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Applications of Antiviral Nanoparticles in Cancer Therapy
Published in Devarajan Thangadurai, Saher Islam, Charles Oluwaseun Adetunji, Viral and Antiviral Nanomaterials, 2022
Anusha Konatala, Sai Brahma Penugonda, Fain Parackel, Sudhakar Pola
Ehrlich et al. produced AuNPs bound with the drug heat shock protein 90 inhibitor, 17-AAG, and Cullin-5 (Cul-5) DNA-encoding sequence, this was found to increase the receptiveness of 17 AAG in Cul-5 deficient AU565 cells (Fan et al. 2020). To treat the breast tumour cells, Arunakaran et al. developed AuNPs (3nm) with drug quercetin in MDA-MB-231 and MCF-7 breast cancer cell lines. The results depicted that free-drug quercetin is less potent compared to the AuNP-quercetin conjugate in battling breast cancer. Studies conducted by Coulter et al. explain that the AuNPs conjugated with the drug maytansine analog DM1 (MTC-100038) to treat murine hepatocellular cancer. This conjugated chemotherapy in hepatocellular tumours enhanced systemic tolerability (Hale et al. 2019).
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Antibodies and toxins as well as a combination of both, the antibody-drug conjugates (ADCs), are among others used for an aimed interaction with specific cancer cells resulting in apoptosis. Their action relies on inducing DNA breaks or on binding to microtubules playing important roles in eukaryotic cells including cell proliferation, trafficking, signaling, and migration (Dumontet and Jordan, 2010). The preparation of ADCs comprises the choice of a suited target antigen, the isolation and characterization of potent toxins and the development of stable linkers between Ab and toxin that guarantee a release of the toxin only after the ADC is internalized (Dingermann and Zündorf, 2014). An example is shown in the opposite scheme with the ADC trastuzumab emtansine where the highly cytotoxic maytansine, a 19-membered lactam, with an additional sulfhydryl group is bound via the SMCC (succinimidyl trans-4-(N-maleimidomethyl)cyclohexane-1-carboxylate) crosslinker to the mAb that was developed by Genentech for women with inoperable, locally advanced or metastatic HER2-positive breast cancer. Whereas trastuzumab alone stops growth of cancer cells by binding to the HER2/neu receptor, emtansine enters cells and destroys them by binding to microtubules. For reviews on monoclonal antibodies in cancer therapy see, e.g., Scott (2012, 2012a), Baldo (2016), Ndoja and Lima (2017).
Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The second most popular family of payloads at the time of writing are the maytansine analogues (or “maytansinoids”) such as mertansine (also known as DM1) the IP which is owned by ImmunoGen Inc (Figure 7.16). Maytansine (USAN), or maitansine (INN), is a macrolide of the ansamycin family of macrolides originally isolated from the maytenus genus of flowering plants such as the Ethiopian shrub, Maytenus ovatus (later re-named Maytenus serrate in 1972). Figure 7.16B shows the maytansine-producing tree maytenus boaria (Mayten) which, along with other plants of this genus, is distributed throughout Central and South America, Asia, and Africa. Plants of this genus grow in a very wide variety of climates, from tropical to sub-polar. A. The natural product maytansine, isolated from plant species such as Maytenus boaria (Mayten), an evergreen tree of the family Celastraceae native to South America (shown in B) (Image from Wikipedia, “Maytenus boaria – San Luis Obispo Botanical Garden – DSC05987” by Daderot, shared under the CC0 1.0 Universal Public Domain Dedication. (https://creativecommons.org/publicdomain/zero/1.0/deed.en)); C. The derivative of maytansine known as “ertansine” (or DM1) which can be joined (shown in red) through a linker to an antibody; D. Related ertansine derivatives DM3 and DM4 which differ only in the number of methyl groups adjacent to the sulfhydryl attachment point.
Investigational immunotherapy targeting CD19 for the treatment of acute lymphoblastic leukemia
Published in Expert Opinion on Investigational Drugs, 2021
Antibody-drug conjugates (ADC) enhance the cytotoxic efficacy of monoclonal antibodies and are attractive for the treatment of B-ALL, since the approval of inotuzumab ozogamicin, an anti CD22 ADC, in this indication. A clinical trial using coltuximab ravtansine (SAR3419), an anti‐CD19-humanized monoclonal antibody chemically linked to a maytansine derivate, was closed early due to low overall response rates (25.5%, duration of response 1.9 months) and high toxicity (5 discontinuations, grade 3 peripheral motor neuropathy) [16]. Another compound, denintuzumab mafodotin, was tested in 72 patients with B-ALL, lymphoblastic lymphoma and Burkitt lymphoma/leukemia. The overall response rate was 35% in the 3-weekly schedule, but 56% of the patients developed ocular adverse events [17].
Maytansine-bearing antibody-drug conjugates induce in vitro hallmarks of immunogenic cell death selectively in antigen-positive target cells
Published in OncoImmunology, 2019
Maxine Bauzon, Penelope M. Drake, Robyn M. Barfield, Brandon M. Cornali, Igor Rupniewski, David Rabuka
ICD was originally described as a type of apoptotic caspase-dependent cell death32, yet more recent studies have shown that ICD can be mediated via multiple regulated forms of cell death, including necroptosis.31,33,34 Maytansine and its related structural analogs have been previously shown to kill cells via an apoptotic mechanism involving mitotic arrest and p53 activation,35,36 events that can occur upstream of caspase-dependent apoptosis in some settings.37 We used a flow cytometric assay to determine whether maytansine operated through a similar process on BT474 and BJAB cells. Specifically, we monitored treated cells for reactivity with Annexin V protein, which recognizes cell surface-exposed phosphatidylserine and serves as a common marker of early-stage apoptotic cells.38 Cells in late stage-apoptosis and necrosis were identified by their inability to exclude propidium iodide (PI). Thus, we defined apoptotic cells as Annexin V+/PI-, and necrotic cells as Annexin V+/PI+. Untreated BT474 and BJAB cells both comprised predominately (85–92%) viable, non-apoptotic cells (Annexin V-/PI-). When treated with maytansine (100 nM) both the BT474 and BJAB cell lines showed increases in the percentages of apoptotic cells at early time points, with the percentages of necrotic cells increasing at later time points (Figure 4), supporting the interpretation that cells were dying via an apoptotic mechanism. In keeping with the results of our previous studies, the reaction kinetics differed between the two target cell lines, with BT474 cell responses lagging behind BJAB cell responses by 24 h or more.
Zein nanoparticles as nontoxic delivery system for maytansine in the treatment of non-small cell lung cancer
Published in Drug Delivery, 2020
Xianglong Yu, Huichao Wu, Haiyan Hu, Ziyi Dong, Yunni Dang, Qi Qi, Yan Wang, Shouying Du, Yang Lu
Lung cancer remains the leading cause of cancer-related mortality worldwide and non-small cell lung carcinoma (NSCLC) represents approximately 85% of all new lung cancer diagnosis (Fitzmaurice et al., 2018; Prabhu et al., 2018). Maytansine (DM1) is a powerful tubulin polymerization inhibitor whose antitumor mechanism inhibits cell mitosis like vinblastine and vincristine, but its antitumor activity in vitro was higher than vincristine and paclitaxel 20–100 times, 24–270 times, respectively (Issell & Crooke, 1978; Wishart et al., 2008). Therefore, DM1 can effectively treat various malignancies including breast cancer, melanoma, multiple myeloma, liver cancer and lung cancer (Kusari et al., 2016; Zhong et al., 2017). Although DM1 has high antitumor activity, its clinical application was limited due to strong side effects, narrow therapeutic window and poor water solubility (Kupchan et al., 1972; Blum et al., 1978; Junttila et al., 2011). These properties make it promising as a targeted drug. In order to overcome those effects of DM1 and improve clinical application, antibody-drug conjugates (AMCs) are currently the most widely used technology. At present, more than ten types of antibody-maytansinoid conjugates have entered various phases of clinical trials (Chudasama et al., 2016; de Goeij & Lambert, 2016; Taplin et al., 2018). It has to be noted, however, that the clinical use of AMCs, is challenged by their poor stability, low drug content, high cost, small scale production, relatively narrow therapeutic index, limited clinical success, off-target toxicities of payloads and potential immunogenicity (Perez et al., 2014; Tolcher, 2016; Mecklenburg, 2018).