity and tumor-targeting properties, coupled with multifunctional diagnostic imaging and enhanced treatment efficacy, have drawn tremendous attention due to their enormous potential for medical applications. Herein, we report a new kind of biocompatible and tumor-targeting magneto-gold@fluorescent polymer nanoparticle (MGFs-LyP-1), which is based on ultra-small magneto-gold (Fe 3 O 4 -Au) nanoparticles and NIR emissive fluorescent polymers by a solvent-mediated method. This kind of nanoparticle could be taken up efficiently and simultaneously serve for in vivo tumor targeting T 1 &T 2 -MRI/CT/near infrared (NIR) fluorescence bioimaging. Furthermore, the nanoparticles exhibit small size, higher tumor targeting accumulation, excellent cytocompatibility for long-term tracking, and no disturbing cell proliferation and differentiation. Moreover, clear and convincing evidence proves that as-synthesized MGFs-LyP-1 could elicit genuine autophagy via inducing autophagosome formation, which offers a definite synergistic effect to enhance cancer therapy with doxorubicin (DOX) at a nontoxic concentration through enhancement of the autophagy flux. Meanwhile, the as-prepared nanoparticles could be rapidly cleared from mice without any obvious organ impairment. The results indeed reveal a promising prospect of an MGFs-LyP-1 contrast agent with low toxicity and high efficiency for promising application in biomedicine.

Synthesizing and binding dual-mode poly (lactic-co-glycolic acid) (PLGA) nanobubbles for cancer targeting and imaging.

PubMed

Xu, Jeff S; Huang, Jiwei; Qin, Ruogu; Hinkle, George H; Povoski, Stephen P; Martin, Edward W; Xu, Ronald X

2010-03-01

Accurate assessment of tumor boundaries and recognition of occult disease are important oncologic principles in cancer surgeries. However, existing imaging modalities are not optimized for intraoperative cancer imaging applications. We developed a nanobubble (NB) contrast agent for cancer targeting and dual-mode imaging using optical and ultrasound (US) modalities. The contrast agent was fabricated by encapsulating the Texas Red dye in poly (lactic-co-glycolic acid) (PLGA) NBs and conjugating NBs with cancer-targeting ligands. Both one-step and three-step cancer-targeting strategies were tested on the LS174T human colon cancer cell line. For the one-step process, NBs were conjugated with the humanized HuCC49 Delta C(H)2 antibody to target the over-expressed TAG-72 antigen. For the three-step process, cancer cells were targeted by successive application of the biotinylated HuCC49 Delta C(H)2 antibody, streptavidin, and the biotinylated NBs. Both one-step and three-step processes successfully targeted the cancer cells with high binding affinity. NB-assisted dual-mode imaging was demonstrated on a gelatin phantom that embedded multiple tumor simulators at different NB concentrations. Simultaneous fluorescence and US images were acquired for these tumor simulators and linear correlations were observed between the fluorescence/US intensities and the NB concentrations. Our research demonstrated the technical feasibility of using the dual-mode NB contrast agent for cancer targeting and simultaneous fluorescence/US imaging. (c) 2009 Elsevier Ltd. All rights reserved.

Imaging Tumor Cell Movement In Vivo

PubMed Central

Entenberg, David; Kedrin, Dmitriy; Wyckoff, Jeffrey; Sahai, Erik; Condeelis, John; Segall, Jeffrey E.

2013-01-01

This unit describes the methods that we have been developing for analyzing tumor cell motility in mouse and rat models of breast cancer metastasis. Rodents are commonly used both to provide a mammalian system for studying human tumor cells (as xenografts in immunocompromised mice) as well as for following the development of tumors from a specific tissue type in transgenic lines. The Basic Protocol in this unit describes the standard methods used for generation of mammary tumors and imaging them. Additional protocols for labeling macrophages, blood vessel imaging, and image analysis are also included. PMID:23456602

Effects of linker modification on tumor-to-kidney contrast of 68Ga-labeled PSMA-targeted imaging probes.

PubMed

Kuo, Hsiou-Ting; Pan, Jinhe; Zhang, Zhengxing; Lau, Joseph; Merkens, Helen; Zhang, Chengcheng; Colpo, Nadine; Lin, Kuo-Shyan; Benard, Francois

2018-06-19

68Ga-PSMA-11 is currently the most popular prostate-specific membrane antigen (PSMA) radioligand used in the clinic to detect prostate cancer and metastases. However, the high uptake of 68Ga-PSMA-11 in kidneys can create halo-artifacts resulting in lower detection sensitivity for lesions adjacent to the kidneys. In this study, we developed two 68Ga-labeled PSMA-targeted tracers, 68Ga-HTK01166 and 68Ga-HTK01167, based on 68Ga-PSMA-617 with the goal of improving tumor-to-kidney ratio compared to 68Ga-PSMA-11. The 2-naphthylalanine (2-Nal) in PSMA-617 was replaced with 2-indanylglycine (Igl) or 3,3-diphenylalanine (Dip) to synthesize HTK01166 and HTK01167, respectively. Binding affinities (Ki) of Ga-PSMA-11, Ga-PSMA-617, Ga-HTK01166 and Ga-HTK01167 to PSMA were 3.13 ± 0.40, 1.23 ± 0.08, 5.74 ± 2.48 and 25.7 ± 9.84 nM, respectively, as determined by in vitro competition binding assays. 68Ga labeling was performed in HEPES buffer with microwave heating, and 68Ga-labeled PSMA-11, PSMA-617, HTK01166 and HTK01167 were obtained in 46 - 69% average decay-corrected radiochemical yield with >99% radiochemical purity and 62.9 - 152 GBq/μmol average specific activity. PET imaging and biodistribution studies were performed in mice bearing PSMA-expressing LNCap prostate cancer xenografts. All tracers enabled clear visualization of tumors in PET images with excellent tumor-to-background contrast. The uptake values (%ID/g) for tumor and kidneys at 1 h post-injection were 8.91 ± 0.86 and 204 ± 70.6 for 68Ga-PSMA-11, 16.7 ± 2.30 and 29.2 ± 5.14 for 68Ga-PSMA-617, 14.1 ± 4.40 and 147 ± 59.6 for 68Ga-HTK01166, and 7.79 ± 1.65 and 4.30 ± 1.80 for 68Ga-HTK01167. The tumor-to-kidney ratios for 68Ga-labeled PSMA-11, PSMA-617, HTK01166 and HTK01167 were 0.05 ± 0.02, 0.63 ± 0.10, 0.10 ± 0.02 and 1.98 ± 0.63, respectively. Compared with 68Ga-PSMA-617, 68Ga-HTK01166 showed comparable tumor uptake, and almost 5-fold higher kidney uptake; whereas 68Ga-HTK01167 exhibited lower

Improved Tumor Targeting and Longer Retention Time of NIR Fluorescent Probes Using Bioorthogonal Chemistry.

PubMed

Zhang, Xianghan; Wang, Bo; Zhao, Na; Tian, Zuhong; Dai, Yunpeng; Nie, Yongzhan; Tian, Jie; Wang, Zhongliang; Chen, Xiaoyuan

2017-01-01

The traditional labeling method for targeted NIR fluorescence probes requires directly covalent-bonded conjugation of targeting domains and fluorophores in vitro . Although this strategy works well, it is not sufficient for detecting or treating cancers in vivo , due to steric hindrance effects that relatively large fluorophore molecules exert on the configurations and physiological functions of specific targeting domains. The copper-free, "click-chemistry"-assisted assembly of small molecules in living systems may enhance tumor accumulation of fluorescence probes by improving the binding affinities of the targeting factors. Here, we employed a vascular homing peptide, GEBP11, as a targeting factor for gastric tumors, and we demonstrate its effectiveness for in vivo imaging via click-chemistry-mediated conjugation with fluorescence molecules in tumor xenograft mouse models. This strategy showed higher binding affinities than those of the traditional conjugation method, and our results showed that the tumor accumulation of click-chemistry-mediated probes are 11-fold higher than that of directly labeled probes. The tracking life was prolonged by 12-fold, and uptake of the probes into the kidney was reduced by 6.5-fold. For lesion tumors of different sizes, click-chemistry-mediated probes can achieve sufficient signal-to-background ratios (3.5-5) for in vivo detection, and with diagnostic sensitivity approximately 3.5 times that of traditional labeling probes. The click-chemistry-assisted detection strategy utilizes the advantages of "small molecule" probes while not perturbing their physiological functions; this enables tumor detection with high sensitivity and specific selectivity.

In vivo EPR imaging of differential tumor targeting using cis-3,4-di(acetoxymethoxycarbonyl)-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl

PubMed Central

Redler, Gage; Barth, Eugene D.; Bauer, Kenneth S.; Kao, Joseph P.Y.; Rosen, Gerald M.; Halpern, Howard J.

2015-01-01

Purpose EPR spectroscopy promises quantitative images of important physiologic markers of animal tumors and normal tissues, such as pO2, pH, and thiol redox status. These parameters of tissue function are conveniently reported by tailored nitroxides. For defining tumor physiology, it is vital that nitroxides are selectively localized in tumors relative to normal tissue. Furthermore, these paramagnetic species should be specifically taken up by cells of the tumor, thereby reporting on both the site of tumor formation and the physiological status of the tissue. This study investigates the tumor localization of the novel nitroxide, cis-3,4-di(acetoxymethoxycarbonyl)-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl 3 relative to the corresponding di-acid 4. Methods We obtained images of nitroxide 3 infused intravenously into C3H mice bearing 0.5-cm3 FSa fibrosarcoma on the leg, and compared these with images of similar tumors infused with nitroxide 4. Results The ratio of spectral intensity from within the tumor-bearing region to that of normal tissue was higher in the mice injected with 3 relative to 4. Conclusion This establishes the possibility of tumor imaging with a nitroxide with intracellular distribution and provides the basis for EPR images of animal models to investigate the relationship between crucial aspects of tumor microenvironment and malignancy and its response to therapy. PMID:23776127

Brain's tumor image processing using shearlet transform

NASA Astrophysics Data System (ADS)

Cadena, Luis; Espinosa, Nikolai; Cadena, Franklin; Korneeva, Anna; Kruglyakov, Alexey; Legalov, Alexander; Romanenko, Alexey; Zotin, Alexander

2017-09-01

Brain tumor detection is well known research area for medical and computer scientists. In last decades there has been much research done on tumor detection, segmentation, and classification. Medical imaging plays a central role in the diagnosis of brain tumors and nowadays uses methods non-invasive, high-resolution techniques, especially magnetic resonance imaging and computed tomography scans. Edge detection is a fundamental tool in image processing, particularly in the areas of feature detection and feature extraction, which aim at identifying points in a digital image at which the image has discontinuities. Shearlets is the most successful frameworks for the efficient representation of multidimensional data, capturing edges and other anisotropic features which frequently dominate multidimensional phenomena. The paper proposes an improved brain tumor detection method by automatically detecting tumor location in MR images, its features are extracted by new shearlet transform.

Development of Y-shaped peptide for constructing nanoparticle systems targeting tumor-associated macrophages in vitro and in vivo

NASA Astrophysics Data System (ADS)

Yan, Lu; Gao, Yunxiang; Pierce, Ryan; Dai, Liming; Kim, Julian; Zhang, Mei

2014-04-01

Tumor-associated macrophage (TAM) is increasingly being viewed as a target of great interest in tumor microenvironment due to its important role in the progression and metastasis of cancers. It has been shown that TAM indeed overexpresses unique surface marker legumain. In this study, we designed and synthesized a Y-shaped legumain-targeting peptide (Y-Leg) with functional groups allowing for further conjugation with imaging and therapeutic moieties (vide infra). The in vitro cell experiments using FITC-conjugated Y-Leg revealed its specific and selective interaction with M2-polarized macrophages (i.e., TAMs) with preference to M1 macrophages, and that the interaction was not interfered with by conjugating FITC to its functional group. Further, we constructed a nanotube system by grafting Y-Leg onto oxidized carbon nanotubes (OCNTs) loaded with paramagnetic Fe3O4 nanoparticles. The intravenous injection of the resultant Y-Leg-OCNT/Fe3O4 nanotubes to 4T1 mammary tumor-bearing mouse led to the magnetic resonance imaging (MRI) of TAM-infiltrated tumor microenvironment, revealing the targeting specificity of Y-Leg-conjugated nanotubes in vivo. The Y shape of peptide and its functional groups containing amines and imidazole can protonate at different pHs, contributing to the in vitro and in vivo targeting specificity. This study represents the first development of novel peptide and peptide-grafted nanotube system targeting M2-polarized TAMs in vivo. The methodology developed in this study is applicable to the construction of various multifunctional nanoparticle systems for selectively targeting, imaging and manipulating of TAMs for the diagnosis and treatment of cancers and inflammatory diseases identified with macrophage-infiltrated disease tissue.

Imaging of gastroenteropancreatic neuroendocrine tumors

PubMed Central

Tan, Eik Hock; Tan, Cher Heng

2011-01-01

Imaging of gastroenteropancreatic neuroendocrine tumors can be broadly divided into anatomic and functional techniques. Anatomic imaging determines the local extent of the primary lesion, providing crucial information required for surgical planning. Functional imaging, not only determines the extent of metastatic disease spread, but also provides important information with regard to the biologic behavior of the tumor, allowing clinicians to decide on the most appropriate forms of treatment. We review the current literature on this subject, with emphasis on the strengths of each imaging modality. PMID:21603312

Biomimetic HDL nanoparticle mediated tumor targeted delivery of indocyanine green for enhanced photodynamic therapy.

PubMed

Wang, Yazhe; Wang, Cheng; Ding, Yang; Li, Jing; Li, Min; Liang, Xiao; Zhou, Jianping; Wang, Wei

2016-12-01

Photodynamic therapy has emerged as a promising strategy for cancer treatment. To ensure the efficient delivery of a photosensitizer to tumor for anticancer effect, a safe and tumor-specific delivery system is highly desirable. Herein, we introduce a novel biomimetic nanoparticle named rHDL/ICG (rHDL/I), by loading amphiphilic near-infrared (NIR) fluorescent dye indocyanine green (ICG) into reconstituted high density lipoproteins (rHDL). In this system, rHDL can mediate photoprotection effect and receptor-guided tumor-targeting transportation of cargos into cells. Upon NIR irradiation, ICG can generate fluorescent imaging signals for diagnosis and monitoring therapeutic activity, and produce singlet oxygen to trigger photodynamic therapy (PDT). Our studies demonstrated that rHDL/I exhibited excellent size and fluorescence stability, light-triggered controlled release feature, and neglectable hemolytic activity. It also showed equivalent NIR response compared to free ICG under laser irradiation. Importantly, the fluorescent signal of ICG loaded in rHDL/I could be visualized subcellularly in vitro and exhibited metabolic distribution in vivo, presenting superior tumor targeting and internalization. This NIR-triggered image-guided nanoparticle produced outstanding therapeutic outcomes against cancer cells, demonstrating great potential of biomimetic delivery vehicles in future clinical practice. Copyright © 2016 Elsevier B.V. All rights reserved.

Tumor environment changed by combretastatin derivative (Cderiv) pretreatment that leads to effective tumor targeting, MRI studies, and antitumor activity of polymeric micelle carrier systems.

PubMed

Shiraishi, Kouichi; Harada, Yoshiko; Kawano, Kumi; Maitani, Yoshie; Hori, Katsuyoshi; Yanagihara, Kazuyoshi; Takigahira, Misato; Yokoyama, Masayuki

2012-01-01

To evaluate effect of a vascular disrupting agent, a combretastatin derivative (Cderiv), on tumor targeting for polymeric micelle carrier systems, containing either a diagnostic MRI contrast agent or a therapeutic anticancer drug. Cderiv was pre-administered 72 h before polymeric micelle MRI contrast agent injection. Accumulation of the MRI contrast agent in colon 26 murine tumor was evaluated with or without pretreatment of Cderiv by ICP and MRI. Significantly higher accumulation of the MRI contrast agent was found in tumor tissues when Cderiv was administered at 72 h before MRI contrast agent injection. T(1)-weighted images of the tumor exhibited substantial signal enhancement in tumor area at 24 h after the contrast agent injection. In T(1)-weighted images, remarkable T(1)-signal enhancements were observed in part of tumor, not in whole tumor. These results indicate that Cderiv pretreatment considerably enhanced the permeability of the tumor blood vessels. Antitumor activity of adriamycin encapsulated polymeric micelles with the Cderiv pretreatment suppressed tumor growth in 44As3 human gastric scirrhous carcinoma-bearing nude mice. Pretreatment of Cderiv enhanced tumor permeability, resulting in higher accumulation of polymeric micelle carrier systems in solid tumors.

Convection-enhanced delivery of targeted quantum dot-immunoliposome hybrid nanoparticles to intracranial brain tumor models.

PubMed

Weng, Kevin C; Hashizume, Rintaro; Noble, Charles O; Serwer, Laura P; Drummond, Daryl C; Kirpotin, Dmitri B; Kuwabara, Anne M; Chao, Lucy X; Chen, Fanqing F; James, Charles D; Park, John W

2013-12-01

The aim of this work is to evaluate combining targeting strategy and convection-enhanced delivery in brain tumor models by imaging quantum dot-immunoliposome hybrid nanoparticles. An EGF receptor-targeted, quantum dot-immunoliposome hybrid nanoparticle (QD-IL) was synthesized. In vitro uptake was measured by flow cytometry and intracellular localization was imaged by confocal microscopy. In the in vivo study, QD-ILs were delivered to intracranial xenografts via convection-enhanced delivery and fluorescence was monitored noninvasively in real-time. QD-ILs exhibited specific and efficient uptake in vitro and exhibited approximately 1.3- to 5.0-fold higher total fluorescence compared with nontargeted counterpart in intracranial brain tumor xenografts in vivo. QD-ILs serve as an effective imaging agent in vitro and in vivo, and the data suggest that ligand-directed liposomal nanoparticles in conjunction with convection-enhanced delivery may offer therapeutic benefits for glioblastoma treatment as a result of specific and efficient uptake by malignant cells.

Metalloporphyrins and their uses as imageable tumor-targeting agents for radiation therapy

DOEpatents

Miura, Michiko; Slatkin, Daniel N.

2003-05-20

The present invention covers halogenated derivatives of boronated porphyrins containing multiple carborane cages having the formula ##STR1## which selectively accumulate in neoplastic tissue within the irradiation volume and thus can be used in cancer therapies including, but not limited to, boron neutron- capture therapy and photodynamic therapy. The present invention also covers methods for using these halogenated derivatives of boronated porphyrins in tumor imaging and cancer treatment.

Use of novel metalloporphyrins as imageable tumor-targeting agents for radiation therapy

DOEpatents

Miura, Michiko; Slatkin, Daniel N.

2005-10-04

The present invention covers halogenated derivatives of boronated phorphyrins containing multiple carborane cages having the formula ##STR1## which selectively accumulate in neoplastic tissue within the irradiation volume and thus can be used in cancer therapies including, but not limited to, boron neutron-capture therapy and photodynamic therapy. The present invention also covers methods for using these halogenated derivatives of boronated porphyrins in tumor imaging and cancer treatment.

Use of PET and Other Functional Imaging to Guide Target Delineation in Radiation Oncology.

PubMed

Verma, Vivek; Choi, J Isabelle; Sawant, Amit; Gullapalli, Rao P; Chen, Wengen; Alavi, Abass; Simone, Charles B

2018-06-01

Molecular and functional imaging is increasingly being used to guide radiotherapy (RT) management and target delineation. This review summarizes existing data in several disease sites of various functional imaging modalities, chiefly positron emission tomography/computed tomography (PET/CT), with respect to RT target definition and management. For gliomas, differentiation between postoperative changes and viable tumor is discussed, as well as focal dose escalation and reirradiation. Head and neck neoplasms may also benefit from precise PET/CT-based target delineation, especially for cancers of unknown primary; focal dose escalation is also described. In lung cancer, PET/CT can influence coverage of tumor volumes, dose escalation, and adaptive management. For cervical cancer, PET/CT as an adjunct to magnetic resonance imaging planning is discussed, as are dose escalation and delineation of avoidance targets such as the bone marrow. The emerging role of choline-based PET for prostate cancer and its impact on dose escalation is also described. Lastly, given the essential role of PET/CT for target definition in lymphoma, phase III trials of PET-directed management are reviewed, along with novel imaging modalities. Taken together, molecular and functional imaging approaches offer a major step to individualize radiotherapeutic care going forward. Copyright © 2018 Elsevier Inc. All rights reserved.

Brain tumor segmentation using holistically nested neural networks in MRI images.

PubMed

Zhuge, Ying; Krauze, Andra V; Ning, Holly; Cheng, Jason Y; Arora, Barbara C; Camphausen, Kevin; Miller, Robert W

2017-10-01

Gliomas are rapidly progressive, neurologically devastating, largely fatal brain tumors. Magnetic resonance imaging (MRI) is a widely used technique employed in the diagnosis and management of gliomas in clinical practice. MRI is also the standard imaging modality used to delineate the brain tumor target as part of treatment planning for the administration of radiation therapy. Despite more than 20 yr of research and development, computational brain tumor segmentation in MRI images remains a challenging task. We are presenting a novel method of automatic image segmentation based on holistically nested neural networks that could be employed for brain tumor segmentation of MRI images. Two preprocessing techniques were applied to MRI images. The N4ITK method was employed for correction of bias field distortion. A novel landmark-based intensity normalization method was developed so that tissue types have a similar intensity scale in images of different subjects for the same MRI protocol. The holistically nested neural networks (HNN), which extend from the convolutional neural networks (CNN) with a deep supervision through an additional weighted-fusion output layer, was trained to learn the multiscale and multilevel hierarchical appearance representation of the brain tumor in MRI images and was subsequently applied to produce a prediction map of the brain tumor on test images. Finally, the brain tumor was obtained through an optimum thresholding on the prediction map. The proposed method was evaluated on both the Multimodal Brain Tumor Image Segmentation (BRATS) Benchmark 2013 training datasets, and clinical data from our institute. A dice similarity coefficient (DSC) and sensitivity of 0.78 and 0.81 were achieved on 20 BRATS 2013 training datasets with high-grade gliomas (HGG), based on a two-fold cross-validation. The HNN model built on the BRATS 2013 training data was applied to ten clinical datasets with HGG from a locally developed database. DSC and sensitivity of

Nano-sized metabolic precursors for heterogeneous tumor-targeting strategy using bioorthogonal click chemistry in vivo.

PubMed

Lee, Sangmin; Jung, Seulhee; Koo, Heebeom; Na, Jin Hee; Yoon, Hong Yeol; Shim, Man Kyu; Park, Jooho; Kim, Jong-Ho; Lee, Seulki; Pomper, Martin G; Kwon, Ick Chan; Ahn, Cheol-Hee; Kim, Kwangmeyung

2017-12-01

Herein, we developed nano-sized metabolic precursors (Nano-MPs) for new tumor-targeting strategy to overcome the intrinsic limitations of biological ligands such as the limited number of biological receptors and the heterogeneity in tumor tissues. We conjugated the azide group-containing metabolic precursors, triacetylated N-azidoacetyl-d-mannosamine to generation 4 poly(amidoamine) dendrimer backbone. The nano-sized dendrimer of Nano-MPs could generate azide groups on the surface of tumor cells homogeneously regardless of cell types via metabolic glycoengineering. Importantly, these exogenously generated 'artificial chemical receptors' containing azide groups could be used for bioorthogonal click chemistry, regardless of phenotypes of different tumor cells. Furthermore, in tumor-bearing mice models, Nano-MPs could be mainly localized at the target tumor tissues by the enhanced permeation and retention (EPR) effect, and they successfully generated azide groups on tumor cells in vivo after an intravenous injection. Finally, we showed that these azide groups on tumor tissues could be used as 'artificial chemical receptors' that were conjugated to bioorthogonal chemical group-containing liposomes via in vivo click chemistry in heterogeneous tumor-bearing mice. Therefore, overall results demonstrated that our nano-sized metabolic precursors could be extensively applied to new alternative tumor-targeting technique for molecular imaging and drug delivery system, regardless of the phenotype of heterogeneous tumor cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

Imaging of tumor hypermetabolism with near-infrared fluorescence contrast agents

NASA Astrophysics Data System (ADS)

Chen, Yu; Zheng, Gang; Zhang, Zhihong; Blessington, Dana; Intes, Xavier; Achilefu, Samuel I.; Chance, Britton

2004-08-01

We have developed a high sensitivity near-infrared (NIR) optical imaging system for non-invasive cancer detection through molecular labeled fluorescent contrast agents. Near-infrared (NIR) imaging can probe tissue deeply thus possess the potential for non-invasively detection of breast or lymph node cancer. Recent developments in molecular beacons can selectively label various pre-cancer/cancer signatures and provide high tumor to background contrast. To increase the sensitivity in detecting fluorescent photons and the accuracy of localization, phase cancellation (in- and anti-phase) device is employed. This frequency-domain system utilizes the interference-like pattern of diffuse photon density wave to achieve high detection sensitivity and localization accuracy for the fluorescent heterogeneity embedded inside the scattering media. The opto-electronic system consists of the laser sources, fiber optics, interference filter to select the fluorescent photons and the high sensitivity photon detector (photomultiplier tube). The source-detector pair scans the tissue surface in multiple directions and the two-dimensional localization image can be obtained using goniometric reconstruction. In vivo measurements with tumor-bearing mouse model using the novel Cypate-mono-2-deoxy-glucose (Cypate-2-D-Glucosamide) fluorescent contrast agent, which targets the enhanced tumor glycolysis, demonstrated the feasibility on detection of 2 cm deep subsurface tumor in the tissue-like medium, with a localization accuracy within 2 ~ 3 mm. This instrument has the potential for tumor diagnosis and imaging, and the accuracy of the localization suggests that this system could help to guide the clinical fine-needle biopsy. This portable device would be complementary to X-ray mammogram and provide add-on information on early diagnosis and localization of early breast tumor.

Six-color intravital two-photon imaging of brain tumors and their dynamic microenvironment.

PubMed

Ricard, Clément; Debarbieux, Franck Christian

2014-01-01

The majority of intravital studies on brain tumor in living animal so far rely on dual color imaging. We describe here a multiphoton imaging protocol to dynamically characterize the interactions between six cellular components in a living mouse. We applied this methodology to a clinically relevant glioblastoma multiforme (GBM) model designed in reporter mice with targeted cell populations labeled by fluorescent proteins of different colors. This model permitted us to make non-invasive longitudinal and multi-scale observations of cell-to-cell interactions. We provide examples of such 5D (x,y,z,t,color) images acquired on a daily basis from volumes of interest, covering most of the mouse parietal cortex at subcellular resolution. Spectral deconvolution allowed us to accurately separate each cell population as well as some components of the extracellular matrix. The technique represents a powerful tool for investigating how tumor progression is influenced by the interactions of tumor cells with host cells and the extracellular matrix micro-environment. It will be especially valuable for evaluating neuro-oncological drug efficacy and target specificity. The imaging protocol provided here can be easily translated to other mouse models of neuropathologies, and should also be of fundamental interest for investigations in other areas of systems biology.

Tumor target amplification: Implications for nano drug delivery systems.

PubMed

Seidi, Khaled; Neubauer, Heidi A; Moriggl, Richard; Jahanban-Esfahlan, Rana; Javaheri, Tahereh

2018-04-10

Tumor cells overexpress surface markers which are absent from normal cells. These tumor-restricted antigenic signatures are a fundamental basis for distinguishing on-target from off-target cells for ligand-directed targeting of cancer cells. Unfortunately, tumor heterogeneity impedes the establishment of a solid expression pattern for a given target marker, leading to drastic changes in quality (availability) and quantity (number) of the target. Consequently, a subset of cancer cells remains untargeted during the course of treatment, which subsequently promotes drug-resistance and cancer relapse. Since target inefficiency is only problematic for cancer treatment and not for treatment of other pathological conditions such as viral/bacterial infections, target amplification or the generation of novel targets is key to providing eligible antigenic markers for effective targeted therapy. This review summarizes the limitations of current ligand-directed targeting strategies and provides a comprehensive overview of tumor target amplification strategies, including self-amplifying systems, dual targeting, artificial markers and peptide modification. We also discuss the therapeutic and diagnostic potential of these approaches, the underlying mechanism(s) and established methodologies, mostly in the context of different nanodelivery systems, to facilitate more effective ligand-directed cancer cell monitoring and targeting. Copyright © 2018 Elsevier B.V. All rights reserved.

Nanofitin as a New Molecular-Imaging Agent for the Diagnosis of Epidermal Growth Factor Receptor Over-Expressing Tumors.

PubMed

Goux, Marine; Becker, Guillaume; Gorré, Harmony; Dammicco, Sylvestre; Desselle, Ariane; Egrise, Dominique; Leroi, Natacha; Lallemand, François; Bahri, Mohamed Ali; Doumont, Gilles; Plenevaux, Alain; Cinier, Mathieu; Luxen, André

2017-09-20

Epidermal growth-factor receptor (EGFR) is involved in cell growth and proliferation and is over-expressed in malignant tissues. Although anti-EGFR-based immunotherapy became a standard of care for patients with EGFR-positive tumors, this strategy of addressing cancer tumors by targeting EGFR with monoclonal antibodies is less-developed for patient diagnostic and monitoring. Indeed, antibodies exhibit a slow blood clearance, which is detrimental for positron emission tomography (PET) imaging. New molecular probes are proposed to overcome such limitations for patient monitoring, making use of low-molecular-weight protein scaffolds as alternatives to antibodies, such as Nanofitins with better pharmacokinetic profiles. Anti-EGFR Nanofitin B10 was reformatted by genetic engineering to exhibit a unique cysteine moiety at its C-terminus, which allows the development of a fast and site-specific radiolabeling procedure with 18 F-4-fluorobenzamido-N-ethylamino-maleimide ( 18 F-FBEM). The in vivo tumor targeting and imaging profile of the anti-EGFR Cys-B10 Nanofitin was investigated in a double-tumor xenograft model by static small-animal PET at 2 h after tail-vein injection of the radiolabeled Nanofitin 18 F-FBEM-Cys-B10. The image showed that the EGFR-positive tumor (A431) is clearly delineated in comparison to the EGFR-negative tumor (H520) with a significant tumor-to-background contrast. 18 F-FBEM-Cys-B10 demonstrated a significantly higher retention in A431 tumors than in H520 tumors at 2.5 h post-injection with a A431-to-H520 uptake ratio of 2.53 ± 0.18 and a tumor-to-blood ratio of 4.55 ± 0.63. This study provides the first report of Nanofitin scaffold used as a targeted PET radiotracer for in vivo imaging of EGFR-positive tumor, with the anti-EGFR B10 Nanofitin used as proof-of-concept. The fast generation of specific Nanofitins via a fully in vitro selection process, together with the excellent imaging features of the Nanofitin scaffold, could facilitate the

Prostate-specific membrane antigen targeted imaging and therapy of prostate cancer using a PSMA inhibitor as a homing ligand.

PubMed

Kularatne, Sumith A; Wang, Kevin; Santhapuram, Hari-Krishna R; Low, Philip S

2009-01-01

Prostate cancer (PCa) is a major cause of mortality and morbidity in Western society today. Current methods for detecting PCa are limited, leaving most early malignancies undiagnosed and sites of metastasis in advanced disease undetected. Major deficiencies also exist in the treatment of PCa, especially metastatic disease. In an effort to improve both detection and therapy of PCa, we have developed a PSMA-targeted ligand that delivers attached imaging and therapeutic agents selectively to PCa cells without targeting normal cells. The PSMA-targeted radioimaging agent (DUPA-(99m)Tc) was found to bind PSMA-positive human PCa cells (LNCaP cell line) with nanomolar affinity (K(D) = 14 nM). Imaging and biodistribution studies revealed that DUPA-(99m)Tc localizes primarily to LNCaP cell tumor xenografts in nu/nu mice (% injected dose/gram = 11.3 at 4 h postinjection; tumor-to-muscle ratio = 75:1). Two PSMA-targeted optical imaging agents (DUPA-FITC and DUPA-rhodamine B) were also shown to efficiently label PCa cells and to internalize and traffic to intracellular endosomes. A PSMA-targeted chemotherapeutic agent (DUPA-TubH) was demonstrated to kill PSMA-positive LNCaP cells in culture (IC(50) = 3 nM) and to eliminate established tumor xenografts in nu/nu mice with no detectable weight loss. Blockade of tumor targeting upon administration of excess PSMA inhibitor (PMPA) and the absence of targeting to PSMA-negative tumors confirmed the specificity of each of the above targeted reagents for PSMA. Tandem use of the imaging and therapeutic agents targeted to the same receptor could allow detection, staging, monitoring, and treatment of PCa with improved accuracy and efficacy.

Synthesis and evaluation of Tc-99m and fluorescence-labeled elastin-derived peptide, VAPG for multimodal tumor imaging in murine tumor model.

PubMed

Kim, Myoung Hyoun; Kim, Chang Guhn; Kim, Seul-Gi; Kim, Dae-Weung

2017-12-01

We developed a Tc-99m and fluorescence-labeled peptide, Tc-99m TAMRA-GHEG-ECG-VAPG to target tumor cells and evaluated the diagnostic performance as a dual-modality imaging agent for tumor in a murine model. TAMRA-GHEG-ECG-VAPG was synthesized by using Fmoc solid-phase peptide synthesis. Radiolabeling of TAMRA-GHEG-ECG-VAPG with Tc-99m was done by using ligand exchange via tartrate. Binding affinity and in vitro cellular uptake studies were performed. Gamma camera imaging, biodistribution, and ex vivo imaging studies were performed in murine models with SW620 tumors. Tumor tissue slides were prepared and analyzed with immunohistochemistry by using confocal microscopy. After radiolabeling procedures with Tc-99m, Tc-99m TAMRA-GHEG-ECG-VAPG complexes were prepared in high yield (>96%). The K d of Tc-99m TAMRA-GHEG-ECG-VAPG determined by saturation binding was 16.8 ± 3.6 nM. Confocal microscopy images of SW620 cells incubated with TAMRA-GHEG-ECG-VAPG showed strong fluorescence in the cytoplasm. Gamma camera imaging revealed substantial uptake of Tc-99m TAMRA-GHEG-ECG-VAPG in tumors. Tumor uptake was effectively blocked by the coinjection of an excess concentration of VAPG. Specific uptake of Tc-99m TAMRA-GHEG-ECG-VAPG was confirmed by biodistribution, ex vivo imaging, and immunohistochemistry stain studies. In vivo and in vitro studies revealed substantial uptake of Tc-99m TAMRA-GHEG-ECG-VAPG in tumor cells. Tc-99m TAMRA-GHEG-ECG-VAPG has potential as a dual-modality tumor imaging agent. Copyright © 2017 John Wiley & Sons, Ltd.

Pharmacological and Physical Vessel Modulation Strategies to Improve EPR-mediated Drug Targeting to Tumors

PubMed Central

Ojha, Tarun; Pathak, Vertika; Shi, Yang; Hennink, Wim; Moonen, Chrit; Storm, Gert; Kiessling, Fabian; Lammers, Twan

2018-01-01

The performance of nanomedicine formulations depends on the Enhanced Permeability and Retention (EPR) effect. Prototypic nanomedicine-based drug delivery systems, such as liposomes, polymers and micelles, aim to exploit the EPR effect to accumulate at pathological sites, to thereby improve the balance between drug efficacy and toxicity. Thus far, however, tumor-targeted nanomedicines have not yet managed to achieve convincing therapeutic results, at least not in large cohorts of patients. This is likely mostly due to high inter- and intra-patient heterogeneity in EPR. Besides developing (imaging) biomarkers to monitor and predict EPR, another strategy to address this heterogeneity is the establishment of vessel modulation strategies to homogenize and improve EPR. Over the years, several pharmacological and physical co-treatments have been evaluated to improve EPR-mediated tumor targeting. These include pharmacological strategies, such as vessel permeabilization, normalization, disruption and promotion, as well as physical EPR enhancement via hyperthermia, radiotherapy, sonoporation and phototherapy. In the present manuscript, we summarize exemplary studies showing that pharmacological and physical vessel modulation strategies can be used to improve tumor-targeted drug delivery, and we discuss how these advanced combination regimens can be optimally employed to enhance the (pre-) clinical performance of tumor-targeted nanomedicines. PMID:28697952

Pharmacological and physical vessel modulation strategies to improve EPR-mediated drug targeting to tumors.

PubMed

Ojha, Tarun; Pathak, Vertika; Shi, Yang; Hennink, Wim E; Moonen, Chrit T W; Storm, Gert; Kiessling, Fabian; Lammers, Twan

2017-09-15

The performance of nanomedicine formulations depends on the Enhanced Permeability and Retention (EPR) effect. Prototypic nanomedicine-based drug delivery systems, such as liposomes, polymers and micelles, aim to exploit the EPR effect to accumulate at pathological sites, to thereby improve the balance between drug efficacy and toxicity. Thus far, however, tumor-targeted nanomedicines have not yet managed to achieve convincing therapeutic results, at least not in large cohorts of patients. This is likely mostly due to high inter- and intra-patient heterogeneity in EPR. Besides developing (imaging) biomarkers to monitor and predict EPR, another strategy to address this heterogeneity is the establishment of vessel modulation strategies to homogenize and improve EPR. Over the years, several pharmacological and physical co-treatments have been evaluated to improve EPR-mediated tumor targeting. These include pharmacological strategies, such as vessel permeabilization, normalization, disruption and promotion, as well as physical EPR enhancement via hyperthermia, radiotherapy, sonoporation and phototherapy. In the present manuscript, we summarize exemplary studies showing that pharmacological and physical vessel modulation strategies can be used to improve tumor-targeted drug delivery, and we discuss how these advanced combination regimens can be optimally employed to enhance the (pre-) clinical performance of tumor-targeted nanomedicines. Copyright © 2017 Elsevier B.V. All rights reserved.

Holographic optical coherence imaging of tumor spheroids

NASA Astrophysics Data System (ADS)

Yu, P.; Mustata, M.; Turek, J. J.; French, P. M. W.; Melloch, M. R.; Nolte, D. D.

2003-07-01

We present depth-resolved coherence-domain images of living tissue using a dynamic holographic semiconductor film. An AlGaAs photorefractive quantum-well device is used in an adaptive interferometer that records coherent backscattered (image-bearing) light from inside rat osteogenic sarcoma tumor spheroids up to 1 mm in diameter in vitro. The data consist of sequential holographic image frames at successive depths through the tumor represented as a visual video "fly-through." The images from the tumor spheroids reveal heterogeneous structures presumably caused by necrosis and microcalcifications characteristic of human tumors in their early avascular growth.

Antibody-targeted interleukin 2 stimulates T-cell killing of autologous tumor cells.

PubMed Central

Gillies, S D; Reilly, E B; Lo, K M; Reisfeld, R A

1992-01-01

A genetically engineered fusion protein consisting of a chimeric anti-ganglioside GD2 antibody (ch14.18) and interleukin 2 (IL2) was tested for its ability to enhance the killing of autologous GD2-expressing melanoma target cells by a tumor-infiltrating lymphocyte line (660 TIL). The fusion of IL2 to the carboxyl terminus of the immunoglobulin heavy chain did not reduce IL2 activity as measured in a standard proliferation assay using either mouse or human T-cell lines. Antigen-binding activity was greater than that of the native chimeric antibody. The ability of resting 660 TIL cells to kill their autologous GD2-positive target cells was enhanced if the target cells were first coated with the fusion protein. This stimulation of killing was greater than that of uncoated cells in the presence of equivalent or higher concentrations of free IL2. Such antibody-cytokine fusion proteins may prove useful in targeting the biological effect of IL2 and other cytokines to tumor cells and in this way stimulate their immune destruction. Images PMID:1741398

Smart Cancer Cell Targeting Imaging and Drug Delivery System by Systematically Engineering Periodic Mesoporous Organosilica Nanoparticles.

PubMed

Lu, Nan; Tian, Ying; Tian, Wei; Huang, Peng; Liu, Ying; Tang, Yuxia; Wang, Chunyan; Wang, Shouju; Su, Yunyan; Zhang, Yunlei; Pan, Jing; Teng, Zhaogang; Lu, Guangming

2016-02-10

The integration of diagnosis and therapy into one nanoplatform, known as theranostics, has attracted increasing attention in the biomedical areas. Herein, we first present a cancer cell targeting imaging and drug delivery system based on engineered thioether-bridged periodic mesoporous organosilica nanoparticles (PMOs). The PMOs are stably and selectively conjugated with near-infrared fluorescence (NIRF) dye Cyanine 5.5 (Cy5.5) and anti-Her2 affibody on the outer surfaces to endow them with excellent NIRF imaging and cancer targeting properties. Also, taking the advantage of the thioether-group-incorporated mesopores, the release of chemotherapy drug doxorubicin (DOX) loaded in the PMOs is responsive to the tumor-related molecule glutathione (GSH). The drug release percentage reaches 84.8% in 10 mM of GSH solution within 24 h, which is more than 2-fold higher than that without GSH. In addition, the drug release also exhibits pH-responsive, which reaches 53.6% at pH 5 and 31.7% at pH 7.4 within 24 h. Confocal laser scanning microscopy and flow cytometry analysis demonstrate that the PMOs-based theranostic platforms can efficiently target to and enter Her2 positive tumor cells. Thus, the smart imaging and drug delivery nanoplatforms induce high tumor cell growth inhibition. Meanwhile, the Cy5.5 conjugated PMOs perform great NIRF imaging ability, which could monitor the intracellular distribution, delivery and release of the chemotherapy drug. In addition, cell viability and histological assessments show the engineered PMOs have good biocompatibility, further encouraging the following biomedical applications. Over all, the systemically engineered PMOs can serve as a novel cancer cell targeting imaging and drug delivery platform with NIRF imaging, GSH and pH dual-responsive drug release, and high tumor cell targeting ability.

Identification and Characterization of a Suite of Tumor Targeting Peptides for Non-Small Cell Lung Cancer

NASA Astrophysics Data System (ADS)

McGuire, Michael J.; Gray, Bethany Powell; Li, Shunzi; Cupka, Dorothy; Byers, Lauren Averett; Wu, Lei; Rezaie, Shaghayegh; Liu, Ying-Horng; Pattisapu, Naveen; Issac, James; Oyama, Tsukasa; Diao, Lixia; Heymach, John V.; Xie, Xian-Jin; Minna, John D.; Brown, Kathlynn C.

2014-03-01

Tumor targeting ligands are emerging components in cancer therapies. Widespread use of targeted therapies and molecular imaging is dependent on increasing the number of high affinity, tumor-specific ligands. Towards this goal, we biopanned three phage-displayed peptide libraries on a series of well-defined human non-small cell lung cancer (NSCLC) cell lines, isolating 11 novel peptides. The peptides show distinct binding profiles across 40 NSCLC cell lines and do not bind normal bronchial epithelial cell lines. Binding of specific peptides correlates with onco-genotypes and activation of particular pathways, such as EGFR signaling, suggesting the peptides may serve as surrogate markers. Multimerization of the peptides results in cell binding affinities between 0.0071-40 nM. The peptides home to tumors in vivo and bind to patient tumor samples. This is the first comprehensive biopanning for isolation of high affinity peptidic ligands for a single cancer type and expands the diversity of NSCLC targeting ligands.

Identification and Characterization of a Suite of Tumor Targeting Peptides for Non-Small Cell Lung Cancer

PubMed Central

McGuire, Michael J.; Gray, Bethany Powell; Li, Shunzi; Cupka, Dorothy; Byers, Lauren Averett; Wu, Lei; Rezaie, Shaghayegh; Liu, Ying-Horng; Pattisapu, Naveen; Issac, James; Oyama, Tsukasa; Diao, Lixia; Heymach, John V.; Xie, Xian-Jin; Minna, John D.; Brown, Kathlynn C.

2014-01-01

Tumor targeting ligands are emerging components in cancer therapies. Widespread use of targeted therapies and molecular imaging is dependent on increasing the number of high affinity, tumor-specific ligands. Towards this goal, we biopanned three phage-displayed peptide libraries on a series of well-defined human non-small cell lung cancer (NSCLC) cell lines, isolating 11 novel peptides. The peptides show distinct binding profiles across 40 NSCLC cell lines and do not bind normal bronchial epithelial cell lines. Binding of specific peptides correlates with onco-genotypes and activation of particular pathways, such as EGFR signaling, suggesting the peptides may serve as surrogate markers. Multimerization of the peptides results in cell binding affinities between 0.0071–40 nM. The peptides home to tumors in vivo and bind to patient tumor samples. This is the first comprehensive biopanning for isolation of high affinity peptidic ligands for a single cancer type and expands the diversity of NSCLC targeting ligands. PMID:24670678

Cy5.5-labeled Affibody molecule for near-infrared fluorescent optical imaging of epidermal growth factor receptor positive tumors

NASA Astrophysics Data System (ADS)

Miao, Zheng; Ren, Gang; Liu, Hongguang; Jiang, Lei; Cheng, Zhen

2010-05-01

Affibody protein is an engineered protein scaffold with a three-helical bundle structure. Affibody molecules of small size (7 kD) have great potential for targeting overexpressed cancer biomarkers in vivo. To develop an Affibody-based molecular probe for in vivo optical imaging of epidermal growth factor receptor (EGFR) positive tumors, an anti-EGFR Affibody molecule, Ac-Cys-ZEGFR:1907 (7 kD), is site-specifically conjugated with a near-IR fluorescence dye, Cy5.5-mono-maleimide. Using fluorescent microscopy, the binding specificity of the probe Cy5.5-ZEGFR:1907 is checked by a high-EGFR-expressing A431 cell and low-EGFR-expressing MCF7 cells. The binding affinity of Cy5.5-ZEGFR:1907 (KD) to EGFR is 43.6+/-8.4 nM, as determined by flow cytometry. For an in vivo imaging study, the probe shows fast tumor targeting and good tumor contrast as early as 0.5 h postinjection (p.i.) for A431 tumors, while MCF7 tumors are barely visible. An ex vivo imaging study also demonstrates that Cy5.5-ZEGFR:1907 has high tumor, liver, and kidney uptakes at 24 h p.i.. In conclusion, Cy5.5-ZEGFR:1907 shows good affinity and high specificity to the EGFR. There is rapid achievement of good tumor-to-normal-tissue contrasts of Cy5.5-ZEGFR:1907, thus demonstrating its potential for EGFR-targeted molecular imaging of cancers.

Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment

PubMed Central

Moreno, Paola; Ramos-Álvarez, Irene; Moody, Terry W.; Jensen, Robert T.

2016-01-01

Introduction Despite remarkable advances in tumor treatment, many patients still die from common tumors (breast, prostate, lung, CNS, colon, and pancreas), and thus, new approaches are needed. Many of these tumors synthesize bombesin (Bn)-related peptides and over-express their receptors (BnRs), hence functioning as autocrine-growth-factors. Recent studies support the conclusion that Bn-peptides/BnRs are well-positioned for numerous novel antitumor treatments, including interrupting autocrine-growth via the use of over-expressed receptors for imaging and targeting cytotoxic-compounds, either by direct-coupling or combined with nanoparticle-technology. Areas covered The unique ability of common neoplasms to synthesize, secrete, and show a growth/proliferative/differentiating response due to BnR over-expression, is reviewed, both in general and with regard to the most frequently investigated neoplasms (breast, prostate, lung, and CNS). Particular attention is paid to advances in the recent years. Also considered are the possible therapeutic approaches to the growth/differentiation effect of Bn-peptides, as well as the therapeutic implication of the frequent BnR over-expression for tumor-imaging and/or targeted-delivery. Expert opinion Given that Bn-related-peptides/BnRs are so frequently ectopically-expressed by common tumors, which are often malignant and become refractory to conventional treatments, therapeutic interventions using novel approaches to Bn-peptides and receptors are being explored. Of particular interest is the potential of reproducing BnRs in common tumors, such as the recent success of utilizing overexpression of somatostatin-receptors by neuroendocrine-tumors to provide the most sensitive imaging methods and targeted delivery of cytotoxic-compounds. PMID:26981612

Targeting of tumor endothelium by RGD-grafted PLGA-nanoparticles.

PubMed

Danhier, Fabienne; Pourcelle, Vincent; Marchand-Brynaert, Jacqueline; Jérôme, Christine; Feron, Olivier; Préat, Véronique

2012-01-01

The destruction of the neovessels in solid tumors can cause the death of tumor cells resulting from the lack of oxygen and nutrients. Peculiarities of the tumor vasculature, however, also position angiogenic endothelial cells as obvious targets to address cytotoxic drugs into the tumor. In particular, the identification of a three-amino acids sequence, arginine-glycine-aspartate (RGD), as a fundamental recognition site for proliferating endothelial attachment to the extracellular matrix leads to the development of tumor-targeting ligands for nanoparticles. The RGD peptide can target the α(v)β(3) integrin overexpressed by the tumor endothelium, and thereby increases the accumulation of drug-loaded RGD-grafted nanoparticles. RGD-nanoparticles may thus extravasate more efficiently and enter the tumor via the enhanced permeability and retention (EPR) effect. This combination of active and passive processes leads to the penetration of nanoparticles into the tumor tissue, followed by cellular uptake and intracellular delivery of the cytotoxic payload. Since cancer cells may also express α(v)β(3) integrin, the entrapping of RGD-nanoparticles into the tumor interstitial fluid may yet be facilitated through direct binding to cancer cells. Here, we describe methods used for the preparation of RGD-nanoparticles and for the validation of their potential of tumor endothelium targeting both in vitro and in vivo. We also illustrate how RGD-nanoparticles may be more suited than nontargeted modalities for the tumor delivery of poorly soluble and/or highly cytotoxic drugs, using different mouse tumor xenograft models. Copyright © 2012 Elsevier Inc. All rights reserved.

Multifunctional nanosheets based on folic acid modified manganese oxide for tumor-targeting theranostic application

NASA Astrophysics Data System (ADS)

Hao, Yongwei; Wang, Lei; Zhang, Bingxiang; Zhao, Hongjuan; Niu, Mengya; Hu, Yujie; Zheng, Cuixia; Zhang, Hongling; Chang, Junbiao; Zhang, Zhenzhong; Zhang, Yun

2016-01-01

It is highly desirable to develop smart nanocarriers with stimuli-responsive drug-releasing and diagnostic-imaging functions for cancer theranostics. Herein, we develop a reduction and pH dual-responsive tumor theranostic platform based on degradable manganese dioxide (MnO2) nanosheets. The MnO2 nanosheets with a size of 20-60 nm were first synthesized and modified with (3-Aminopropyl) trimethoxysilane (APTMS) to get amine-functionalized MnO2, and then functionalized by NH2-PEG2000-COOH (PEG). The tumor-targeting group, folic acid (FA), was finally conjugated with the PEGylated MnO2 nanosheets. Then, doxorubicin (DOX), a chemotherapeutic agent, was loaded onto the modified nanosheets through a physical adsorption, which was designated as MnO2-PEG-FA/DOX. The prepared MnO2-PEG-FA/DOX nanosheets with good biocompatibility can not only efficiently deliver DOX to tumor cells in vitro and in vivo, leading to enhanced anti-tumor efficiency, but can also respond to a slightly acidic environment and high concentration of reduced glutathione (GSH), which caused degradation of MnO2 into manganese ions enabling magnetic resonance imaging (MRI). The longitudinal relaxation rate r 1 was 2.26 mM-1 s-1 at pH 5.0 containing 2 mM GSH. These reduction and pH dual-responsive biodegradable nanosheets combining efficient MRI and chemotherapy provide a novel and promising platform for tumor-targeting theranostic application.

Dual targeting and enhanced cytotoxicity to HER2-overexpressing tumors by immunoapoptotin-armored mesenchymal stem cells.

PubMed

Cai, Yanhui; Xi, Yujing; Cao, Zhongyuan; Xiang, Geng; Ni, Qingrong; Zhang, Rui; Chang, Jing; Du, Xiao; Yang, Angang; Yan, Bo; Zhao, Jing

2016-10-10

Mesenchymal stem cells (MSCs) are promising vehicles for the delivery of anticancer agents in cancer therapy. However, the tumor targeting of loaded therapeutics is essential. Here, we explored a dual-targeting strategy to incorporate tumor-tropic MSC delivery with HER2-specific killing by the immunoapoptotin e23sFv-Fdt-tBid generated in our previous studies. The MSC engineering allowed simultaneous immunoapoptotin secretion and bioluminescence detection of the modified MSCs. Systemic administration of the immunoapoptotin-engineered MSCs was investigated in human HER2-reconstituted syngeneic mouse models of orthotopic and metastatic breast cancer, as well as in a xenograft nude mouse model of orthotopic gastric cancer. In vivo dual tumor targeting was confirmed by local accumulation of the bioluminescence-imaged MSCs and persistence of His-immunostained immunoapoptotins in tumor sites. The added tumor preference of MSC-secreted immunoapoptotins resulted in a significantly stronger antitumor effect compared with purified immunoapoptotins and Jurkat-delivered immunoapoptotins. This immunoapoptotin-armored MSC strategy provides a rationale for its use in extended malignancies by combining MSC mobility with redirected immunoapoptotins against a given tumor antigen. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Tumor-specific detection of an optically targeted antibody combined with a quencher-conjugated neutravidin "quencher-chaser": a dual "quench and chase" strategy to improve target to nontarget ratios for molecular imaging of cancer.

PubMed

Ogawa, Mikako; Kosaka, Nobuyuki; Choyke, Peter L; Kobayashi, Hisataka

2009-01-01

In vivo molecular cancer imaging with monoclonal antibodies has great potential not only for cancer detection, but also for cancer characterization. However, the prolonged retention of intravenously injected antibody in the blood causes low target tumor-to-background ratio (TBR). Avidin has been used as a "chase" to clear the unbound, circulating biotinylated antibody and decrease the background signal. Here, we utilize a combined approach of a fluorescence resonance energy transfer (FRET) quenched antibody with an "avidin chase" to increase TBR. Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor type 2 (HER2), was biotinylated and conjugated with the near-infrared (NIR) fluorophore Alexa680 to synthesize Tra-Alexa680-biotin. Next, the FRET quencher, QSY-21, was conjugated to avidin, neutravidin (nAv), or streptavidin (sAv), thus creating Av-QSY21, nAv-QSY21, or sAv-QSY21 as "chasers". The fluorescence was quenched in vitro by binding Tra-Alexa680-biotin to Av-QSY21, nAv-QSY21, or sAv-QSY21. To evaluate if the injection of quencher-conjugated avidin derivatives can improve target TBR by using a dual "quench and chase" strategy, both target (3T3/HER2+) and nontarget (Balb3T3/ZsGreen) tumor-bearing mice were employed. The "FRET quench" effect induced by all the QSY21 avidin-based conjugates reduced but did not totally eliminate background signal from the blood pool. The addition of nAv-QSY21 administration increased target TBR mainly because of the "chase" effect where unbound conjugated antibody was preferentially cleared to the liver. The relatively slow clearance of unbound nAv-QSY21 leads to further reductions in background signal by leaking out of the vascular space and binding to unbound antibodies in the extravascular space of tumors, resulting in decreased nontarget tumor-to-background ratios but increased target TBR due to the "FRET quench" effect, because target-bound antibodies were internalized and could not bind

Optical Imaging of Mammary and Prostate Tumors in Living Animals using a Synthetic Near Infrared Zinc(II)-Dipicolylamine Probe for Anionic Cell Surfaces

PubMed Central

Smith, Bryan A.; Akers, Walter J.; Leevy, W. Matthew; Lampkins, Andrew J.; Xiao, Shuzhang; Wolter, William; Suckow, Mark A.; Achilefu, Samuel; Smith, Bradley D.

2009-01-01

In vivo optical imaging shows that a fluorescent imaging probe, comprised of a near-infrared fluorophore attached to an affinity group containing two zinc(II)-dipicolylamine (Zn-DPA) units, targets prostate and mammary tumors in two different xenograft animal models. The tumor selectivity is absent with control fluorophores whose structures do not have appended Zn-DPA targeting ligands. Ex vivo biodistribution and histological analyses indicate that the probe is targeting the necrotic regions of the tumors, which is consistent with in vitro microscopy showing selective targeting of the anionic membrane surfaces of dead and dying cells. PMID:20014845

Enhancing in vivo tumor boundary delineation with structured illumination fluorescence molecular imaging and spatial gradient mapping

NASA Astrophysics Data System (ADS)

Sun, Jessica; Miller, Jessica P.; Hathi, Deep; Zhou, Haiying; Achilefu, Samuel; Shokeen, Monica; Akers, Walter J.

2016-08-01

Fluorescence imaging, in combination with tumor-avid near-infrared (NIR) fluorescent molecular probes, provides high specificity and sensitivity for cancer detection in preclinical animal models, and more recently, assistance during oncologic surgery. However, conventional camera-based fluorescence imaging techniques are heavily surface-weighted such that surface reflection from skin or other nontumor tissue and nonspecific fluorescence signals dominate, obscuring true cancer-specific signals and blurring tumor boundaries. To address this challenge, we applied structured illumination fluorescence molecular imaging (SIFMI) in live animals for automated subtraction of nonspecific surface signals to better delineate accumulation of an NIR fluorescent probe targeting α4β1 integrin in mice bearing subcutaneous plasma cell xenografts. SIFMI demonstrated a fivefold improvement in tumor-to-background contrast when compared with other full-field fluorescence imaging methods and required significantly reduced scanning time compared with diffuse optical spectroscopy imaging. Furthermore, the spatial gradient mapping enhanced highlighting of tumor boundaries. Through the relatively simple hardware and software modifications described, SIFMI can be integrated with clinical fluorescence imaging systems, enhancing intraoperative tumor boundary delineation from the uninvolved tissue.

Update on the imaging of malignant perivascular epithelioid cell tumors (PEComas).

PubMed

Phillips, Catherine H; Keraliya, Abhishek R; Shinagare, Atul B; Ramaiya, Nikhil H; Tirumani, Sree Harsha

2016-02-01

Malignant perivascular epithelioid cell tumors (PEComas) are a histologic group of mesenchymal neoplasms that share a distinctive histological phenotype, the perivascular epithelioid cell. These tumors are known for their perivascular distribution. Malignant PEComas have a female predominance and are associated with aggressive disease and poor prognosis, making timely diagnosis critical to management. Imaging features of malignant PEComas are nonspecific and mimic other benign and malignant neoplasms. Surgery is the mainstay in the management of malignant PEComas. Promising novel molecular targeted therapies like m-TOR inhibitors have been shown to be effective in the metastatic setting. The aim of this review is to familiarize radiologists with the imaging appearances of and potential therapies for primary and metastatic malignant PEComa.

Groupwise registration of MR brain images with tumors.

PubMed

Tang, Zhenyu; Wu, Yihong; Fan, Yong

2017-08-04

A novel groupwise image registration framework is developed for registering MR brain images with tumors. Our method iteratively estimates a normal-appearance counterpart for each tumor image to be registered and constructs a directed graph (digraph) of normal-appearance images to guide the groupwise image registration. Particularly, our method maps each tumor image to its normal appearance counterpart by identifying and inpainting brain tumor regions with intensity information estimated using a low-rank plus sparse matrix decomposition based image representation technique. The estimated normal-appearance images are groupwisely registered to a group center image guided by a digraph of images so that the total length of 'image registration paths' to be the minimum, and then the original tumor images are warped to the group center image using the resulting deformation fields. We have evaluated our method based on both simulated and real MR brain tumor images. The registration results were evaluated with overlap measures of corresponding brain regions and average entropy of image intensity information, and Wilcoxon signed rank tests were adopted to compare different methods with respect to their regional overlap measures. Compared with a groupwise image registration method that is applied to normal-appearance images estimated using the traditional low-rank plus sparse matrix decomposition based image inpainting, our method achieved higher image registration accuracy with statistical significance (p  =  7.02  ×  10 -9 ).

Targeting tumor hypoxia with 2-nitroimidazole-indocyanine green dye conjugates

PubMed Central

Xu, Yan; Zanganeh, Saeid; Mohammad, Innus; Aguirre, Andres; Wang, Tianheng; Yang, Yi; Kuhn, Liisa; Smith, Michael B.

2013-01-01

Abstract. Tumor hypoxia is a major indicator of treatment resistance to chemotherapeutic drugs, and fluorescence optical tomography has tremendous potential to provide clinically useful, functional information by identifying tumor hypoxia. The synthesis of a 2-nitroimidazole-indocyanine green conjugate using a piperazine linker (piperazine-2-nitroimidazole-ICG) capable of robust fluorescent imaging of tumor hypoxia is described. In vivo mouse tumor imaging studies were completed and demonstrate an improved imaging capability of the new dye relative to an earlier version of the dye that was synthesized with an ethanolamine linker (ethanolamine-2-nitroimidazole-ICG). Mouse tumors located at imaging depths of 1.5 and 2.0 cm in a turbid medium were imaged at various time points after intravenous injection of the dyes. On average, the reconstructed maximum fluorescence concentration of the tumors injected with piperazine-2-nitroimidazole-ICG was twofold higher than that injected with ethanolamine-2-nitroimidazole-ICG within 3 h postinjection period and 1.6 to 1.7 times higher beyond 3 h postinjection. The untargeted bis-carboxylic acid ICG completely washed out after 3 h postinjection. Thus, the optimal window to assess tumor hypoxia is beyond 3 h postinjection. These findings were supported with fluorescence images of histological sections of tumor samples and an immunohistochemistry technique for identifying tumor hypoxia. PMID:23764695

Targeted delivery of cancer-specific multimodal contrast agents for intraoperative detection of tumor boundaries and therapeutic margins

NASA Astrophysics Data System (ADS)

Xu, Ronald X.; Xu, Jeff S.; Huang, Jiwei; Tweedle, Michael F.; Schmidt, Carl; Povoski, Stephen P.; Martin, Edward W.

2010-02-01

Background: Accurate assessment of tumor boundaries and intraoperative detection of therapeutic margins are important oncologic principles for minimal recurrence rates and improved long-term outcomes. However, many existing cancer imaging tools are based on preoperative image acquisition and do not provide real-time intraoperative information that supports critical decision-making in the operating room. Method: Poly lactic-co-glycolic acid (PLGA) microbubbles (MBs) and nanobubbles (NBs) were synthesized by a modified double emulsion method. The MB and NB surfaces were conjugated with CC49 antibody to target TAG-72 antigen, a human glycoprotein complex expressed in many epithelial-derived cancers. Multiple imaging agents were encapsulated in MBs and NBs for multimodal imaging. Both one-step and multi-step cancer targeting strategies were explored. Active MBs/NBs were also fabricated for therapeutic margin assessment in cancer ablation therapies. Results: The multimodal contrast agents and the cancer-targeting strategies were tested on tissue simulating phantoms, LS174 colon cancer cell cultures, and cancer xenograft nude mice. Concurrent multimodal imaging was demonstrated using fluorescence and ultrasound imaging modalities. Technical feasibility of using active MBs and portable imaging tools such as ultrasound for intraoperative therapeutic margin assessment was demonstrated in a biological tissue model. Conclusion: The cancer-specific multimodal contrast agents described in this paper have the potential for intraoperative detection of tumor boundaries and therapeutic margins.

Prodrugs for Improving Tumor Targetability and Efficiency

PubMed Central

Mahato, Rubi; Tai, Wanyi; Cheng, Kun

2011-01-01

As the mainstay in the treatment of various cancers for several decades, chemotherapy is successful but still faces challenges including non-selectivity and high toxicity. Improving the selectivity is therefore a critical step to improve the therapeutic efficacy of chemotherapy. Prodrug is one of the most promising approaches to increase the selectivity and efficacy of a chemotherapy drug. The classical prodrug approach is to improve the pharmaceutical properties (solubility, stability, permeability, irritation, distribution, etc.) via a simple chemical modification. This review will focus on various targeted prodrug designs that have been developed to increase the selectivity of chemotherapy drugs. Various tumor-targeting ligands, transporter-associated ligands, and polymers can be incorporated in a prodrug to enhance the tumor uptake. Prodrugs can also be activated by enzymes that are specifically expressed at a higher level in tumors, leading to a selective anti-tumor effect. This can be achieved by conjugating the enzyme to a tumor-specific antibody, or delivering a vector expressing the enzyme into tumor cells. PMID:21333700

P-selectin is a nanotherapeutic delivery target in the tumor microenvironment.

PubMed

Shamay, Yosi; Elkabets, Moshe; Li, Hongyan; Shah, Janki; Brook, Samuel; Wang, Feng; Adler, Keren; Baut, Emily; Scaltriti, Maurizio; Jena, Prakrit V; Gardner, Eric E; Poirier, John T; Rudin, Charles M; Baselga, José; Haimovitz-Friedman, Adriana; Heller, Daniel A

2016-06-29

Disseminated tumors are poorly accessible to nanoscale drug delivery systems because of the vascular barrier, which attenuates extravasation at the tumor site. We investigated P-selectin, a molecule expressed on activated vasculature that facilitates metastasis by arresting tumor cells at the endothelium, for its potential to target metastases by arresting nanomedicines at the tumor endothelium. We found that P-selectin is expressed on cancer cells in many human tumors. To develop a targeted drug delivery platform, we used a fucosylated polysaccharide with nanomolar affinity to P-selectin. The nanoparticles targeted the tumor microenvironment to localize chemotherapeutics and a targeted MEK (mitogen-activated protein kinase kinase) inhibitor at tumor sites in both primary and metastatic models, resulting in superior antitumor efficacy. In tumors devoid of P-selectin, we found that ionizing radiation guided the nanoparticles to the disease site by inducing P-selectin expression. Radiation concomitantly produced an abscopal-like phenomenon wherein P-selectin appeared in unirradiated tumor vasculature, suggesting a potential strategy to target disparate drug classes to almost any tumor. Copyright © 2016, American Association for the Advancement of Science.

Dual-targeted and pH-sensitive Doxorubicin Prodrug-Microbubble Complex with Ultrasound for Tumor Treatment

PubMed Central

Luo, Wanxian; Wen, Ge; Yang, Li; Tang, Jiao; Wang, Jianguo; Wang, Jihui; Zhang, Shiyu; Zhang, Li; Ma, Fei; Xiao, Liling; Wang, Ying; Li, Yingjia

2017-01-01

In this study, we investigated the potential of a dual-targeted pH-sensitive doxorubicin prodrug-microbubble complex (DPMC) in ultrasound (US)-assisted antitumor therapy. The doxorubicin prodrug (DP) consists of a succinylated-heparin carrier conjugated with doxorubicin (DOX) via hydrazone linkage and decorated with dual targeting ligands, folate and cRGD peptide. Combination of microbubble (MB) and DP, generated via avidin-biotin binding, promoted intracellular accumulation and improved therapeutic efficiency assisted by US cavitation and sonoporation. Aggregates of prepared DP were observed with an inhomogeneous size distribution (average diameters: 149.6±29.8 nm and 1036.2±38.8 nm, PDI: 1.0) while DPMC exhibited a uniform distribution (average diameter: 5.804±2.1 μm), facilitating its usage for drug delivery. Notably, upon US exposure, DPMC was disrupted and aggregated DP dispersed into homogeneous small-sized nanoparticles (average diameter: 128.6±42.3 nm, PDI: 0.21). DPMC could target to angiogenic endothelial cells in tumor region via αvβ3-mediated recognition and subsequently facilitate its specific binding to tumor cells mediated via recognition of folate receptor (FR) after US exposure. In vitro experiments showed higher tumor specificity and killing ability of DPMC with US than free DOX and DP for breast cancer MCF-7 cells. Furthermore, significant accumulation and specificity for tumor tissues of DPMC with US were detected using in vivo fluorescence and ultrasound molecular imaging, indicating its potential to integrate tumor imaging and therapy. In particular, through inducing apoptosis, inhibiting cell proliferation and antagonizing angiogenesis, DPMC with US produced higher tumor inhibition rates than DOX or DPMC without US in MCF-7 xenograft tumor-bearing mice while inducing no obvious body weight loss. Our strategy provides an effective platform for the delivery of large-sized or aggregated particles to tumor sites, thereby extending their

Development of a mucin4-targeting SPIO contrast agent for effective detection of pancreatic tumor cells in vitro and in vivo.

PubMed

Wu, Shou-Cheng; Chen, Yu-Jen; Lin, Yi-Jan; Wu, Tung-Ho; Wang, Yun-Ming

2013-11-27

In search of a unique and reliable contrast agent targeting pancreatic adenocarcinoma, new multifunctional nanoparticles (MnMEIO-silane-NH2-(MUC4)-mPEG NPs) were successfully developed in this study. Mucin4-expression levels were determined through different imaging studies in a panel of pancreatic tumor cells (HPAC, BxPC-3, and Panc-1) both in vitro and in vivo studies. The in vitro T2-weighted MR imaging study in HPAC and Panc-1 tumor cells treated with NPs showed -89.1 ± 5.7% and -0.9 ± 0.2% contrast enhancement, whereas in in vivo study, it is found to be -81.5 ± 4.5% versus -19.6 ± 5.2% (24 h postinjection, 7.0 T), respectively. The T2-weighted MR and optical imaging studies revealed that the novel contrast agent can specifically and effectively target to mucin4-expressing tumors in nude mice. Hence, it is suggested that MnMEIO-silane-NH2-(MUC4)-mPEG NPs are able to provide an efficient and targeted delivery of MUC4 antibodies to mucin4-expressing pancreatic tumors.

Tracking tumor boundary in MV-EPID images without implanted markers: A feasibility study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Xiaoyong, E-mail: xiaoyong@ieee.org; Homma, Noriyasu, E-mail: homma@ieee.org; Ichiji, Kei, E-mail: ichiji@yoshizawa.ecei.tohoku.ac.jp

2015-05-15

tracking tumor boundary in EPID images by using a LSM-based algorithm. Experimental results conducted on phantom and clinical EPID images demonstrated the effectiveness of the tracking algorithm for visible tumor target. Compared with previous tracking methods, the authors’ algorithm has the potential to improve the tracking accuracy in radiation therapy. In addition, real-time tumor boundary information within the irradiation field will be potentially useful for further applications, such as adaptive beam delivery, dose evaluation.« less