The Experts below are selected from a list of 13713 Experts worldwide ranked by ideXlab platform
Dario Neri - One of the best experts on this subject based on the ideXlab platform.
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Automated and enhanced extraction of a small molecule-Drug Conjugate using an enzyme-inhibitor interaction based SPME tool followed by direct analysis by ESI-MS
Analytical and Bioanalytical Chemistry, 2019Co-Authors: Sahar Ghiasikhou, Dario Neri, Samuele Cazzamalli, Jörg Scheuermann, Renato ZenobiAbstract:We report a novel, fast, and automatic SPME-based method capable of extracting a small molecule-Drug Conjugate (SMDC) from biological matrices. Our method relies on the extraction of the Drug Conjugate followed by direct elution into an electrospray mass spectrometer (ESI-MS) source for qualitative and quantitative analysis. We designed a tool for extracting the targeting head of a recently synthesized SMDC, which includes acetazolamide (AAZ) as high-affinity ligand specific to carbonic anhydrase IX. Specificity of the extraction was achieved through systematic optimization. The design of the extraction tool is based on noncovalent and reversible interaction between AAZ and CAII that is immobilized on the SPME extraction phase. Using this approach, we showed a 330% rise in extracted AAZ signal intensity compared to a control, which was performed in the absence of CAII. A linear dynamic range from 1.2 to 25 μg/ml was found. The limits of detection (LOD) of extracted AAZ from phosphate-buffered saline (PBS) and human plasma were 0.4 and 1.2 μg/ml, respectively. This with a relative standard deviation of less than 14% ( n = 40) covers the therapeutic range. Graphical abstract
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A small-molecule Drug Conjugate for the treatment of carbonic anhydrase IX expressing tumors
Angewandte Chemie - International Edition, 2014Co-Authors: Nikolaus Krall, Ct Supuran, Goncalo J L Bernardes, Francesca Pretto, Willy Decurtins, Claudiu T Supuran, Dario NeriAbstract:Antibody-Drug Conjugates are a very promising class of new anticancer agents, but the use of small-molecule ligands for the targeted delivery of cytotoxic Drugs into solid tumors is less well established. Here, we describe the first small-molecule Drug Conjugates for the treatment of carbonic anhydrase IX expressing solid tumors. Using ligand-dye Conjugates we demonstrate that such molecules can preferentially accumulate inside antigen-positive lesions, have fast targeting kinetics and good tumor-penetrating properties, and are easily accessible by total synthesis. A disulfide-linked Drug Conjugate with the maytansinoid DM1 as the cytotoxic payload and a derivative of acetazolamide as the targeting ligand exhibited a potent antitumor effect in SKRC52 renal cell carcinoma in vivo. It was furthermore superior to sunitinib and sorafenib, both small-molecule standard-of-care Drugs for the treatment of kidney cancer.
Michael J Ramsey - One of the best experts on this subject based on the ideXlab platform.
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characterization of intact antibody Drug Conjugate variants using microfluidic capillary electrophoresis mass spectrometry
Analytical Chemistry, 2016Co-Authors: Erin A Redman, Jason A Starkey, Scott J Mellors, Michael J RamseyAbstract:In this work, we utilize capillary electrophoresis–mass spectrometry (CE–MS) in an integrated microfluidic platform to analyze an intact, lysine-linked antibody Drug Conjugate (ADC) in order to assess post translational modifications and Drug load variants. The initial charge heterogeneity of the unConjugated IgG-2 monoclonal antibody (mAb) was assessed by separating intact charge variants. Three main charge variants were resolved in the CE dimension. These variants were attributed to pyroglutamic acid formation and decarboxylation on the primary structure of the mAb through characteristic mass shifts and changes in electrophoretic mobility. Additionally, glycoforms of the antibody charge variants were identified in the deconvoluted mass spectra. The observed glycoforms and their distribution compared favorably to a released N-glycan analysis performed on the mAb. After conjugation, the ADC was analyzed using the same microchip CE–MS method. The addition of a Drug load resulted in a decrease in mobility a...
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Characterization of Intact Antibody Drug Conjugate Variants Using Microfluidic Capillary Electrophoresis–Mass Spectrometry
2016Co-Authors: Erin A Redman, Scott J Mellors, Jason A. Starkey, Michael J RamseyAbstract:In this work, we utilize capillary electrophoresis–mass spectrometry (CE–MS) in an integrated microfluidic platform to analyze an intact, lysine-linked antibody Drug Conjugate (ADC) in order to assess post translational modifications and Drug load variants. The initial charge heterogeneity of the unConjugated IgG-2 monoclonal antibody (mAb) was assessed by separating intact charge variants. Three main charge variants were resolved in the CE dimension. These variants were attributed to pyroglutamic acid formation and decarboxylation on the primary structure of the mAb through characteristic mass shifts and changes in electrophoretic mobility. Additionally, glycoforms of the antibody charge variants were identified in the deconvoluted mass spectra. The observed glycoforms and their distribution compared favorably to a released N-glycan analysis performed on the mAb. After conjugation, the ADC was analyzed using the same microchip CE–MS method. The addition of a Drug load resulted in a decrease in mobility and an increase in mass of 3145 Da. Five main species that differed in their respective Drug-to-antibody ratios (DAR) were fully resolved in the CE separation, with each DAR displaying the same variant population observed on the unConjugated mAb. A DAR range of 0–4 was observed with an average of 1.7 Drug loads. The DAR distribution generated from the microfluidic CE–MS data compared favorably to results from infusion-ESI-MS and imaging CE (iCE) analysis of the ADC, techniques commonly used for intact mAb and ADC characterization
Deyue Yan - One of the best experts on this subject based on the ideXlab platform.
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amphiphilic Drug Drug Conjugate for cancer therapy with combination of chemotherapeutic and antiangiogenesis Drugs
Science China-chemistry, 2020Co-Authors: Mo Sun, Xinyuan Zhu, Qiuhui Qian, Leilei Shi, Qunfang Liu, Linzhu Zhou, Jianmin Yue, Deyue YanAbstract:The progression and metastasis of solid tumors strongly rely on the process of forming nascent blood vessels. However, using angiogenesis inhibitors alone does not meet the cancer treatment needs. Herein, we used the amphiphilic Drug-Drug Conjugate (ADDC) strategy to fabricate a new Drug Conjugate with the combination of chemotherapeutic Drug and antiangiogenesis Drug together. With one-step esterification of hydrophilic floxuridine (FUDR) and hydrophobic pseudolaric acid B (PAB), the Conjugate was synthesized. The amphiphilic property of FUDR-PAB Conjugate induced the self-assembly to form nanoparticles in water. From further in vitro and in vivo experiments, this FUDR-PAB Conjugate does not only have a high antitumor effect, but also shows efficient antianiogenesis property. These results offer a promising ADDC strategy for designing Drugs with combination of chemotherapeutic Drug and antiangiogenesis Drug together.
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synergistic combination chemotherapy of camptothecin and floxuridine through self assembly of amphiphilic Drug Drug Conjugate
Bioconjugate Chemistry, 2015Co-Authors: Ping Huang, Xinyuan Zhu, Linzhu Zhou, Yao Wang, Deyue YanAbstract:Combination chemotherapy has been widely applied in cancer treatment; however, the cocktail administration of combination chemotherapy could cause the nonuniform biodistribution of anticancer agents, thus impairing the therapeutic efficacy. In the present study, to address this concern, we proposed a novel strategy of preparing self-assembled nanoparticles from amphiphilic Drug–Drug Conjugate for synergistic combination chemotherapy. The Conjugate was synthesized by two-step esterification of hydrophobic camptothecin (CPT) and hydrophilic floxuridine (FUDR) through a linker compound. Because of its amphiphilic nature, the CPT-FUDR Conjugate self-assembled into stable nanoparticles which could simultaneously release fixed dosage of the two Drugs in cancer cells. In vitro studies demonstrated synergistic anticancer efficacy of the CPT-FUDR nanoparticles including improved cell apoptosis, varied cell cycle arrest, as well as effective inhibition of cancer cell proliferation.
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combination of small molecule proDrug and nanoDrug delivery amphiphilic Drug Drug Conjugate for cancer therapy
Journal of the American Chemical Society, 2014Co-Authors: Ping Huang, Xinyuan Zhu, Dali Wang, Wei Huang, Yongfeng Zhou, Daxiang Cui, Deyue YanAbstract:All Drugs for cancer therapy face several transportation barriers on their tortuous journey to the action sites. To overcome these barriers, an effective Drug delivery system for cancer therapy is imperative. Here, we develop a Drug self-delivery system for cancer therapy, in which anticancer Drugs can be delivered by themselves without any carriers. To demonstrate this unique approach, an amphiphilic Drug–Drug Conjugate (ADDC) has been synthesized from the hydrophilic anticancer Drug irinotecan (Ir) and the hydrophobic anticancer Drug chlorambucil (Cb) via a hydrolyzable ester linkage. The amphiphilic Ir–Cb Conjugate self-assembles into nanoparticles in water and exhibits longer blood retention half-life compared with the free Drugs, which facilitates the accumulation of Drugs in tumor tissues and promotes their cellular uptake. A benefit of the nanoscale characteristics of the Ir–Cb ADDC nanoparticles is that the multiDrug resistance (MDR) of tumor cells can be overcome efficiently. After cellular inter...
Philip M Murphy - One of the best experts on this subject based on the ideXlab platform.
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hematopoietic chimerism and donor specific skin allograft tolerance after non genotoxic cd117 antibody Drug Conjugate conditioning in mhc mismatched allotransplantation
Nature Communications, 2019Co-Authors: Agnieszka Czechowicz, Amelia Scheck, Derrick J Rossi, Philip M MurphyAbstract:Hematopoietic chimerism after allogeneic bone marrow transplantation may establish a state of donor antigen-specific tolerance. However, current allotransplantation protocols involve genotoxic conditioning which has harmful side-effects and predisposes to infection and cancer. Here we describe a non-genotoxic conditioning protocol for fully MHC-mismatched bone marrow allotransplantation in mice involving transient immunosuppression and selective depletion of recipient hematopoietic stem cells with a CD117-antibody-Drug-Conjugate (ADC). This protocol resulted in multilineage, high level (up to 50%), durable, donor-derived hematopoietic chimerism after transplantation of 20 million total bone marrow cells, compared with ≤ 2.1% hematopoietic chimerism from 50 million total bone marrow cells without conditioning. Moreover, long-term survival of bone marrow donor-type but not third party skin allografts is achieved in CD117-ADC-conditioned chimeric mice without chronic immunosuppression. The only observed adverse event is transient elevation of liver enzymes in the first week after conditioning. These results provide proof-of-principle for CD117-ADC as a non−genotoxic, highly-targeted conditioning agent in allotransplantation and tolerance protocols. Transplantation of allogeneic bone marrow helps establish chimerism that may induce tolerance to tissue grafts. Here the authors show that a CD117-antibody-Drug-Conjugate helps precondition the recipients for inducing mixed chimerism and allo-tolerance without clear adverse effects or the need for chronic immune suppression.
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Hematopoietic chimerism and donor-specific skin allograft tolerance after non-genotoxic CD117 antibody-Drug-Conjugate conditioning in MHC-mismatched allotransplantation
Nature Publishing Group, 2019Co-Authors: Agnieszka Czechowicz, Amelia Scheck, Derrick J Rossi, Philip M MurphyAbstract:Transplantation of allogeneic bone marrow helps establish chimerism that may induce tolerance to tissue grafts. Here the authors show that a CD117-antibody-Drug-Conjugate helps precondition the recipients for inducing mixed chimerism and allo-tolerance without clear adverse effects or the need for chronic immune suppression
Erin A Redman - One of the best experts on this subject based on the ideXlab platform.
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characterization of intact antibody Drug Conjugate variants using microfluidic capillary electrophoresis mass spectrometry
Analytical Chemistry, 2016Co-Authors: Erin A Redman, Jason A Starkey, Scott J Mellors, Michael J RamseyAbstract:In this work, we utilize capillary electrophoresis–mass spectrometry (CE–MS) in an integrated microfluidic platform to analyze an intact, lysine-linked antibody Drug Conjugate (ADC) in order to assess post translational modifications and Drug load variants. The initial charge heterogeneity of the unConjugated IgG-2 monoclonal antibody (mAb) was assessed by separating intact charge variants. Three main charge variants were resolved in the CE dimension. These variants were attributed to pyroglutamic acid formation and decarboxylation on the primary structure of the mAb through characteristic mass shifts and changes in electrophoretic mobility. Additionally, glycoforms of the antibody charge variants were identified in the deconvoluted mass spectra. The observed glycoforms and their distribution compared favorably to a released N-glycan analysis performed on the mAb. After conjugation, the ADC was analyzed using the same microchip CE–MS method. The addition of a Drug load resulted in a decrease in mobility a...
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Characterization of Intact Antibody Drug Conjugate Variants Using Microfluidic Capillary Electrophoresis–Mass Spectrometry
2016Co-Authors: Erin A Redman, Scott J Mellors, Jason A. Starkey, Michael J RamseyAbstract:In this work, we utilize capillary electrophoresis–mass spectrometry (CE–MS) in an integrated microfluidic platform to analyze an intact, lysine-linked antibody Drug Conjugate (ADC) in order to assess post translational modifications and Drug load variants. The initial charge heterogeneity of the unConjugated IgG-2 monoclonal antibody (mAb) was assessed by separating intact charge variants. Three main charge variants were resolved in the CE dimension. These variants were attributed to pyroglutamic acid formation and decarboxylation on the primary structure of the mAb through characteristic mass shifts and changes in electrophoretic mobility. Additionally, glycoforms of the antibody charge variants were identified in the deconvoluted mass spectra. The observed glycoforms and their distribution compared favorably to a released N-glycan analysis performed on the mAb. After conjugation, the ADC was analyzed using the same microchip CE–MS method. The addition of a Drug load resulted in a decrease in mobility and an increase in mass of 3145 Da. Five main species that differed in their respective Drug-to-antibody ratios (DAR) were fully resolved in the CE separation, with each DAR displaying the same variant population observed on the unConjugated mAb. A DAR range of 0–4 was observed with an average of 1.7 Drug loads. The DAR distribution generated from the microfluidic CE–MS data compared favorably to results from infusion-ESI-MS and imaging CE (iCE) analysis of the ADC, techniques commonly used for intact mAb and ADC characterization
