- Photoactivatable prodrug for simultaneous release of mertansine and CO along with a BODIPY derivative as a luminescent marker in mitochondria: a proof of concept for NIR image-guided cancer therapy
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Controlled and efficient activation is the crucial aspect of designing an effective prodrug. Herein we demonstrate a proof of concept for a light activatable prodrug with desired organelle specificity. Mertansine, a benzoansamacrolide, is an efficient microtubule-targeting compound that binds at or near the vinblastine-binding site in the mitochondrial region to induce mitotic arrest and cell death through apoptosis. Despite its efficacy even in the nanomolar level, this has failed in stage 2 of human clinical trials owing to the lack of drug specificity and the deleterious systemic toxicity. To get around this problem, a recent trend is to develop an antibody-conjugatable maytansinoid with improved tumor/organelle-specificity and lesser systematic toxicity. Endogenous CO is recognized as a regulator of cellular function and for its obligatory role in cell apoptosis. CO blocks the proliferation of cancer cells and effector T cells, and the primary target is reported to be the mitochondria. We report herein a new mitochondria-specific prodrug conjugate (Pro-DC) that undergoes a photocleavage reaction on irradiation with a 400 nm source (1.0 mW cm?2) to induce a simultaneous release of the therapeutic components mertansine and CO along with a BODIPY derivative (BODIPY(PPH3)2) as a luminescent marker in the mitochondrial matrix. The efficacy of the process is demonstrated using MCF-7 cells and could effectively be visualized by probing the intracellular luminescence ofBODIPY(PPH3)2. This provides a proof-of-concept for designing a prodrug for image-guided combination therapy for mainstream treatment of cancer.
- Tiwari, Rajeshwari,Shinde, Prashant S.,Sreedharan, Sreejesh,Dey, Anik Kumar,Vallis, Katherine A.,Mhaske, Santosh B.,Pramanik, Sumit Kumar,Das, Amitava
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- Ado-trastuzumab emtansine (T-DM1): An antibody-drug conjugate (ADC) for HER2-positive breast cancer
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Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the antitumor properties of the humanized anti-human epidermal growth factor receptor 2 (HER2) antibody, trastuzumab, with the maytansinoid, DM1, a potent microtubule-disrupting agent, joined by a stable linker. Upon binding to HER2, the conjugate is internalized via receptor-mediated endocytosis, and an active derivative of DM1 is subsequently released by proteolytic degradation of the antibody moiety within the lysosome. Initial clinical evaluation led to a phase III trial in advanced HER2-positive breast cancer patients who had relapsed after prior treatment with trastuzumab and a taxane, which showed that T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine. In 2013, T-DM1 received FDA approval for the treatment of patients with HER2-positive metastatic breast cancer who had previously received trastuzumab and a taxane, separately or in combination, the first ADC to receive full approval based on a randomized study.
- Lambert, John M.,Chari, Ravi V. J.
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- Maytansine dechloridation compound, intermediate, preparation method of compound and application
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The invention discloses a maytansine dechloridation compound as shown in a formula I, an intermediate, a preparation method of the compound and an application. The invention provides the maytansine dechloridation compound as shown in the formula I. The maytansine dechloridation compound can be used as an impurity standard substance for impurity research of maytansine DM1 to establish an analysis method for maytansine DM1 quality control, and a proper method is selected to effectively remove the impurities. The quality of maytansine DM1 and even ADC drugs and the safety and effectiveness of clinical application can be improved. The invention also provides the preparation method and the intermediate of the maytansine dechloridation compound as shown in the formula I.
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- Semisynthetic Maytansine analogues for the targeted treatment of cancer
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Maytansine, a highly cytotoxic natural product, failed as an anticancer agent in human clinical trials because of unacceptable systemic toxicity. The potent cell killing ability of maytansine can be used in a targeted delivery approach for the selective destruction of cancer cells. A series of new maytansinoids, bearing a disulfide or thiol substituent were synthesized. The chain length of the ester side chain and the degree of steric hindrance on the carbon atom bearing the thiol substituent were varied. Several of these maytansinoids were found to be even more potent in vitro than maytansine. The targeted delivery of these maytansinoids, using monoclonal antibodies, resulted in a high, specific killing of the targeted cells in vitro and remarkable antitumor activity in vivo.
- Widdison, Wayne C.,Wilhelm, Sharon D.,Cavanagh, Emily E.,Whiteman, Kathleen R.,Leece, Barbara A.,Kovtun, Yelena,Goldmacher, Victor S.,Xie, Hongsheng,Steeves, Rita M.,Lutz, Robert J.,Zhao, Robert,Wang, Lintao,Bl?ttler, Walter A.,Chari, Ravi V. J.
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p. 4392 - 4408
(2007/10/03)
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