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2014  (15 / Total 98 )

  • 1
    Yu Q‡, Dong C‡, Zhang J, Shi J, Jia B, Wang F*, Gan Z*. Synthesis of poly(ethylene glycol)-b-poly(N-(2-hydroxypropyl) methacrylamide) block copolymers with well-defined structures and their influence on in vivo circulation and biodistribution. Polym Chem. 2014, 5, 5617-5627.

    Abstract

    Well-defined water-soluble block copolymers poly(ethylene glycol)-b-poly(N-(2-hydroxypropyl) methacrylamide-co-N-methacryloylglycylglycine) (PEG-b-P(HPMA-co-MAGG)) with different compositions and narrow polydispersity were synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization. The in vivo blood clearance and biodistribution of copolymers with different compositions were studied in normal BALB/c mice. The results showed that the electronegative copolymers were rapidly eliminated from blood and tended to accumulate in the liver and spleen. However, the copolymers with neutral or a small amount of negative charges showed a prolonged circulation time and low non-specific organ uptake. Combined with the quantitative analysis of in vitro hepatocyte uptake, we conclude that this was due to the balance between (i) the electrostatic repulsion between the copolymer and the cell membrane and (ii) the tendency of macrophage-like cells to capture the negative charged copolymers. This work also revealed the significant roles of the PEG chain length, negative charge and molecular weight for the copolymers as anticancer drug carriers with prolonged circulation time and optimal biodistribution.

    http://dx.doi.org/10.1039/c4py00681j

  • 2
    Dong C, Liu Z*, Wang F*. Peptide-based radiopharmaceuticals for targeted tumor therapy. Curr Med Chem. 2014;21(1):139-52.

    Abstract

    A series of radiolabeled peptides have been designed and optimized for tumor-targeted peptide receptor radionuclide therapy (PRRT). Pre-clinical and clinical applications of PRRT have shown promising results on tumor response, overall survival, and quality of life in patients with several kinds of tumors. (90)Y-DOTA-TOC and (177)Lu-DOTA-TATE are two of the most common radiopharmaceuticals with symptomatic improvements and complete clinical data. In addition to somatostatin analogs, radiolabeled peptides have been developed to target the relative receptors overexpressed in the tumors, such as integrin αvβ3, gastrin-releasing peptide receptor (GRPR), melanocortin-1 receptor (MC1-R), cholecystokinin (CCK) receptor, and glucagon-like peptide-1 receptor (GLP-1R). Several strategies have been designed to improve the therapeutic efficacy of PRRT. For instance, radiolabeled peptides could be optimized by the amino acid modification and radionuclide selection. Healthy tissue protective agents and multi-cycle procedures could effectively decrease the side effects of PRRT. Furthermore, combination treatments, including PRRT combined with surgery, chemotherapeutic agents, or radiosensitizing agents could be applied to increase the effectiveness of PRRT. In this review, the current progress of peptide-based radiopharmaceuticals for tumor-targeted PRRT was summarized. Radiopharmaceuticals currently under clinical investigation were also described.http://www.eurekaselect.com/114557/article

  • 3
    Ma T, Liu H, Sun X, Gao L, Shi J, Zhao H, Jia B, Wang F, Liu Z. Serial in Vivo Imaging Using a Fluorescence Probe Allows Identification of Tumor Early Response to Cetuximab Immunotherapy. Mol Pharm. 2014.

    Abstract

    Cetuximab is an antiepidermal growth factor receptor (EGFR) monoclonal antibody that has received the approval of the Food and Drug Administration (FDA) for cancer treatment. However, most clinical studies indicate that cetuximab can only elicit positive effects on a subset of cancer patients. Inthis study, we investigated whether near-infrared fluorescence (NIRF) imaging of tumor vascular endothelial growth factor (VEGF) expression could be a biomarker for tumor early response to cetuximab therapy in preclinical wild-type and mutant tumor models of the KRAS gene. The treatment efficacy of cetuximab was determined in both HT-29 (wild-type KRAS) and HTC-116 (mutant KRAS) human colon cancer models. A VEGF-specific optical imaging probe (Dye755-Ran) was synthesized by conjugating ranibizumab (an anti-VEGF antibody Fab fragment) with a NIRF dye. Serialoptical scans with Dye755-Ran were performed in HT-29 and HTC-116 xenograft models. By using longitudinal NIRF imaging, we were able to detectearly tumor response on day 3 and day 5 after initiation of cetuximab treatment in the cetuximab-responsive HT-29 tumor model. Enzyme-linked immunosorbent assay (ELISA) confirmed that cetuximab treatment inhibited human VEGF expression in the KRAS wild-type HT-29 tumor but not inthe KRAS mutant HCT-116 tumor. We have demonstrated that the antitumor effect of cetuximab can be noninvasively monitored by serialfluorescence imaging using Dye755-Ran. VEGF expression detected by optical imaging could serve as a sensitive biomarker for tumor early responseto drugs that directly or indirectly act on VEGF.

    http://dx.doi.org/10.1021/mp5002944

  • 4
    Shi J, Jin Z, Liu X, Fan D, Sun Y, Zhao H, Zhu Z, Liu Z, Jia B, Wang F. PET Imaging of Neovascularization with (68)Ga-3PRGD2 for Assessing Tumor Early Response to Endostar Antiangiogenic Therapy. Mol Pharm. 2014;11:3915-3922.

    Abstract

    Antiangiogenic therapy is an effective strategy to inhibit tumor growth. Endostar, as an approved antiangiogenesis agent, inhibits the newborn vascular endothelial cells, causing the decrease of integrin αvβ3 expression. Radiolabeled 3PRGD2, a novel PEGlayted RGD dimer probe (PEG4-E[PEG4-c(RGDfK)]2) showed highly specific targeting capability to integrin αvβ3, which could be used for monitoring the efficacy of Endostar antiangiogenic therapy. In this study, (68)Ga-3PRGD2 PET imaging was performed in Endostar treated/untreated Lewis Lung Carcinoma (LLC) mice on days 3, 7, 14, and 21 post-treatment for monitoring the tumor response to Endostar treatment, with the (18)F-FDG imaging as control. As a result, (68)Ga-3PRGD2 PET reflected the tumor response to Endostar antiangiogenic therapy much earlier (day 3 post-treatment vs day 14 post-treatment) and more accurately than that of (18)F-FDG metabolic imaging, which provides new opportunities to develop individualized therapeutic approaches, establish optimized dosages and dose intervals for effective treatment that improve the survival rate of patients.

    http://dx.doi.org/10.1021/mp5003202

  • 5
    Li D, Zhao X, Zhang L, Li F, Ji N, Gao Z, Wang J, Kang P, Liu Z, Shi J, Chen X, Zhu Z. (68)Ga-PRGD2 PET/CT in the Evaluation of Glioma: A Prospective Study. Mol Pharm. 2014;11:3923-3929.

    Abstract

    Integrin αvβ3 is overexpressed in both neovasculature and glioma cells. We aimed to evaluate (68)gallium-BNOTA-PRGD2 ((68)Ga-PRGD2) as a new reagent for noninvasive integrin αvβ3 imaging in glioma patients. With informed consent, 12 patients with suspicious brain glioma, as diagnosed by enhanced magnetic resonance imaging (MRI) scanning, were enrolled to undergo (68)Ga-PRGD2 PET/CT and (18)F-FDG PET/CT scans before surgery. The preoperative images were compared and correlated with the pathologically determined WHO grade. Next, the expression of integrin αvβ3, CD34, and Ki-67 were determined by immunohistochemical staining of the resected brain tumor tissue. Our findings demonstrated that (68)Ga-PRGD2 specifically accumulated in the brain tumors that were rich of integrin αvβ3 and other neovasculature markers, but not in the brain parenchyma other than the choroid plexus. Therefore, (68)Ga-PRGD2 PET/CT was able to evaluate the glioma demarcation more specifically than (18)F-FDG PET/CT. The maximum standardized uptake values (SUVmax) of (68)Ga-PRGD2, rather than those of (18)F-FDG, were significantly correlated with the glioma grading. The maximum tumor-to-brain ratios (TBRmax) of both tracers were significantly correlated with glioma grading, whereas (68)Ga-PRGD2 seemed to be more superior to (18)F-FDG in differentiating high-grade glioma (HGG) from low-grade glioma (LGG). Moreover, (68)Ga-PRGD2 PET/CT showed different accumulation patterns for HGG of WHO grades III and IV. This is the first noninvasive integrin imaging study, to the best of our knowledge, conducted in preoperative patients with different grades of glioma, and it preliminarily indicated the effectiveness of this novel method for evaluating glioma grading and demarcation.

    http://dx.doi.org/10.1021/mp5003224

  • 6
    Wang X, Li D, Deuther-Conrad W, Lu J, Xie Y, Jia B, Cui M, Steinbach J, Brust P, Liu B, Jia H. Novel cyclopentadienyl tricarbonyl (99m)Tc complexes containing 1-piperonylpiperazine moiety: potential imaging probes for sigma-1 receptors. J Med Chem. 2014;57:7113-7125.

    Abstract

    We report the design, synthesis, and evaluation of a series of novel cyclopentadienyl tricarbonyl (99m)Tc complexes as potent σ1 receptor radioligands. Rhenium compounds 3-(4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl)propylcarbonylcyclopentadienyl tricarbonyl rhenium (10a) and 4-(4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl)butylcarbonylcyclopentadienyl tricarbonyl rhenium (10b) possessed high in vitro affinity for σ1 receptors and moderate to high selectivity for σ2 receptors and the vesicular acetylcholine transporter. Biodistribution studies in mice demonstrated high initial brain uptake for corresponding (99m)Tc derivatives [(99m)Tc]23 and [(99m)Tc]24 of 2.94 and 2.13% injected dose (ID)/g, respectively, at 2 min postinjection. Pretreatment of haloperidol significantly reduced the radiotracer accumulation of [(99m)Tc]23 or [(99m)Tc]24 in the brain. Studies of the cellular uptake of [(99m)Tc]23 in C6 and DU145 tumor cells demonstrated a reduction of accumulation by incubation with haloperidol, 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine (SA4503), or 1,3-di-o-tolyl-guanidine (DTG). Furthermore, blocking studies in C6 glioma-bearing mice confirmed the specific binding of [(99m)Tc]23 to σ1 receptors in the tumor.

    http://dx.doi.org/10.1021/jm5009488

  • 7
    Shi J, Fan D, Dong C, Liu H, Jia B, Zhao H, Jin X, Liu Z, Li F, Wang F. Anti-tumor effect of integrin targeted (177)Lu-3PRGD2 and combined therapy with Endostar. Theranostics. 2014;4:256-266.

    Abstract

    PURPOSE:

    Targeted radiotherapy (TRT) is an emerging approach for tumor treatment. Previously, 3PRGD2 (a dimeric RGD peptide with 3 PEG4 linkers) has been demonstrated to be of advantage for integrin αvβ3 targeting. Given the promising results of (99m)Tc-3PRGD2 for lung cancer detection in human beings, we are encouraged to investigate the radiotherapeutic efficacy of radiolabeled 3PRGD2. The goal of this study was to investigate and optimize the integrin αvβ3 mediated therapeutic effect of (177)Lu-3PRGD2 in the animal model.

    EXPERIMENTAL DESIGN:

    Biodistribution, gamma imaging and maximum tolerated dose (MTD) studies of (177)Lu-3PRGD2 were performed. The targeted radiotherapy (TRT) with single dose and repeated doses as well as the combined therapy of TRT and the anti-angiogenic therapy (AAT) with Endostar were conducted in U87MG tumor model. The hematoxylin and eosin (H&E) staining and immunochemistry (IHC) were performed post-treatment to evaluate the therapeutic effect.

    RESULTS:

    The U87MG tumor uptake of (177)Lu-3PRGD2 was relatively high (6.03 ± 0.65 %ID/g, 4.62 ± 1.44 %ID/g, 3.55 ± 1.08 %ID/g, and 1.22 ± 0.18 %ID/g at 1 h, 4 h, 24 h, and 72 h postinjection, respectively), and the gamma imaging could visualize the tumors clearly. The MTD of (177)Lu-3PRGD2 in nude mice (>111 MBq) was twice to that of (90)Y-3PRGD2 (55.5 MBq). U87MG tumor growth was significantly delayed by (177)Lu-3PRGD2 TRT. Significantly increased anti-tumor effects were observed in the two doses or combined treatment groups.

    CONCLUSION:

    The two-dose TRT and combined therapy with Endostar potently enhanced the tumor growth inhibition, but the former does not need to inject daily for weeks, avoiding a lot of unnecessary inconvenience and suffering for patients, which could potentially be rapidly translated into clinical practice in the future.

    http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24505234/

  • 8
    Liu H, Wu Y, Wang F, Liu Z. Molecular imaging of integrin alphavbeta6 expression in living subjects. Am J Nucl Med Mol Imaging. 2014;4:333-345.

    Abstract

    Integrins, a family of cell adhesion molecules composed of α and β heterodimeric subunits, are involved in a wide range of cell-extracellular matrix and cell-cell interactions. The study of integrin family members as targets for molecular imaging and therapy has been generally limited with the exception of integrin αvβ3. vβ6, a member of the integrin family, is expressed at low or undetectable levels in normal tissues, but is widely upregulated during many pathological and physiological processes, especially cancer and fibrosis, making it a promising target for molecular imaging. Noninvasive and quantitative imaging of integrin vβ6 expression would be very useful for disease diagnosis, treatment monitoring, and prognosis assessment. Although various molecular probes have been developed for positron emission tomography and single-photon emission computed tomography imaging of integrin vβ6 expression in preclinical animal models, further research efforts are required to optimize integrin vβ6-targeting probes for future potential clinical applications in the fields of oncology and beyond.

    http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24982819/

  • 9
    Zeng J, Jia B, Qiao R, Wang C, Jing L, Wang F, Gao M. In situ 111In-doping for achieving biocompatible and non-leachable 111In-labeled Fe3O4 nanoparticles. Chem Commun (Camb). 2014;50:2170-2172.

    Abstract

    The present study reports a new approach for synthesizing (111)In-radiolabeled biocompatible Fe3O4 nanoparticles. Radioactive (111)In is doped in situ into the lattice of Fe3O4 nanoparticles to achieve robust radiolabeling for accurately tracing PEGylated Fe3O4 particles in vivo.

    http://dx.doi.org/10.1039/c3cc48948e

  • 10
    Sun X, Ma T, Liu H, Yu X, Wu Y, Shi J, Jia B, Zhao H, Wang F, Liu Z. Longitudinal monitoring of tumor antiangiogenic therapy with near-infrared fluorophore-labeled agents targeted to integrin alphavbeta3 and vascular endothelial growth factor. Eur J Nucl Med Mol Imaging. 2014;41:1428-1439.
  • 11
    Liu Z, Ma T, Liu H, Jin Z, Sun X, Zhao H, Shi J, Jia B, Li F, Wang F. 177Lu-labeled antibodies for EGFR-targeted SPECT/CT imaging and radioimmunotherapy in a preclinical head and neck carcinoma model. Mol Pharm. 2014;11:800-807.
  • 12
    Liu Z, Liu H, Ma T, Sun X, Shi J, Jia B, Sun Y, Zhan J, Zhang H, Zhu Z, Wang F. Integrin alphavbeta6-Targeted SPECT Imaging for Pancreatic Cancer Detection. J Nucl Med. 2014;55:989-994.
  • 13
    Ma T, Sun X, Cui L, Gao L, Wu Y, Liu H, Zhu Z, Wang F, Liu Z. Molecular Imaging Reveals Trastuzumab-Induced Epidermal Growth Factor Receptor Downregulation In Vivo. J Nucl Med. 2014;55:1002-1007.
  • 14
    Liu Z, Sun X, Liu H, Ma T, Shi J, Jia B, Zhao H, Wang F. Early assessment of tumor response to gefitinib treatment by noninvasive optical imaging of tumor vascular endothelial growth factor expression in animal models. J Nucl Med. 2014;55:818-823.
  • 15
    Liu L, Song Y, Gao S, Ji T, Zhang H, Ji B, Chen B, Jia B, Wang F, Xu Z, Ma Q. (99)mTc-3PRGD2 scintimammography in palpable and nonpalpable breast lesions. Mol Imaging. 2014;13.

    Abstract

    The aim of this study was to explore the diagnostic performance of 99mTc-3(poly-(ethylene glycol),PEG)4-RGD2 (99mTc-3PRGD2) scintimammography (SMM) in patients with either palpable or nonpalpable breast lesions and compare SMM to mammography to assess the possible incremental value of SMM in breast cancer detection. We also investigated the αvβ3 expression in malignant and benign breast lesions. Ninety-four patients with 110 lesions were included in this study. Mammograms were evaluated according to the Breast Imaging Reporting and Data System (BI-RADS) by a specialized imaging radiologist. Prone SMM was performed 1 hour after injection of 99mTc-3PRGD2. Scintigraphic images were interpreted independently by two experienced nuclear medicine physicians using a three-point system, and the kappa value was calculated to determine the interreader agreement. The McNemar test was used to compare SMM and mammography with respect to sensitivity, specificity, and accuracy. Diagnostic values for breast cancer detection were evaluated for each lesion. Immunohistochemistry was performed to evaluate integrin αvβ3 expression. Histopathology revealed 46 malignant lesions and 64 benign lesions. The overall sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of SMM were 83%, 73%, 77%, 69%, and 85%, respectively. The kappa value between the two reviewers was 0.63. The diagnostic values of SMM were higher than those of mammography in evaluating overall breast lesions. A sensitivity of 91% was achieved when SMM and mammography results were combined with 60% of all false-negative mammography findings classified as true-positive results by SMM. Integrin αvβ3 expression was positively identified using SMM imaging. SMM is a promising tool to avoid unnecessary biopsies when used in addition to mammography and can be used to image αvβ3 expression in breast cancer with good image quality.

    http://dx.doi.org/10.2310/7290.2014.00010

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