The Experts below are selected from a list of 162 Experts worldwide ranked by ideXlab platform
Rengbiao Mei - One of the best experts on this subject based on the ideXlab platform.
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Maytansine-loaded star-shaped folate-core PLA-TPGS nanoparticles enhancing anticancer activity.
American journal of translational research, 2014Co-Authors: Xiaolong Tang, Hong Dai, Yongxiang Zhu, Ye Tian, Rongbo Zhang, Rengbiao MeiAbstract:The efficient delivery of therapeutic molecule agents into target cells of interest is a critical challenge to broad application of non-viral vector systems. In this research, Maytansine-loaded star-shaped folate-core polylactide-D-α-tocopheryl polyethylene glycol 1000 succinate (FA-PLA-TPGS) block copolymer was applied to be a vector of Maytansine for folate receptor positive (FR(+)) breast cancer therapy. The uptake of Maytansine nanoparticles by SKBR3 cells were observed by fluorescence microscopy and confocal laser scanning microscopy. The cell viability of Maytansine-NPs in SKBR3 cells was assessed according to the changed level of intracellular microtubules and apoptosis-associated proteins. The cytotoxicity of the SKBR3 cells was significantly increased by Maytansine-NPs when compared with control groups. In conclusion, the Maytansine-NPs offer a considerable potential formulation for FR-expressing tumor targeting biotherapy.
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Original Article Maytansine-loaded star-shaped folate-core PLA-TPGS nanoparticles enhancing anticancer activity
2014Co-Authors: Xiaolong Tang, Hong Dai, Yongxiang Zhu, Ye Tian, Rongbo Zhang, Rengbiao MeiAbstract:* Equal contributors. Received July 6, 2014; Accepted August 20, 2014; Epub October 11, 2014; Published October 15, 2014 Abstract: The efficient delivery of therapeutic molecule agents into target cells of interest is a critical challenge to broad application of non-viral vector systems. In this research, Maytansine-loaded star-shaped folate-core polylactide-D-α-tocopheryl polyethylene glycol 1000 succinate (FA-PLA-TPGS) block copolymer was applied to be a vector of Maytansine for folate receptor positive (FR + ) breast cancer therapy. The uptake of Maytansine nanoparti- cles by SKBR3 cells were observed by fluorescence microscopy and confocal laser scanning microscopy. The cell vi - ability of Maytansine-NPs in SKBR3 cells was assessed according to the changed level of intracellular microtubules and apoptosis-associated proteins. The cytotoxicity of the SKBR3 cells was significantly increased by Maytansine- NPs when compared with control groups. In conclusion, the Maytansine-NPs offer a considerable potential formula- tion for FR-expressing tumor targeting biotherapy.
Kenneth K. Chan - One of the best experts on this subject based on the ideXlab platform.
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metabolism studies of the anti tumor agent Maytansine and its analog ansamitocin p 3 using liquid chromatography tandem mass spectrometry
Journal of Mass Spectrometry, 2005Co-Authors: Zhongfa Liu, Heinz G. Floss, John M. Cassady, Kenneth K. ChanAbstract:Maytansine, a potent clinically evaluated plant-derived anti-tumor drug, and its microbial counterpart, ansamitocin P-3, showed a substantially higher cytoxicity than many other anti-tumor drugs. Owing to a shortage of material and lack of sufficiently sensitive analytical methods at the time, no metabolism studies were apparently carried out in conjunction with the initial preclinical and clinical studies on Maytansine, but some products of decomposition during the period of storage of the formulated drug were reported. In the current study, the in vitro metabolism of Maytansine and ansamitocin P-3 was studied after incubation with rat and human liver microsomes in the presence of NADPH, and with rat and human plasma and whole blood, using liquid chromatography/multi-stage mass spectrometry. Unchanged ansamitocin P-3 and 11 metabolites and unchanged Maytansine and seven metabolites were profiled and the structures of some metabolites were tentatively assigned based on their multi-stage electrospray ion-trap mass fragmentation data and in some cases accurate mass measurement. The major pathway of ansamitocin P-3 metabolism in human liver microsomes appears to be demethylation at C-10. Oxidation and sequential oxidation/demethylation also occurred, although to a lesser extent. However, the major pathway of Maytansine metabolism in human liver microsomes is N-demethylation of the methylamide of the ester moiety. Several minor pathways including O/N-demethylation, oxidation and hydrolysis of the ester bond were also observed. There were no differences in Maytansine metabolism between rat and human liver microsomes; however, the rate of metabolism of ansamitocin P-3 was different in rat and human liver microsomes. About 20% of ansamitocin P-3 was converted to its metabolites in rat liver microsomes and about 70% in human liver microsomes under the same conditions. Additionally, 10-O-demethylated ansamitocin P-3 was also detected in the urine after i.v. bolus administration of ansamitocin P-3 to Sprague-Dawley male rats. No metabolites were detected following incubation of Maytansine and ansamitocin P-3 with human and rat whole blood and plasma.
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Metabolism studies of the anti‐tumor agent Maytansine and its analog ansamitocin P‐3 using liquid chromatography/tandem mass spectrometry
Journal of mass spectrometry : JMS, 2005Co-Authors: Zhongfa Liu, Heinz G. Floss, John M. Cassady, Kenneth K. ChanAbstract:Maytansine, a potent clinically evaluated plant-derived anti-tumor drug, and its microbial counterpart, ansamitocin P-3, showed a substantially higher cytoxicity than many other anti-tumor drugs. Owing to a shortage of material and lack of sufficiently sensitive analytical methods at the time, no metabolism studies were apparently carried out in conjunction with the initial preclinical and clinical studies on Maytansine, but some products of decomposition during the period of storage of the formulated drug were reported. In the current study, the in vitro metabolism of Maytansine and ansamitocin P-3 was studied after incubation with rat and human liver microsomes in the presence of NADPH, and with rat and human plasma and whole blood, using liquid chromatography/multi-stage mass spectrometry. Unchanged ansamitocin P-3 and 11 metabolites and unchanged Maytansine and seven metabolites were profiled and the structures of some metabolites were tentatively assigned based on their multi-stage electrospray ion-trap mass fragmentation data and in some cases accurate mass measurement. The major pathway of ansamitocin P-3 metabolism in human liver microsomes appears to be demethylation at C-10. Oxidation and sequential oxidation/demethylation also occurred, although to a lesser extent. However, the major pathway of Maytansine metabolism in human liver microsomes is N-demethylation of the methylamide of the ester moiety. Several minor pathways including O/N-demethylation, oxidation and hydrolysis of the ester bond were also observed. There were no differences in Maytansine metabolism between rat and human liver microsomes; however, the rate of metabolism of ansamitocin P-3 was different in rat and human liver microsomes. About 20% of ansamitocin P-3 was converted to its metabolites in rat liver microsomes and about 70% in human liver microsomes under the same conditions. Additionally, 10-O-demethylated ansamitocin P-3 was also detected in the urine after i.v. bolus administration of ansamitocin P-3 to Sprague-Dawley male rats. No metabolites were detected following incubation of Maytansine and ansamitocin P-3 with human and rat whole blood and plasma.
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Recent developments in the maytansinoid antitumor agents.
Chemical & pharmaceutical bulletin, 2004Co-Authors: John M. Cassady, Heinz G. Floss, Kenneth K. Chan, Eckhard LeistnerAbstract:Maytansine and its congeners have been isolated from higher plants, mosses and from an Actinomycete, Actinosynnema pretiosum. Many of these compounds are antitumor agents of extraordinary potency, yet phase II clinical trials with Maytansine proved disappointing. The chemistry and biology of maytansinoids has been reviewed repeatedly in the late 1970s and early 1980s; the present review covers new developments in this field during the last two decades. These include the use of maytansinoids as "warheads" in tumor-specific antibodies, preliminary metabolism studies, investigations of their biosynthesis at the biochemical and genetic level, and ecological issues related to the occurrence of such typical microbial metabolites in higher plants.
Xiaolong Tang - One of the best experts on this subject based on the ideXlab platform.
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Maytansine-loaded star-shaped folate-core PLA-TPGS nanoparticles enhancing anticancer activity.
American journal of translational research, 2014Co-Authors: Xiaolong Tang, Hong Dai, Yongxiang Zhu, Ye Tian, Rongbo Zhang, Rengbiao MeiAbstract:The efficient delivery of therapeutic molecule agents into target cells of interest is a critical challenge to broad application of non-viral vector systems. In this research, Maytansine-loaded star-shaped folate-core polylactide-D-α-tocopheryl polyethylene glycol 1000 succinate (FA-PLA-TPGS) block copolymer was applied to be a vector of Maytansine for folate receptor positive (FR(+)) breast cancer therapy. The uptake of Maytansine nanoparticles by SKBR3 cells were observed by fluorescence microscopy and confocal laser scanning microscopy. The cell viability of Maytansine-NPs in SKBR3 cells was assessed according to the changed level of intracellular microtubules and apoptosis-associated proteins. The cytotoxicity of the SKBR3 cells was significantly increased by Maytansine-NPs when compared with control groups. In conclusion, the Maytansine-NPs offer a considerable potential formulation for FR-expressing tumor targeting biotherapy.
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Original Article Maytansine-loaded star-shaped folate-core PLA-TPGS nanoparticles enhancing anticancer activity
2014Co-Authors: Xiaolong Tang, Hong Dai, Yongxiang Zhu, Ye Tian, Rongbo Zhang, Rengbiao MeiAbstract:* Equal contributors. Received July 6, 2014; Accepted August 20, 2014; Epub October 11, 2014; Published October 15, 2014 Abstract: The efficient delivery of therapeutic molecule agents into target cells of interest is a critical challenge to broad application of non-viral vector systems. In this research, Maytansine-loaded star-shaped folate-core polylactide-D-α-tocopheryl polyethylene glycol 1000 succinate (FA-PLA-TPGS) block copolymer was applied to be a vector of Maytansine for folate receptor positive (FR + ) breast cancer therapy. The uptake of Maytansine nanoparti- cles by SKBR3 cells were observed by fluorescence microscopy and confocal laser scanning microscopy. The cell vi - ability of Maytansine-NPs in SKBR3 cells was assessed according to the changed level of intracellular microtubules and apoptosis-associated proteins. The cytotoxicity of the SKBR3 cells was significantly increased by Maytansine- NPs when compared with control groups. In conclusion, the Maytansine-NPs offer a considerable potential formula- tion for FR-expressing tumor targeting biotherapy.
Michael Spiteller - One of the best experts on this subject based on the ideXlab platform.
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Chemical crosstalk between plants and microorganisms: Camptothecin and Maytansine as an example
2020Co-Authors: Michael SpitellerAbstract:Backgroud: Studies on microbe-host interactions in plant aimed at understanding the role of these associations and their utility in pharmaceutical and agricultural sectors are gaining impetus. Several recent studies have lent evidence to the fact that certain so-called “plant metabolites” are actually biosynthesized by associated endophytic microorganisms. Aims: We wanted to elucidate the biosynthesis of the important anticancer drug Maytansine in Celastraceae plants in order to elucidate its actual producer(s), which has been an open question since its discovery in the 1970s. Results: We showed that Maytansine is actually a biosynthetic product of root-associated endophytic bacterial community in Putterlickia verrucosa and Putterlickia retrospinosa plants. This interesting outcome provided the scientific basis to investigate the actual producer(s) responsible for Maytansine biosynthesis in Maytenus plants. Endophytic communities harboring different tissues of Maytenus serrata originating from Cameroon were investigated using a combination of bioanalytical tools such as HPLC-HRMSn and MALDI-MSI, and targeted genome mining techniques to elucidate the source and sites of Maytansine biosynthesis. We proved that the biosynthesis of Maytansine in M. serrata is shared between the endophytic bacterial community colonizing the stem and the host plant containing non-culturable cryptic endophytes. Conclusion: Our work demonstrates that Maytansine is biosynthesized in M. serrata only when the host plant joins forces with its selected and very eco-specific endophytic bacterial community.
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Spatial profiling of Maytansine during the germination process of Maytenus senegalensis seeds.
Fitoterapia, 2017Co-Authors: Dennis Eckelmann, Souvik Kusari, Michael SpitellerAbstract:The ecological role of Maytansine, an important antineoplastic and antimicrobial compound with high cytotoxicity, particularly as a chemical defense compound has remained elusive since its discovery in the 1970s in Maytenus and Putterlickia plants. In the present study, we have used MALDI-imaging-HRMS to visualize the occurrence as well as spatial and temporal distribution of Maytansine in a Maytenus senegalensis plant, seeds obtained from the mother plant during seeding stage, through the germination of the seeds, and finally up to the establishment of seedlings (or daughter plants). Although the mother plant was devoid of Maytansine, the bioactive compound was found to be distributed in the cotyledons and the endosperm of the seeds with an augmented accretion towards the seed coat. Furthermore, Maytansine was always detected in the emerging seedlings, particularly the cortex encompassing the radicle, hypocotyl, and epicotyl. The typical pattern of accumulation of Maytansine not only in the seeds but also during germination provides a proof-of-concept that M. senegalensis is ecologically primed to trigger the production of Maytansine in vulnerable tissues such as seeds during plant reproduction. By utilizing Maytansine as chemical defense compound against predators and/or pathogens, the plant can ensure viability of the seeds and successful germination, thus leading to the next generation of daughter plants.
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Occurrence and spatial distribution of maytansinoids in Putterlickia pyracantha, an unexplored resource of anticancer compounds.
Fitoterapia, 2016Co-Authors: Dennis Eckelmann, Souvik Kusari, Michael SpitellerAbstract:Maytansinoids possess remarkable antibiotic activities along with high cytotoxicity, many of which are currently used (or in clinical trials) in the treatment of breast cancer. Celastraceous plants and their associated microorganisms serve as an important resource of maytansinoids. Here, we report the occurrence and structural elucidation of several maytansinoids in Putterlickia pyracantha plants bioprospected in South Africa. In addition to Maytansine, which is already known to be present in this species, we show the presence of maytanprine, maytanbutine, maytanvaline, normaytancyprine and an abundant Maytansine precursor in different tissues using high-resolution mass spectrometry. Furthermore, we identified two new hydroxylated maytansinoids by HRMS(2) analyses. We also employed MALDI-imaging-HRMS to study the spatial distribution and localization of the maytansinoids within the different plant tissues. On the one hand, the fragmentation pathways of the maytansinoids we report herein using HRMS(n) will allow quick identification of these compounds in the future without isolating from the natural resources. On the other hand, MALDI-imaging-HRMS revealed insights into the plausible ecological roles and biosynthetic pathways of these compounds in P. pyracantha plants.
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Cross-species biosynthesis of Maytansine in Maytenus serrata
RSC Advances, 2016Co-Authors: Parijat Kusari, Dennis Eckelmann, Souvik Kusari, Sebastian Zühlke, Oliver Kayser, Michael SpitellerAbstract:Endophytic bacterial communities harboring different tissues of Maytenus serrata originating from Cameroon were investigated using targeted genome mining techniques coupled to bioanalytical approaches to elucidate the source of Maytansine biosynthesis. It was revealed that the host plant, along with its cryptic endophytic microflora, produces the biosynthetically unique core structural moiety 3-amino-5-hydroxybenzoic acid (AHBA) that serves as the unique starter unit for Maytansine biosynthesis. However, the biosynthetic step of halogenase-mediated incorporation of chlorine, which is missing in the host plant, is accomplished by the culturable stem endophytic bacterial community. Our results provide new insights into plant-endophyte communication for the biosynthesis of Maytansine.
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Endophytes Are Hidden Producers of Maytansine in Putterlickia Roots
2015Co-Authors: Souvik Kusari, Parijat Kusari, Sebastian Gottfried, Kathrin Louven, Ute Hentschel, Oliver Kayser, Marc Lamshöft, Sebastian Zühlke, Michael SpitellerAbstract:Several recent studies have lent evidence to the fact that certain so-called plant metabolites are actually biosynthesized by associated microorganisms. In this work, we show that the original source organism(s) responsible for the biosynthesis of the important anticancer and cytotoxic compound Maytansine is the endophytic bacterial community harbored specifically within the roots of Putterlickia verrucosa and P. retrospinosa plants. Evaluation of the root endophytic community by chemical characterization of their fermentation products using HPLC-HRMSn, along with a selective microbiological assay using the Maytansine-sensitive type strain Hamigera avellanea revealed the endophytic production of Maytansine. This was further confirmed by the presence of AHBA synthase genes in the root endophytic communities. Finally, MALDI-imaging-HRMS was used to demonstrate that Maytansine produced by the endophytes is typically accumulated mainly in the root cortex of both plants. Our study, thus, reveals that Maytansine is actually a biosynthetic product of root-associated endophytic microorganisms. The knowledge gained from this study provides fundamental insights on the biosynthesis of so-called plant metabolites by endophytes residing in distinct ecological niches
Manu Lopus - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic Discovery Maytansinoid-Antibody Conjugates In Suppressing Microtubule Dynamic Ins
2016Co-Authors: Emin Oroudjev, Manu Lopus, Leslie Wilson, Yelena Kovtun, Charlene Audet, Hans Erickson, Ravi Chari, Mary Ann JAbstract:Maytansine and its analogues (maytansinoids) are po noid e sho es inh le ant the fr edium ration tapha h con le dyn tratio bolit icrotu macrolid (4, 5). Ma that bin Similar t microtub maytans in cells t In hum therapeu effects o powerfu valuable drug de maytans studies i oid con-ctor re-showed oreover, tansine, tumors-MCC-linker
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Antibody-DM1 conjugates as cancer therapeutics.
Cancer letters, 2011Co-Authors: Manu LopusAbstract:Synthetic derivatives of the microtubule-targeted agent Maytansine, commonly known as drug maytansinoids or DMs, are emerging as potential cancer therapeutics. DM1 is an antibody-conjugatable maytansinoid that was developed to overcome systemic toxicity associated with Maytansine and to enhance tumor-specific delivery. Antibody-DM1 conjugates showed promising results in preclinical and clinical evaluations. However, the molecular mechanism of the drug component DM1 was largely unknown. Recently, researchers have examined the mechanism of DM1 at molecular and cellular levels. According to their findings, DM1 binds at the tips of microtubules and suppresses the dynamicity of microtubules. The antibody-DM1 conjugate cleaves inside cells and releases the active drug in a time-dependent manner. The suppression of microtubule dynamics by DM1 induces mitotic arrest and cell death.
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Maytansine and Cellular Metabolites of Antibody-Maytansinoid Conjugates Strongly Suppress Microtubule Dynamics by Binding to Microtubules
Molecular cancer therapeutics, 2010Co-Authors: Manu Lopus, Emin Oroudjev, Leslie Wilson, Sharon D. Wilhelm, Wayne C. Widdison, Ravi V. J. Chari, Mary Ann JordanAbstract:Maytansine is a potent microtubule-targeted compound that induces mitotic arrest and kills tumor cells at subnanomolar concentrations. However, its side effects and lack of tumor specificity have prevented successful clinical use. Recently, antibody-conjugated Maytansine derivatives have been developed to overcome these drawbacks. Several conjugates show promising early clinical results. We evaluated the effects on microtubule polymerization and dynamic instability of Maytansine and two cellular metabolites (S-methyl-DM1 and S-methyl-DM4) of antibody-maytansinoid conjugates that are potent in cells at picomolar levels and that are active in tumor-bearing mice. Although S-methyl-DM1 and S-methyl-DM4 inhibited polymerization more weakly than Maytansine, at 100 nmol/L they suppressed dynamic instability more strongly than Maytansine (by 84% and 73%, respectively, compared with 45% for Maytansine). However, unlike Maytansine, S-methyl-DM1 and S-methyl-DM4 induced tubulin aggregates detectable by electron microscopy at concentrations ≥2 μmol/L, with S-methyl-DM4 showing more extensive aggregate formation than S-methyl-DM1. Both Maytansine and S-methyl-DM1 bound to tubulin with similar K(D) values (0.86 ± 0.2 and 0.93 ± 0.2 μmol/L, respectively). Tritiated S-methyl-DM1 bound to 37 high-affinity sites per microtubule (K(D), 0.1 ± 0.05 μmol/L). Thus, S-methyl-DM1 binds to high-affinity sites on microtubules 20-fold more strongly than vinblastine. The high-affinity binding is likely at microtubule ends and is responsible for suppression of microtubule dynamic instability. Also, at higher concentrations, S-methyl-DM1 showed low-affinity binding either to a larger number of sites on microtubules or to sedimentable tubulin aggregates. Overall, the Maytansine derivatives that result from cellular metabolism of the antibody conjugates are themselves potent microtubule poisons, interacting with microtubules as effectively as or more effectively than the parent molecule.
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Maytansine derivatives and metabolites of antibody-maytansinoid conjugates inhibit microtubule polymerization and strongly suppress microtubule dynamics
Cancer Research, 2008Co-Authors: Manu Lopus, Emin Oroudjev, Leslie Wilson, Wayne C. Widdison, Ravi V. J. Chari, Sharon Wilhelm, Mary Ann JordanAbstract:1406 Maytansine is a potent microtubule-targeted compound that induces mitotic arrest and kills tumor cells at sub-nanomolar concentrations. Maytansine analogs, DM1 and DM4 (collectively DMx), were conjugated to monoclonal antibodies that selectively bind to antigens expressed on the surface of cancer cells. These antibody-maytansinoid conjugates displayed antigen-specific cytotoxicity in vitro and potent anti-tumor activity in vivo. Several antibody-DM1 and antibody-DM4 conjugates are currently undergoing clinical evaluation. We have investigated the ability of maytansinoid derivatives and metabolites derived from antibody-maytansinoid conjugates to inhibit microtubule polymerization and to suppress dynamic instability of microtubules assembled from bovine brain tubulin. In addition, we examined the stoichiometry of binding to microtubules and dissociation constant (Kd) of one thioether derivative, S-methyl DM1 (DM1-Me). DM1-Me inhibited the assembly of tubulin in a concentration-dependent manner with an IC50 of 4 ± 0.1 µM. Using 3[H]DM1-Me, we found that this compound binds to microtubules in a concentration-dependent fashion with a stoichiometry of 33 molecules of DM1-Me bound per microtubule at 0.1 µM. The dissociation constant (Kd) for the binding of DM1-Me to microtubules is found to be 0.4 µM, indicating strong binding of the maytansinoid to microtubules. The effects of DM1-Me, DM4-Me (S-methyl DM4) and several major target cell-derived metabolites of antibody-DM1 and antibody-DM4 conjugates on microtubule dynamic instability were studied by real-time imaging of axoneme-seeded microtubules assembled from bovine brain tubulin using differential interference contrast microscopy. The maytansinoids (0.1 µM) strongly suppressed microtubule dynamics. For instance, DM1-Me decreased the growing and shortening rates of microtubules by 24% and 67%, respectively. In addition, DM1-Me suppressed catastrophe and rescue frequencies by 90 % and 44 %, respectively. The overall dynamicity of microtubules was decreased by 87% by DM1-Me, and by 74% by DM4-Me. DM1-Me, DM4-Me and several of the target cell-derived metabolites were more potent than the parent compound Maytansine, which suppressed the dynamicity of microtubules by 52%. These data, along with the previous finding of the low systemic toxicity and favorable pharmacokinetic behavior of antibody-maytansinoid conjugates bolsters the potential of DMx conjugates in cancer chemotherapy. Supported by grants NIH CA 57291 and NS13560.