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Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy  [PDF]
Xiaoxiao Li,Jianjun Hou,Chao Wang,Xinjie Liu,Hongyan He,Ping Xu,Zhenjun Yang,Zili Chen,Yun Wu,Lihe Zhang
Molecules , 2013, DOI: 10.3390/molecules181113957
Abstract: Two novel series of RGD-MEKI conjugates derived from a MEK1/2 kinase inhibitor—PD0325901—have been developed for integrin receptor mediated anticancer therapy. The first series, alkoxylamine analog RGD-MEKI conjugates 9a– g showed anti-proliferation activity in melanoma A375 cells by the same mechanism as that of PD0325901. PEGylation increased the IC 50 value of 9f three-fold in the A375 assay, and the multi-cRGD peptide cargo significantly improved the receptor specific anti-proliferation activity of 9g in integrin-overexpressing U87 cells. In the second series, RGD-PD0325901 13 exhibited significantly increased antitumor properties compared to the alkoxylamine analogs by both inhibition of the ERK pathway activity and DNA replication of the cancer cells. Furthermore, 13 displayed more potent anti-proliferation activity in the U87 assay than PD0325901 in a dose-dependent manner. All these data demonstrate that RGD-MEKI conjugates with an ester bond linkage enhanced anticancer efficacy with improved targeting capability toward integrin-overexpressing tumor cells.
Intracellular ZnO Nanorods Conjugated with Protoporphyrin for Local Mediated Photochemistry and Efficient Treatment of Single Cancer Cell
Kishwar S,Asif MH,Nur O,Willander M
Nanoscale Research Letters , 2010,
Abstract: ZnO nanorods (NRs) with high surface area to volume ratio and biocompatibility is used as an efficient photosensitizer carrier system and at the same time providing intrinsic white light needed to achieve cancer cell necrosis. In this letter, ZnO nanorods used for the treatment of breast cancer cell (T47D) are presented. To adjust the sample for intracellular experiments, we have grown the ZnO nanorods on the tip of borosilicate glass capillaries (0.5 μm diameter) by aqueous chemical growth technique. The grown ZnO nanorods were conjugated using protoporphyrin dimethyl ester (PPDME), which absorbs the light emitted by the ZnO nanorods. Mechanism of cytotoxicity appears to involve the generation of singlet oxygen inside the cell. The novel findings of cell-localized toxicity indicate a potential application of PPDME-conjugated ZnO NRs in the necrosis of breast cancer cell within few minutes.
Photovoltaic Devices from Multi-Armed CdS Nanorods and Conjugated Polymer Composites
LIU Yan-Shan,WANG Li,QIN Dong-Huan,CAO Yong,

中国物理快报 , 2006,
Abstract: We demonstrate the preparation of composite photovoltaic devices by using the blends of multi-armed CdS nanorods with conjugated polymer, poly2-methoxy-5-(2'-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV). Multi-armed CdS nanorods are prepared by thermolysing single precursor cadmium ethylxanthate Cd(exan)2] in pure hexadecylamine solution under ambient conditions. The photoluminescence of MEH-PPV can be effectively quenched in the composites at high CdS nanocrystal (nc-CdS)//MEH-PPV ratios. Post-treatment of the multi-armed CdS nanorods by refluxing in pyridine significantly increases the performance of the composite photovoltaic devices. Power conversion efficiency is obtained to be 0.17% under AM 1.5 illumination for this composite device.
Photosensitizer-Conjugated Gold Nanorods for Enzyme-Activatable Fluorescence Imaging and Photodynamic Therapy  [cached]
Boseung Jang, Yongdoo Choi
Theranostics , 2012,
Abstract: We report on the development of photosensitizer-conjugated gold nanorods (MMP2P-GNR) in which photosensitizers were conjugated onto the surface of gold nanorods (GNR) via a protease-cleavable peptide linker. We hypothesized that fluorescence and phototoxicity of the conjugated photosensitizers would be suppressed in their native state, becoming activated only after cleavage by the target protease matrix metalloprotease-2 (MMP2). Quantitative analysis of the fluorescence and singlet oxygen generation (SOG) demonstrated that the MMP2P-GNR conjugate emitted fluorescence intensity corresponding to 0.4% ± 0.01% and an SOG efficiency of 0.89% ± 1.04% compared to free pyropheophorbide-a. From the in vitro cell studies using HT1080 cells that overexpress MMP2 and BT20 cells that lack MMP2, we observed that fluorescence and SOG was mediated by the presence or absence of MMP2 in these cell lines. This novel activatable photosensitizing system may be useful for protease-mediated fluorescence imaging and subsequent photodynamic therapy for various cancers.
RGD-conjugated rod-like viral nanoparticles on 2D scaffold improve bone differentiation of mesenchymal stem cells  [PDF]
Kai Li,Qian Wang
Frontiers in Chemistry , 2014, DOI: 10.3389/fchem.2014.00031
Abstract: Viral nanoparticles have uniform and well-defined nano-structures and can be produced in large quantities. Several plant viral nanoparticles have been tested in biomedical applications due to the lack of mammalian cell infectivity. We are particularly interested in using Tobacco mosaic virus (TMV), which has been demonstrated to enhance bone tissue regeneration, as a tunable nanoscale building block for biomaterials development. Unmodified TMV particles have been shown to accelerate osteogenic differentiation of adult stem cells by synergistically upregulating bone morphogenetic protein 2 (BMP2) and integrin-binding bone sialoprotein (IBSP) expression with dexamethasone. However, their lack of affinity to mammalian cell surface resulted in low initial cell adhesion. In this study, to increase cell binding capacity of TMV based material the chemical functionalization of TMV with arginine-glycine-aspartic acid (RGD) peptide was explored. An azide-derivatized RGD peptide was “clicked” to tyrosine residues on TMV outer surface via an efficient copper(I) catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The ligand spacing is calculated to be 2–4 nm, which could offer a polyvalent ligand clustering effect for enhanced cell receptor signaling, further promoting the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs).
The combination of olaparib and camptothecin for effective radiosensitization
Katsutoshi Miura, Koh-ichi Sakata, Masanori Someya, Yoshihisa Matsumoto, Hideki Matsumoto, Akihisa Takahashi, Masato Hareyama
Radiation Oncology , 2012, DOI: 10.1186/1748-717x-7-62
Abstract: DLD-1 cells (a human colorectal cancer cell line) and H1299 cells (a non-small cell lung cancer cell line) with differences of p53 gene status were used. The survival of these cells was determined by clonogenic assay after treatment with drugs and X-ray irradiation. The γH2AX focus formation assay was performed to examine the influence of olaparib on induction and repair of double-stranded DNA breaks after exposure to radiation or CPT.A radiosensitizing effect of olaparib was seen even at 0.01 μM. Its radiosensitizing effect after exposure for 2 h was similar to that after 24 h. H1299 cells with depletion or mutation of p53 were more radioresistant than H1299 cells with wild-type p53. However, similar enhancement of radiosensitization by olaparib was observed with all of the tested cell lines regardless of the p53 status. Olaparib also sensitized cells to CPT. This sensitizing effect was seen at low concentrations of olaparib such as 0.01 μM, and its sensitizing effect was the same at both 0.01 μM and 1 μM. The combination of olaparib and CPT had a stronger radiosensitizing effect. The results of the γH2AX focus assay corresponded with the clonogenic assay findings.Olaparib enhanced sensitivity to radiation and CPT at low concentrations and after relatively short exposure times such as 2 h. The radiosensitizing effect of olaprib was not dependent on the p53 status of tumor cells. These characteristics could be advantageous for clinical radiotherapy since tumor cells may be exposed to low concentrations of olaparib and/or may have different levels of p53 mutation. The combination of olaparib and CPT had a stronger radiosensitizing effect, indicating that combining a PARP inihibitor with a topoiomerase I inhibitor could be promising for clinical radiosensitization.
Novel RGD-lipid conjugate-modified liposomes for enhancing siRNA delivery in human retinal pigment epithelial cells  [cached]
Chen CW,Lu DW,Yeh MK,Shiau CY
International Journal of Nanomedicine , 2011,
Abstract: Cheng-Wei Chen1, Da-Wen Lu2, Ming-Kung Yeh3, Chia-Yang Shiau4, Chiao-Hsi Chiang1,5 1Graduate Institute of Life Sciences, 2Department of Ophthalmology, Tri-Service General Hospital, 3Institution of Preventive Medicine, 4Graduate Institute of Medical Sciences, 5School of Pharmacy, National Defense Medical Center, Neihu, Taipei, Taiwan Background: Human retinal pigment epithelial cells are promising target sites for small interfering RNA (siRNA) that might be used for the prevention and/or treatment of choroidal neovascularization by inhibiting the expression of angiogenic factor; for example, by downregulating expression of the vascular endothelial growth factor gene. Methods: A novel functional lipid, DSPE-PEG-RGD, a Arg(R)-Gly(G)-Asp(D) motif peptide conjugated to 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine- N-[maleimide (polyethylene glycol)-2000], was synthesized for the preparation of siRNA-loaded RGD-PEGylated liposomes to enhance uptake of encapsulated siRNA in retinal pigment epithelial cells. Various liposomes, with 1 mol% and 5 mol% PEGylated lipid or 1 mol% and 5 mol% RGD-PEGylated lipid, were fabricated. Results: Characterization of the liposomes, including siRNA entrapment efficiency, average particle size and ζ-potential, were determined to be as follows: >96%, 129.7 ± 51 to 230.7 ± 60.7 nm, and 17.3 ± 0.6 to 32 ± 1.3 mV, respectively. For the in vitro retinal pigment epithelial cell studies, the RGD-PEGylated liposomes had high delivery efficiency with siRNA delivery, about a four-fold increase compared with the PEGylated liposomes. Comparison of the various liposomes showed that the 1 mol% RGD-modified liposome had less cytotoxicity and higher siRNA delivery efficiency than the other liposomes. The antibody blocking assay confirmed that uptake of the 1 mol% RGD-PEGylated liposome was via integrin receptor-mediated endocytosis in retinal pigment epithelial cells. Conclusion: The results of this study suggest that RGD-PEGylated liposomes might be useful for siRNA delivery into retinal pigment epithelial cells by integrin receptor-medicated endocytosis. Keywords: Arg-Gly-Asp, RGD, small interfering RNA, liposome, retinal pigment epithelial cells
The Functions and Applications of RGD in Tumor Therapy and Tissue Engineering  [PDF]
Fen Wang,Yuanyuan Li,Yingqiang Shen,Anming Wang,Shuling Wang,Tian Xie
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms140713447
Abstract: Arginine-Glycine-Aspartic (RGD), is the specific recognition site of integrins with theirs ligands, and regulates cell-cell and cell-extracellular matrix interactions. The RGD motif can be combined with integrins overexpressed on the tumor neovasculature and tumor cells with a certain affinity, becoming the new target for imaging agents, and drugs, and gene delivery for tumor treatment. Further, RGD as a biomimetic peptide can also promote cell adherence to the matrix, prevent cell apoptosis and accelerate new tissue regeneration. Functionalizing material surfaces with RGD can improve cell/biomaterial interactions, which facilitates the generation of tissue-engineered constructs. This paper reviews the main functions and advantages of RGD, describes the applications of RGD in imaging agents, drugs, gene delivery for tumor therapy, and highlights the role of RGD in promoting the development of tissue engineering (bone regeneration, cornea repair, artificial neovascularization) in recent years.
RGD: A comparative genomics platform
Mary Shimoyama, Jennifer R Smith, Tom Hayman, Stan Laulederkind, Tim Lowry, Rajni Nigam, Victoria Petri, Shur-Jen Wang, Melinda Dwinell, Howard Jacob, RGD Team
Human Genomics , 2011, DOI: 10.1186/1479-7364-5-2-124
Abstract: The Rat Genome Database (RGD) (http://rgd.mcw.edu webcite) is recognised as the premier resource for genetic, genomic and phenotype data for the laboratory rat, Rattus norvegicus. Since 1999, RGD has provided a comprehensive catalogue of genes, quantitative trait loci (QTL) and strains, along with software tools to retrieve and display data of interest to investigators using this organism. The disease focus of these researchers often results in the use of multiple model organisms, in addition to clinical studies, in their efforts to elucidate the mechanisms and underlying genetic factors involved in human disease. To meet the needs of such users, RGD focuses its manual curation efforts on the functional, phenotype and pathway data related to specific disease areas and has integrated human and mouse data to create a comprehensive platform for comparative genomics and genetics. Several of these components are highlighted here.The wealth of data at RGD includes genes and QTLs for rat, human and mouse, as well as polymorphic markers for rat and human (Table 1). Information on inbred, outbred, mutant, congenic, consomic and other types of rat strains is also provided. A team of scientific curators validates the identity of genomic elements, provides official nomenclature and annotates these elements with functional data from published literature [1]. With more than 1.3 million published rat research papers, prioritising data for curation is a vital task, and a project approach has proved effective. Such projects revolve around gene families, molecular pathways, ultra-conserved gene sets and diseases.The disease portals (http://rgd.mcw.edu/wg/portals/ webcite) create a structure for prioritising rat data curation and integrating rat, human and mouse information, and provide a platform for researchers easily to access multiple data types related to a particular disease area (Table 2). RGD currently has portals for cardiovascular and neurological diseases, cancer, diabetes
Radiosensitization by the novel DNA intercalating agent vosaroxin
Ira K Gordon, Christian Graves, Whoon J Kil, Tamalee Kramp, Philip Tofilon, Kevin Camphausen
Radiation Oncology , 2012, DOI: 10.1186/1748-717x-7-26
Abstract: Vosaroxin's effect on post-irradiation sensitivity of U251, DU145, and MiaPaca-2 cells was assessed by clonogenic assay. Subsequent mechanistic and in vivo studies were performed with U251 cells. Cell cycle distribution and G2 checkpoint integrity was analyzed by flow cytometry. DNA damage and repair was evaluated by a high throughput gamma-H2AX assay. Apoptosis was assessed by flow cytometry. Mitotic catastrophe was assessed by microscopic evidence of fragmented nuclei by immunofluorescence. In vivo radiosensitization was measured by subcutaneous tumor growth delay.50-100 nmol/L treatment with vosaroxin resulted in radiosensitization of all 3 cell lines tested with a dose enhancement factor of 1.20 to 1.51 measured at a surviving fraction of 0.1. The maximal dose enhancement was seen in U251 cells treated with 75 nmol/L vosaroxin (DEF 1.51). Vosaroxin exposure did not change cell cycle distribution prior to irradiation nor alter G2 checkpoint integrity after irradiation. No difference was seen in the apoptotic fraction regardless of drug or radiation treatment. The number of cells in mitotic catastrophe was significantly greater in irradiated cells treated with vosaroxin than cells receiving radiation only at 72 hr (p = 0.009). Vosaroxin alone did not significantly increase mitotic catastrophe over control (p = 0.53). Cells treated with vosaroxin and radiation maintained significantly higher gamma-H2AX levels than cells treated with vehicle control (p = 0.014), vosaroxin (p = 0.042), or radiation alone (p = 0.039) after 24 hr. In vivo tumor growth delay was 1.5 days for vosaroxin alone (IV 10 mg/kg), 1.0 days for radiation (3 Gy) alone, and 8.6 days for the group treated with vosaroxin 4 hours prior to radiation.Vosaroxin enhanced tumor cell radiosensitivity in vitro and in vivo. The mechanism appears to be related to inhibition of DNA repair and increased mitotic catastrophe.Topoisomerase II inhibitors are a diverse class of anti-cancer drugs that include the anth
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