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(1) A novel DKL [LKlLKlLlkKLLkLL-NH2; K is Lys, L is Leu, k is D-Lys, l is D-Leu] modified probe for positron emission tomography imaging.[TOP]

Pubmed ID :30931855
Publication Date : //
Peptides containing the asparagine-glycine-arginine (NGR) motif can target the tumor neovascular biomarker CD13/aminopeptidase N receptor. D-K6L9 is a tumor-selective anti-cancer peptide. To improve the capacity of NGR peptides to target tumors, we joined the NGR and D-K6L9 peptides to form NKL. Next, we linked 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to NKL and labeled it with gallium 68 (68Ga, t1/2 = 67.7 min) to form 68Ga-DOTA-NKL. This novel probe was characterized in vitro. 68Ga-DOTA-NKL was stable in phosphate buffered saline at room temperature and in human serum at 37°C. We determined that the uptake rate of 68Ga-DOTA-NKL in CD13 receptor-positive 22Rv1 tumor cells was 3.15% ± 0.04 after 2 h, and tested 68Ga-DOTA-NKL using positron emission tomography (PET)/computed tomography imaging in vivo. MicroPET imaging results revealed that 22Rv1 tumor uptake of 68Ga-DOTA-NKL was 8.69 ± 0.20, 6.61 ± 0.22, 3.85 ± 0.06, and 1.41 ± 0.23 percentage injected dose per gram of tissue (%ID/g) at 0.5, 1, 2, and 3 h post-injection (pi), respectively. The tumor-to-background contrast in the subcutaneous human prostate cancer 22Rv1 mouse model was 9.97 ± 1.90. The 68Ga-DOTA-NKL probe has combined tumor-targeting and tumor-selective properties, and may be used to diagnose CD13-positive tumors.

Authors : Liu Yi, Li Xiang, Gao Yongheng, Kang Fei, Ma Xiaowei, Yang Weidong, Wang Jing, Ma Wenhui,

(2) Leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry. Part II.[TOP]

Pubmed ID :30737134
Publication Date : //
Aminopeptidase N (APN) has been proved to be deeply associated with cancer angiogenesis, metastasis and invasion. Therefore, APN gains increasing attention as a promising anti-tumor target. In the current study, we report the design, synthesis, biological evaluation and structure-activity relationship of one new series of leucine ureido derivatives containing the 1,2,3-triazole moiety. Among them, compound 31f was identified as the best APN inhibitor with IC value being two orders of magnitude lower than that of the positive control bestatin. Compound 31f possessed selective cytotoxicity to several tumor cell lines over the normal cell line human umbilical vein endothelial cells (HUVECs). Notably, when combined with 5-fluorouracil (5-Fu), 31f exhibited synergistic anti-proliferation effect against several tumor cell lines. At the same concentration, 31f exhibited much better anti-angiogenesis activities than bestatin in the HUVECs capillary tube formation assay and the rat thoracic aorta rings test. In the in vitro anti-invasion assay, 31f also exhibited superior potency over bestatin. Moreover, considerable in vivo antitumor potencies of 31f alone or in combination with 5-Fu were observed without significant toxic signs in a mouse heptoma H22 tumor transplant model.

Authors : Cao Jiangying, Zang Jie, Kong Xiujie, Zhao Chunlong, Chen Ting, Ran Yingying, Dong Hang, Xu Wenfang, Zhang Yingjie,

(3) Gadofosveset-enhanced MRI as simple surrogate parameter for real-time evaluation of the initial tumour vessel infarction by retargeted tissue factor tTF-NGR.[TOP]

Pubmed ID :30655764
Publication Date : //
Truncated tissue factor (tTF)-NGR consists of the extracellular domain of the human TF and the binding motif NGR. tTF-NGR activates blood coagulation within the tumour vasculature following binding to CD13, and is overexpressed in the endothelial cells of tumour vessels, resulting in tumour vessel infarction and subsequent retardation/regression of tumour growth. The aim of the present study was to investigate gadofosveset-based real-time dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in evaluating the initial therapeutic effects of the anti-vascular tTF-NGR approach. DCE-MRI (3.0 T) was performed in human U87-glioblastoma tumour-bearing nude mice. During a dynamic T1w GE-sequence, a gadolinium-based blood pool contrast agent (gadofosveset) was injected via a tail vein catheter. Following the maximum contrast intensity inside the tumour being obtained, tTF-NGR was injected (controls received NaCl) and the contrast behaviour of the tumour was monitored by ROI analysis. The slope difference of signal intensities between controls and the tTF-NGR group was investigated, as well as the differences between the average area under the curve (AUC) of the two groups. The association between intensity, group (control vs. tTF-NGR group) and time was analysed by fitting a linear mixed model. Following the injection of tTF-NGR, the signal intensity inside the tumours exhibited a statistically significantly stronger average slope decrease compared with the signal intensity of the tumours in the NaCl group. Furthermore, the initial average AUC values of mice treated with tTF-NGR were 5.7% lower than the average AUC of the control animals (P<0.05). Gadofosveset-enhanced MRI enables the visualization of the initial tumour response to anti-vascular treatment in real-time. Considering the clinical application of tTF-NGR, this method may provide a simple alternative parameter for monitoring the tumour response to vascular disrupting agents and certain vascular targeting agents in humans.

Authors : Höink Anna, Persigehl Thorsten, Kwiecien Robert, Balthasar Martin, Mesters Rolf, Berdel Wolfgang, Heindel Walter, Bremer Christoph, Schwöppe Christian,

(4) Novel leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry.[TOP]

Pubmed ID :29859750
Publication Date : //
The over-expression of aminopeptidase N on diverse malignant cells is associated with the tumor angiogenesis and metastasis. In this report, one new series of leucine ureido derivatives containing the triazole moiety was designed, synthesized and evaluated as APN inhibitors. Among them, compound 13v showed the best APN inhibition with an IC value of 0.089 ± 0.007 μM, which was two orders of magnitude lower than that of bestatin (IC = 9.4 ± 0.5 μM). Compound 13v also showed dose-dependent anti-angiogenesis activities. Even at the lower concentration (10 μM), compound 13v presented similar anti-angiogenesis activity compared with bestatin at 100 μM in both the human umbilical vein endothelial cells (HUVECs) capillary tube formation assay and the rat thoracic aorta rings test. Moreover, compared with bestatin, 13v exhibited comparable, if not better in vivo anti-metastasis activity in a mouse H22 pulmonary metastasis model.

Authors : Cao Jiangying, Ma Chunhua, Zang Jie, Gao Shuai, Gao Qianwen, Kong Xiujie, Yan Yugang, Liang Xuewu, Ding Qin'ge, Zhao Chunlong, Wang Binghe, Xu Wenfang, Zhang Yingjie,

(5) NGR (Asn-Gly-Arg)-targeted delivery of coagulase to tumor vasculature arrests cancer cell growth.[TOP]

Pubmed ID :29662195
Publication Date : //
Induction of selective thrombosis and infarction in tumor-feeding vessels represents an attractive strategy to combat cancer. Here we took advantage of the unique coagulation properties of staphylocoagulase and genetically engineered it to generate a new fusion protein with novel anti-cancer properties. This novel bi-functional protein consists of truncated coagulase (tCoa) and an NGR (GNGRAHA) motif that recognizes CD13 and αβ integrin receptors, targeting it to tumor endothelial cells. Herein, we report that tCoa coupled by its C-terminus to an NGR sequence retained its normal binding activity with prothrombin and aβ integrins, as confirmed in silico and in vitro. Moreover, in vivo biodistribution studies demonstrated selective accumulation of FITC-labeled tCoa-NGR fusion proteins at the site of subcutaneously implanted PC3 tumor xenografts in nude mice. Notably, systemic administration of tCoa-NGR to mice bearing 4T1 mouse mammary xenografts or PC3 human prostate tumors resulted in a significant reduction in tumor growth. These anti-tumor effects were accompanied by massive thrombotic occlusion of small and large tumor vessels, tumor infarction and tumor cell death. From these findings, we propose tCoa-NGR mediated tumor infarction as a novel and promising anti-cancer strategy targeting both CD13 and integrin αβ positive tumor neovasculature.

Authors : Seidi Khaled, Jahanban-Esfahlan Rana, Monhemi Hassan, Zare Peyman, Minofar Babak, Daei Farshchi Adli Amir, Farajzadeh Davoud, Behzadi Ramezan, Mesgari Abbasi Mehran, Neubauer Heidi A, Moriggl Richard, Zarghami Nosratollah, Javaheri Tahereh,

(6) Synthesis and biological characterization of ubenimex-fluorouracil conjugates for anti-cancer therapy.[TOP]

Pubmed ID :29202398
Publication Date : //
Previously a novel ubenimex-fluorouracil (5-FU) conjugate, BC-01 was identified and validated as a potent CD13 inhibitor with marked in vitro and in vivo antitumor potency. Herein, further structural modifications of the linker part of BC-01 was carried out to get more potent and stable ubenimex-fluorouracil conjugates. It was striking that most of these conjugates showed even more potent CD13 inhibitory activities than BC-01 and the approved CD13 inhibitor ubenimex. One representative compound 12a displayed significant in vitro anti-proliferation, pro-apoptosis, anti-metastasis, anti-angiogenesis and CD13 cell elimination effects. In vitro stability and in vivo pharmacokinetic study revealed that compound 12a could release ubenimex and 5-FU slowly, which could act as a mutual prodrug of ubenimex and 5-FU. Compared with 5-FU or 5-FU plus ubenimex, 12a exhibited superior in vivo antitumor growth efficiency, even in our mice model of 5-FU-resistant liver cancer. Moreover, 12a exhibited more potent in vivo anti-metastasis and lifespan extension effects compared to the approved 5-FU prodrug capecitabine. Collectively, these results suggest that further optimization and evaluation of 12a as a promising anticancer candidate are warranted to develop effective therapeutic agents for human liver cancer.

Authors : Jiang Yuqi, Li Xiaoyang, Hou Jinning, Huang Yongxue, Wang Xuejian, Jia Yuping, Wang Qingwei, Xu Wenfang, Zhang Jian, Zhang Yingjie,

(7) IL-10-Engineered Human CD4 Tr1 Cells Eliminate Myeloid Leukemia in an HLA Class I-Dependent Mechanism.[TOP]

Pubmed ID :28807569
Publication Date : //
T regulatory cells (Tregs) play a key role in modulating T cell responses. Clinical trials showed that Tregs modulate graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, their ability to mediate anti-leukemic activity (graft-versus-leukemia [GvL]) is largely unknown. Enforced interleukin-10 (IL-10) expression converts human CD4 T cells into T regulatory type 1 (Tr1)-like (CD4) cells that suppress effector T cells in vitro and xenoGvHD in humanized mouse models. In the present study, we show that CD4 cells mediate anti-leukemic effects in vitro and in vivo in a human leukocyte antigen (HLA) class I-dependent but antigen-independent manner. The cytotoxicity mediated by CD4 cells is granzyme B (GzB) dependent, is specific for CD13 target cells, and requires CD54 and CD112 expression on primary leukemic target blasts. CD4 cells adoptively transferred in humanized mouse models directly mediate anti-tumor and anti-leukemic effects. In addition, when co-transferred with peripheral blood mononuclear cells (PBMCs), CD4 cells contribute to the GvL activity but suppress xenoGvHD mediated by the PBMCs. These findings provide for the first time a strong rationale for CD4 cell immunotherapy to prevent GvHD and promote GvL in allo-HSCT for myeloid malignancies.

Authors : Locafaro Grazia, Andolfi Grazia, Russo Fabio, Cesana Luca, Spinelli Antonello, Camisa Barbara, Ciceri Fabio, Lombardo Angelo, Bondanza Attilio, Roncarolo Maria Grazia, Gregori Silvia,

(8) The CNGRCLLII(KLAKLAK)2 peptide shows cytotoxicity against HUVECs by inducing apoptosis: An in vitro and in vivo study.[TOP]

Pubmed ID :28475015
Publication Date : //
Fibrinogen Asn-Gly-Arg motif can specifically recognize and bind to Aminopeptidase N (CD13) on vascular endothelial cells in newly formed tumor vessels. Adipose-derived stem cells can serve as ideal vectors for gene therapy because of their ability of migrating to tumor tissues. First, this study was aimed to design a new peptide (CNGRCLLII(KLAKLAK)2) named CNAK which contains cyclic Asn-Gly-Arg motif and test its biological activity against human umbilical vein endothelial cells. Second, we aimed to construct stably transfected adipose-derived stem cells which express the CNAK peptide and investigate their anti-angiogenic activity in vivo. Adipose-derived stem cells were employed to localize CNAK on vascular endothelial cells in tumors based on their homing property. First of all, the new peptide was synthesized, which effectively entered into CD13+ human umbilical vein endothelial cells and showed cytotoxicity against human umbilical vein endothelial cells. The peptide induced apoptosis of human umbilical vein endothelial cells in a time- and dose-dependent manner, inhibited the expression of Bcl-2, and promoted the expression of Caspase-3 in human umbilical vein endothelial cells. Furthermore, the migration and tube formation of human umbilical vein endothelial cells were inhibited by CNAK. Primary adipose-derived stem cells were then isolated and identified. Stably transfected adipose-derived stem cells which express CNAK peptide (CNAK-ASCs) were successfully established, and the migration of CNAK-ASCs was assessed. In vivo, CNAK-ASCs were found to inhibit the growth and angiogenesis of breast cancer xenografts. This effect may be through inhibiting the secretion of matrix metalloproteinase-2 and membrane type 1-matrix metalloproteinase in vivo. It was also found that CNAK-ASCs reduced the quantity of breast cancer stem cells in tumor tissues. Our data suggested that the new peptide CNAK containing Asn-Gly-Arg motif had anti-angiogenic activity in vitro and in vivo.

Authors : Wang Guanying, Yuan Na, Huang Shangke, Feng Lu, Han Rui, Zhang Yujiao, Ren Juan, Meng Min, Zhao Xinhan,

(9) Targeting peptide functionalized liposomes towards aminopeptidase N for precise tumor diagnosis and therapy.[TOP]

Pubmed ID :28138675
Publication Date : //
Aminopeptidase N (APN/CD13) is closely related to the growth of cancers and is suggested as a suitable target for anti-cancer therapy. Based on the "one-bead-one-compound" (OBOC) approach on a microarray device, we screened out a novel affinity peptide LN (YEVGHRC). It was determined that LN could specifically recognize and bind to APN. Moreover, LN-functionalized liposomes (LN-LS) could achieve efficient nano-encapsulated drug delivery under APN-overexpressing tumor conditions in vitro and in vivo. We expect that LN-LS could provide a new strategy for APN-positive tumor diagnosis and therapy.

Authors : Jia Xiangqian, Han Qiuju, Wang Zihua, Qian Yixia, Jia Yunhong, Wang Weizhi, Hu Zhiyuan,

(10) Superparamagnetic anisotropic nano-assemblies with longer blood circulation in vivo: a highly efficient drug delivery carrier for leukemia therapy.[TOP]

Pubmed ID :27714144
Publication Date : //
Leukemia, unlike solid tumors, has no definite shape and spreads throughout the whole circulatory system, therefore the therapy of leukemia requires medication to stay longer in the circulatory system. Anisotropic nanoparticles, showing longer blood circulating life than that of isotropic nanoparticles reported in previous research, meet the demands of leukemia therapy. Based on this strategy, superparamagnetic anisotropic nano-assemblies (SANs) were fabricated and loaded with vincristine (VCR) to form VCR-SANs. When compared to the same dose of VCR-loaded isotropic nano-assemblies (SINs), the decrease in the leukocytes count and the positive expression ratio of CD13 in the VCR-SANs group were 19.38% and 16.4%, respectively, which indicated the improved anti-leukemia activity of the VCR-SANs. From the results of the pharmacokinetics study, the VCR-SANs remarkably held the amount of drug removed from the whole body per unit time half of the isotropic group and the concentration of drug in blood plasma against time was 2.1 times the isotropic group, demonstrating the rapid and sustained release behavior and longer blood circulation when combined with the results of in vivo tissue distribution studies. In summary, anisotropic nano-assemblies were found to be more promising than isotropic nano-assemblies via our in vivo and in vitro examinations.

Authors : Xiong Fei, Tian Jilai, Hu Ke, Zheng Xiawen, Sun Jianfei, Yan Caiyun, Yao Juan, Song Lina, Zhang Yu, Gu Ning,