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Gábor Mező - One of the best experts on this subject based on the ideXlab platform.
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Improved In Vivo Anti-Tumor and Anti-Metastatic Effect of GnRH-III-Daunorubicin Analogs on Colorectal and Breast Carcinoma Bearing Mice.
International journal of molecular sciences, 2019Co-Authors: Ivan Ranđelović, Gábor Mező, Sabine Schuster, Bence Kapuvári, Gianluca Fossati, Christian Steinkühler, József TóváriAbstract:Among various Homing Devices, gonadotropin-releasing hormone-III (GnRH-III) peptide represents a suitable targeting moiety for drug delivery systems. The anti-tumor activity of the previously developed GnRH-III-[4Lys(Bu),8Lys(Dau=Aoa)] conjugate and the novel synthesized GnRH-III-[2ΔHis,3d-Tic,4Lys(Bu),8Lys(Dau=Aoa)] conjugate, containing the anti-cancer drug daunorubicin, were evaluated. Here, we demonstrate that both GnRH-III-Dau conjugates possess an efficient growth inhibitory effect on more than 20 cancer cell lines, whereby the biological activity is strongly connected to the expression of gonadotropin-releasing hormone receptors (GnRH-R). The novel conjugate showed a higher in vitro anti-proliferative activity and a higher uptake capacity. Moreover, the treatment with GnRH-III-Dau conjugates cause a significant in vivo tumor growth and metastases inhibitory effect in three different orthotopic models, including 4T1 mice and MDA-MB-231 human breast carcinoma, as well as HT-29 human colorectal cancer bearing BALB/s and SCID mice, while toxic side-effects were substantially reduced in comparison to the treatment with the free drug. These findings illustrate that our novel lead compound is a highly promising candidate for targeted tumor therapy in both colon cancer and metastatic breast cancer.
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Development of novel cyclic NGR peptide-daunomycin conjugates with dual targeting property.
Beilstein journal of organic chemistry, 2018Co-Authors: Andrea Angelo Pierluigi Tripodi, Szilárd Tóth, Kata Nóra Enyedi, Gitta Schlosser, Gergely Szakács, Gábor MezőAbstract:Cyclic NGR peptides as Homing Devices are good candidates for the development of drug conjugates for targeted tumor therapy. In our previous study we reported that the Dau=Aoa-GFLGK(c[KNGRE]-GG-)-NH2 conjugate has a significant antitumor activity against both CD13+ HT-1080 human fibrosarcoma and CD13- but integrin positive HT-29 human colon adenocarcinoma cells. However, it seems that the free e-amino group of Lys in the cycle is not necessary for the biological activity. Therefore, we developed novel cyclic NGR peptide-daunomycin conjugates in which Lys was replaced by different amino acids (Ala, Leu, Nle, Pro, Ser). The exchange of the Lys residue in the cycle simplified the cyclization step and resulted in a higher yield. The new conjugates showed lower chemostability against deamidation of Asn than the control compound, thus they had lower selectivity to CD13+ cells. However, the cellular uptake and cytotoxic effect of Dau=Aoa-GFLGK(c[NleNGRE]-GG-)-NH2 was higher in comparison to the control especially on HT-29 cells. Therefore, this conjugate is more suitable for drug targeting with dual targeting property.
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Development of novel cyclic NGR peptide–daunomycin conjugates with dual targeting property
Beilstein-Institut, 2018Co-Authors: Andrea Angelo Pierluigi Tripodi, Szilárd Tóth, Kata Nóra Enyedi, Gitta Schlosser, Gergely Szakács, Gábor MezőAbstract:Cyclic NGR peptides as Homing Devices are good candidates for the development of drug conjugates for targeted tumor therapy. In our previous study we reported that the Dau=Aoa-GFLGK(c[KNGRE]-GG-)-NH2 conjugate has a significant antitumor activity against both CD13+ HT-1080 human fibrosarcoma and CD13− but integrin positive HT-29 human colon adenocarcinoma cells. However, it seems that the free ε-amino group of Lys in the cycle is not necessary for the biological activity. Therefore, we developed novel cyclic NGR peptide–daunomycin conjugates in which Lys was replaced by different amino acids (Ala, Leu, Nle, Pro, Ser). The exchange of the Lys residue in the cycle simplified the cyclization step and resulted in a higher yield. The new conjugates showed lower chemostability against deamidation of Asn than the control compound, thus they had lower selectivity to CD13+ cells. However, the cellular uptake and cytotoxic effect of Dau=Aoa-GFLGK(c[NleNGRE]-GG-)-NH2 was higher in comparison to the control especially on HT-29 cells. Therefore, this conjugate is more suitable for drug targeting with dual targeting property
Norbert Sewald - One of the best experts on this subject based on the ideXlab platform.
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Novel unit B cryptophycin analogues as payloads for targeted therapy.
Beilstein journal of organic chemistry, 2018Co-Authors: Eduard Figueras, Adina Borbély, Mohamed F. Ismail, Marcel Frese, Norbert SewaldAbstract:Cryptophycins are naturally occurring cytotoxins with great potential for chemotherapy. Since targeted therapy provides new perspectives for treatment of cancer, new potent analogues of cytotoxic agents containing functional groups for conjugation to Homing Devices are required. We describe the design, synthesis and biological evaluation of three new unit B cryptophycin analogues. The O-methyl group of the unit B D-tyrosine analogue was replaced by an O-(allyloxyethyl) moiety, an O-(hydroxyethyl) group, or an O-(((azidoethoxy)ethoxy)ethoyxethyl) substituent. While the former two maintain cytotoxicity in the subnanomolar range, the attachment of the triethylene glycol spacer with a terminal azide results in a complete loss of activity. Docking studies of the novel cryptophycin analogues to β-tubulin provided a rationale for the observed cytotoxicities.
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Conjugates of Modified Cryptophycins and RGD-Peptides Enter Target Cells by Endocytosis
2016Co-Authors: Markus Nahrwold, Christine Weiß, Tobias Bogner, Felix Mertink, Jens Conradi, Benedikt Sammet, Ralf Palmisano, Soledad Royo Gracia, Thomas Preuße, Norbert SewaldAbstract:Tumor targeting anticancer drug conjugates that contain a tumor recognition motif (Homing device) are of high current relevance. Cryptophycins, naturally occurring cytotoxic cyclo-depsipeptides, have been modified by total synthesis to provide analogues suitable for conjugation to peptide-based Homing Devices. An array of functionalized β2-amino acids was synthesized and incorporated into cryptophycins. All analogues proved to be highly active in the cytotoxicity assay using the human cervix carcinoma cell line KB-3-1 and its multidrug-resistant subclone KB-V1. Conformational analysis of cryptophycin-52 and two synthetic analogues was performed by NMR and MD methods to obtain information on the influence of the unit C configuration on the overall conformation. An azide-functionalized cryptophycin was connected by CuAAC to an alkyne-containing fluorescently labeled cyclic RGD-peptide as the Homing device for internalization studies. Confocal fluorescence microscopy proved integrin-mediated internalization by endocytosis and final lysosomal localization of the cryptophycin prodrug
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Conjugates of modified cryptophycins and RGD-peptides enter target cells by endocytosis.
Journal of medicinal chemistry, 2013Co-Authors: Markus Nahrwold, Christine Weiß, Tobias Bogner, Felix Mertink, Jens Conradi, Benedikt Sammet, Ralf Palmisano, Soledad Royo Gracia, Thomas Preuße, Norbert SewaldAbstract:Tumor targeting anticancer drug conjugates that contain a tumor recognition motif (Homing device) are of high current relevance. Cryptophycins, naturally occurring cytotoxic cyclo-depsipeptides, have been modified by total synthesis to provide analogues suitable for conjugation to peptide-based Homing Devices. An array of functionalized β(2)-amino acids was synthesized and incorporated into cryptophycins. All analogues proved to be highly active in the cytotoxicity assay using the human cervix carcinoma cell line KB-3-1 and its multidrug-resistant subclone KB-V1. Conformational analysis of cryptophycin-52 and two synthetic analogues was performed by NMR and MD methods to obtain information on the influence of the unit C configuration on the overall conformation. An azide-functionalized cryptophycin was connected by CuAAC to an alkyne-containing fluorescently labeled cyclic RGD-peptide as the Homing device for internalization studies. Confocal fluorescence microscopy proved integrin-mediated internalization by endocytosis and final lysosomal localization of the cryptophycin prodrug.
József Tóvári - One of the best experts on this subject based on the ideXlab platform.
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In Vivo Tumor Growth Inhibition and Antiangiogenic Effect of Cyclic NGR Peptide-Daunorubicin Conjugates Developed for Targeted Drug Delivery
Pathology & Oncology Research, 2019Co-Authors: Andrea Angelo Pierluigi Tripodi, Ivan Ranđelović, Beáta Biri-kovács, Bálint Szeder, Gábor Mező, József TóváriAbstract:Among various Homing Devices, peptides containing the NGR tripeptide sequence represent a promising approach to selectively recognize CD13 receptor isoforms on the surface of tumor cells. They have been successfully used for the delivery of various chemotherapeutic drugs to tumor vessels. Here, we report on the murine plasma stability, in vitro and in vivo antitumor activity of our recently described bioconjugates containing daunorubicin as payload. Furthermore, CD13 expression of KS Kaposi’s Sarcoma cell line and HT-29 human colon carcinoma cell line was investigated. Flow cytometry studies confirm the fast cellular uptake resulting in the rapid delivery of the active metabolite Dau = Aoa-Gly-OH to tumor cells. The increased in vitro antitumor effect might be explained by the faster rearrangement from NGR to iso DGR in case of conjugate 2 (Dau = Aoa-GFLGK(c[NleNGRE]-GG)-NH_2) in comparison with conjugate 1 (Dau = Aoa-GFLGK(c[KNGRE]-GG)-NH_2). Nevertheless, results indicated that both conjugates showed significant effect on inhibition of proliferation in the primary tumor and also on blood vessel formation making them a potential candidate for targeting angiogenesis processes in tumors where CD13 and integrins are involved.
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Improved In Vivo Anti-Tumor and Anti-Metastatic Effect of GnRH-III-Daunorubicin Analogs on Colorectal and Breast Carcinoma Bearing Mice.
International journal of molecular sciences, 2019Co-Authors: Ivan Ranđelović, Gábor Mező, Sabine Schuster, Bence Kapuvári, Gianluca Fossati, Christian Steinkühler, József TóváriAbstract:Among various Homing Devices, gonadotropin-releasing hormone-III (GnRH-III) peptide represents a suitable targeting moiety for drug delivery systems. The anti-tumor activity of the previously developed GnRH-III-[4Lys(Bu),8Lys(Dau=Aoa)] conjugate and the novel synthesized GnRH-III-[2ΔHis,3d-Tic,4Lys(Bu),8Lys(Dau=Aoa)] conjugate, containing the anti-cancer drug daunorubicin, were evaluated. Here, we demonstrate that both GnRH-III-Dau conjugates possess an efficient growth inhibitory effect on more than 20 cancer cell lines, whereby the biological activity is strongly connected to the expression of gonadotropin-releasing hormone receptors (GnRH-R). The novel conjugate showed a higher in vitro anti-proliferative activity and a higher uptake capacity. Moreover, the treatment with GnRH-III-Dau conjugates cause a significant in vivo tumor growth and metastases inhibitory effect in three different orthotopic models, including 4T1 mice and MDA-MB-231 human breast carcinoma, as well as HT-29 human colorectal cancer bearing BALB/s and SCID mice, while toxic side-effects were substantially reduced in comparison to the treatment with the free drug. These findings illustrate that our novel lead compound is a highly promising candidate for targeted tumor therapy in both colon cancer and metastatic breast cancer.
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Improved in vivo antitumor effect of a daunorubicin - GnRH-III bioconjugate modified by apoptosis inducing agent butyric acid on colorectal carcinoma bearing mice
Investigational New Drugs, 2016Co-Authors: Bence Kapuvári, József Tóvári, Rózsa Hegedüs, Ákos Schulcz, Marilena Manea, Alexandra Gacs, Borbála Vincze, Gábor MezőAbstract:Compared to classical chemotherapy, peptide-based drug targeting is a promising therapeutic approach for cancer, which can provide increased selectivity and decreased side effects to anticancer drugs. Among various Homing Devices, gonadotropin-releasing hormone-III (GnRH-III) peptide represents a suitable targeting moiety, in particular in the treatment of hormone independent tumors that highly express GnRH receptors (e.g. colon carcinoma). We have previously shown that GnRH-III[^4Lys(Ac),^8Lys(Dau = Aoa)] bioconjugate, in which daunorubicin was attached via oxime linkage to the ^8Lys of a GnRH-III derivative, exerted significant in vivo antitumor effect on subcutaneously developed HT-29 colon tumor. In contrast, results of the study reported here indicated that this compound was not active on an orthotopically developed tumor. However, if Lys in position 4 was acylated with butyric acid instead of acetic acid, the resulting bioconjugate GnRH-III[^4Lys(Bu),^8Lys(Dau = Aoa)] had significant tumor growth inhibitory effect. Furthermore, it prevented tumor neovascularization, without detectable side effects. Nevertheless, the development of metastases could not be inhibited by the bioconjugate; therefore, its application in combination with a metastasis preventive agent might be necessary in order to achieve complete tumor remission. In spite of this result, the treatment with GnRH-III[^4Lys(Bu),^8Lys(Dau = Aoa)] bioconjugate proved to have significant benefits over the administration of free daunorubicin, which was used at the maximum tolerated dose.
Gert Storm - One of the best experts on this subject based on the ideXlab platform.
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ACTIVE TARGETING WITH PARTICULATE CARRIER SYSTEMS IN THE BLOOD COMPARTMENT
Advanced Drug Delivery Reviews, 1995Co-Authors: Daan J.a. Crommelin, Gerrit L. Scherphof, Gert StormAbstract:Abstract This review deals with active targeting of particulate drug carriers through (1) physico-chemical (e.g., complex formation between a Homing device and a surface exposed molecule at the target site) and (2) physical means. Target sites discussed are restricted to those in the blood circulation. Targets for particulate systems using Homing Devices (physico-chemical approach) are circulating cells and non-cellular material, e.g., red blood cells, T-lymphocytes, B-lymphocytes, and drugs, respectively. Fixed cells and non-cellular material have also been subject of investigation (e.g., endothelial cells and thrombi, respectively). Active targeting in the above areas has been mainly performed with liposomes as carrier systems and monoclonal antibodies or antibody fragments as Homing Devices. Less literature is available on physical targeting approaches in the blood compartment such as targeting through magnetic field gradients, local hyperthermia or artificial embolus formation.
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specific targeting with poly ethylene glycol modified liposomes coupling of Homing Devices to the ends of the polymeric chains combines effective target binding with long circulation times
Biochimica et Biophysica Acta, 1993Co-Authors: Gabriele Blume, Gregor Cevc, M D J A Crommelin, Irma A J M Bakkerwoudenberg, C Kluft, Gert StormAbstract:Abstract One possibility for bringing drugs to their specific targets is to use the drug-laden liposomes that have been made target-specific by the attachment of appropriate proteins. Such ‘directed’ proteoliposomes and most other particles are rapidly removed from the bloodstream, however, by the mononuclear phagocytes in the liver and spleen. This causes suboptimal drug accumulation at the target site. Coating the liposome surface with poly(ethylene glycol) (PEG) may prolong the circulation time of liposomes. Using plasminogen as a Homing device we have shown that the PEG-modified liposomes with such a Homing device coupled to the ends of the long PEG chains may combine long vesicle circulation times in the blood with high target binding capability. The PEG-coated proteoliposomes with Homing Devices attached at the very bilayer surface, on the contrary, are longlived but have only little or no capability to bind to their targets.
Andrea Angelo Pierluigi Tripodi - One of the best experts on this subject based on the ideXlab platform.
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In Vivo Tumor Growth Inhibition and Antiangiogenic Effect of Cyclic NGR Peptide-Daunorubicin Conjugates Developed for Targeted Drug Delivery
Pathology & Oncology Research, 2019Co-Authors: Andrea Angelo Pierluigi Tripodi, Ivan Ranđelović, Beáta Biri-kovács, Bálint Szeder, Gábor Mező, József TóváriAbstract:Among various Homing Devices, peptides containing the NGR tripeptide sequence represent a promising approach to selectively recognize CD13 receptor isoforms on the surface of tumor cells. They have been successfully used for the delivery of various chemotherapeutic drugs to tumor vessels. Here, we report on the murine plasma stability, in vitro and in vivo antitumor activity of our recently described bioconjugates containing daunorubicin as payload. Furthermore, CD13 expression of KS Kaposi’s Sarcoma cell line and HT-29 human colon carcinoma cell line was investigated. Flow cytometry studies confirm the fast cellular uptake resulting in the rapid delivery of the active metabolite Dau = Aoa-Gly-OH to tumor cells. The increased in vitro antitumor effect might be explained by the faster rearrangement from NGR to iso DGR in case of conjugate 2 (Dau = Aoa-GFLGK(c[NleNGRE]-GG)-NH_2) in comparison with conjugate 1 (Dau = Aoa-GFLGK(c[KNGRE]-GG)-NH_2). Nevertheless, results indicated that both conjugates showed significant effect on inhibition of proliferation in the primary tumor and also on blood vessel formation making them a potential candidate for targeting angiogenesis processes in tumors where CD13 and integrins are involved.
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Development of novel cyclic NGR peptide-daunomycin conjugates with dual targeting property.
Beilstein journal of organic chemistry, 2018Co-Authors: Andrea Angelo Pierluigi Tripodi, Szilárd Tóth, Kata Nóra Enyedi, Gitta Schlosser, Gergely Szakács, Gábor MezőAbstract:Cyclic NGR peptides as Homing Devices are good candidates for the development of drug conjugates for targeted tumor therapy. In our previous study we reported that the Dau=Aoa-GFLGK(c[KNGRE]-GG-)-NH2 conjugate has a significant antitumor activity against both CD13+ HT-1080 human fibrosarcoma and CD13- but integrin positive HT-29 human colon adenocarcinoma cells. However, it seems that the free e-amino group of Lys in the cycle is not necessary for the biological activity. Therefore, we developed novel cyclic NGR peptide-daunomycin conjugates in which Lys was replaced by different amino acids (Ala, Leu, Nle, Pro, Ser). The exchange of the Lys residue in the cycle simplified the cyclization step and resulted in a higher yield. The new conjugates showed lower chemostability against deamidation of Asn than the control compound, thus they had lower selectivity to CD13+ cells. However, the cellular uptake and cytotoxic effect of Dau=Aoa-GFLGK(c[NleNGRE]-GG-)-NH2 was higher in comparison to the control especially on HT-29 cells. Therefore, this conjugate is more suitable for drug targeting with dual targeting property.
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Development of novel cyclic NGR peptide–daunomycin conjugates with dual targeting property
Beilstein-Institut, 2018Co-Authors: Andrea Angelo Pierluigi Tripodi, Szilárd Tóth, Kata Nóra Enyedi, Gitta Schlosser, Gergely Szakács, Gábor MezőAbstract:Cyclic NGR peptides as Homing Devices are good candidates for the development of drug conjugates for targeted tumor therapy. In our previous study we reported that the Dau=Aoa-GFLGK(c[KNGRE]-GG-)-NH2 conjugate has a significant antitumor activity against both CD13+ HT-1080 human fibrosarcoma and CD13− but integrin positive HT-29 human colon adenocarcinoma cells. However, it seems that the free ε-amino group of Lys in the cycle is not necessary for the biological activity. Therefore, we developed novel cyclic NGR peptide–daunomycin conjugates in which Lys was replaced by different amino acids (Ala, Leu, Nle, Pro, Ser). The exchange of the Lys residue in the cycle simplified the cyclization step and resulted in a higher yield. The new conjugates showed lower chemostability against deamidation of Asn than the control compound, thus they had lower selectivity to CD13+ cells. However, the cellular uptake and cytotoxic effect of Dau=Aoa-GFLGK(c[NleNGRE]-GG-)-NH2 was higher in comparison to the control especially on HT-29 cells. Therefore, this conjugate is more suitable for drug targeting with dual targeting property