A New Class of 5-Fluoro-2?-deoxyuridine Prodrugs Conjugated with a Tumor-Homing Cyclic Peptide CNGRC by Ester Linkers: Synthesis, Reactivity, and Tumor-Cell?Selective Cytotoxicity

Zhang, Zhouen; Hatta, Hiroshi; Tanabe, Kazuhito; Nishimoto, Sei‐ichi

doi:10.1007/s11095-004-1875-x

Cited by 26 publications

(29 citation statements)

References 31 publications

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“…Other cytotoxic drugs that have been coupled to NGR peptides include platinum (IV) [61], carboplatin [62], 5 fluoro-2'-deoxyuridine prodrug [63], 5-fluorouracil prodrug [64] and the pro-apoptotic peptidomimetic D (KLAKLAKKL-AKLAK) [14]. Regarding this pro-apoptotic peptide, it is interesting to note that the NGR domain (CNGRC) was designed to play the double function of homing the conjugate to tumors and of promoting internalization of D (KLAKLA-KKLAKLAK).…”

Section: Ngr-peptides and Chemotherapeutic/cytotoxic Agentsmentioning

confidence: 99%

Tumor Vasculature Targeting Through NGR Peptide-Based Drug Delivery Systems

Corti

Curnis

2011

CPB

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Various peptide sequences have been discovered by selecting peptide-phage display libraries in vitro against specific receptors or in vivo in tumor-bearing animals. One class of these peptides is characterized by the presence of Asn-Gly-Asp (NGR), a structural motif that can recognize the endothelium and other cells of neoangiogenic vessels. Because of this property these peptides have been used by several investigators to deliver a variety of drugs, cytokines, nanoparticles, viruses and imaging agents to tumor blood vessels. Here we review the reports on these conjugates and discuss the structural, functional and stability properties of NGR embedded into different molecular scaffolds.

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Section: Ngr-peptides and Chemotherapeutic/cytotoxic Agentsmentioning

confidence: 99%

Tumor Vasculature Targeting Through NGR Peptide-Based Drug Delivery Systems

Corti

Curnis

2011

CPB

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“…A 5-FdUrd conjugate bearing the homing peptide CNGRC was found to penetrate into the CD13 positive cells (HT-1080) but not in CD13 negative cells (MDA-MB-231). This enhanced the selective accumulation of 5-FdUrd, resulting in a more effective immunotherapy (24). IC 50 values for conjugate 7 and conjugate 8 are 149 μM and 115 μM respectively.…”

Section: In Vitro Studies On Pt-conjugates: Their Toxicity and Uptakementioning

confidence: 99%

“…Recently, doxorubicin (DOX) and 5-fluoro-2′-deoxyuridine (5-FdUrd) conjugates have successfully been targeted using NGR motif (21, 22). Specifically, DOX-peptide conjugate treated animals had increased life expectancies relative to animals treated with DOX alone (23) and a 5-FdUrd-NGR conjugate produced selective accumulation of 5-FdUrd in tumor cells having CD 13 receptors (24). Haubner et al .…”

Section: Introductionmentioning

confidence: 99%

Peptide Targeting of Platinum Anti-Cancer Drugs

et al. 2009

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Besides various side effects caused by platinum anticancer drugs, they are not efficiently absorbed by the tumor cells. Two Pt-peptide conjugates; cyclic mPeg-CNGRC-Pt (7) and cyclic mPeg-CNGRC-Pten (8) bearing the Asn-Gly-Arg (NGR) targeting sequence, a malonoyl linker and low molecular weight miniPEG groups have been synthesized. The platinum ligand was attached to the peptide via the carboxylic end of the malonate group at the end of the peptide. The pegylated peptide is non toxic and highly soluble in water. Platinum conjugates synthesized using the pegylated peptides are also water soluble with reduced or eliminated peptide immunogenicity. The choice of carboplatin as our untargeted platinum complex was due to the fact that malonate linker chelates platinum in a manner similar to carboplatin. Cell toxicity assay and competition assay on the PC-3 cells (CD13 positive receptors) revealed selective delivery and destruction of PC-3 cells using targeted Pt-peptide conjugates 7 and 8 significantly more than untargeted carboplatin. Platinum uptake on PC-3 cells was 12-fold more for conjugate 7 and 3-fold more for conjugate 8 compared to the untargeted carboplatin indicating selectively activation of the CD13 receptors and delivery of the conjugates to CD13 positive cells. Further analysis on effects of conjugates 7 and 8 on PC-3 cells using caspase-3/7, fluorescence microscopy and DNA fragmentation confirmed that the cells were dying by apoptosis.

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“…C iso DGRC peptides as a targeted delivery of tumor necrosis factor α (TNF) has been explored and shown promising results. C iso DGRC thus appears to be a promising candidate as a tool for targeted delivery of anti-agents for CD13 − /α v β 3 + tumor cells, such as MCF-7 and MDA-MB-231 cell lines [14], [15].…”

Section: Introductionmentioning

confidence: 99%

Antitumor Activity of Antimicrobial Peptides Containing CisoDGRC in CD13 Negative Breast Cancer Cells

et al. 2013

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Backgroud isoAsp-Gly-Arg (isoDGR) is a derivative of the Asn-Gly-Arg (NGR) motif, which is used as a targeted delivery tool to aminopeptidase N (CD13) positive cells. Recent studies have shown that cyclic isoDGR (CisoDGRC) has a more efficient affinity with αvβ3, a type of integrin that overexpresses in tumor cells. Antimicrobial peptides (AMPs) are an efficient antitumor peptide that specifically kills tumor cells. In the present study, we designed antimicrobial peptides containing the CisoDGRC motif (CDAK) and assessed its antitumor activity for CD13−/αvβ3 + breast cancer cells (MCF-7 and MDA-MB-231) in vitro and in vivo.MethodsIn vitro: We assessed the cytotoxicity of CDAK for MCF-7 and MDA-MB-231 breast cancer cells, the human umbilical vein endothelial cell (HUVEC), and human foreskin fibroblasts (HFF). We performed an apoptosis assay using Annexin-V/PI, DNA ladder, mitochondrial membrane potential, and Caspase-3 and Bcl-2. The effect on cell cycles and affinity with cell were tested using flow cytometry and fluorescent microscopy and the effect on invasion was analyzed using an invasion assay. CDAK was injected intravenously into tumor-bearing athymic nude mice in vivo experiment.ResultsCDAK showed cytotoxic activity in MCF-7 and MDA-MB-231 cells, whereas HUVEC and HFF were less sensitive to the peptides. CDAK induced apoptosis, reduced mitochondrial membrane potential, promoted Caspase-3, and inhibited Bcl-2 expression in the two breast cancer cell lines. In addition, CDAK inhibited proliferation of cancer cell through S phase arrest, and own selective affinity with MCF-7 and MDA-MB-231cells, inhibited the invasion of MDA-MB-231 cells. In vivo, CDAK significant inhibited the progression of the tumor and the generation of neovascularization.ConclusionAntimicrobial peptides containing the CisoDGRC (CDAK) motif could efficiently exhibit the antitumor activity for CD13−/αvβ3 + breast cancer cells.

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A New Class of 5-Fluoro-2?-deoxyuridine Prodrugs Conjugated with a Tumor-Homing Cyclic Peptide CNGRC by Ester Linkers: Synthesis, Reactivity, and Tumor-Cell?Selective Cytotoxicity

Abstract: A new class of tumor-targeting 5-FdUrd prodrugs CNF1 and CNF2 were successfully synthesized. These prodrugs targeted a tumor marker APN/CD13 to cause tumor-cell-selective cyctotoxicity due to 5-FdUrd release, the rate of which could be controlled by the structure of ester linker.

Cited by 26 publications

References 31 publications

Tumor Vasculature Targeting Through NGR Peptide-Based Drug Delivery Systems

Tumor Vasculature Targeting Through NGR Peptide-Based Drug Delivery Systems

Peptide Targeting of Platinum Anti-Cancer Drugs

Antitumor Activity of Antimicrobial Peptides Containing CisoDGRC in CD13 Negative Breast Cancer Cells

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