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      International Journal of Nanomedicine (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the application of nanotechnology in diagnostics, therapeutics, and drug delivery systems throughout the biomedical field. Sign up for email alerts here.

      105,621 Monthly downloads/views I 7.033 Impact Factor I 10.9 CiteScore I 1.22 Source Normalized Impact per Paper (SNIP) I 1.032 Scimago Journal & Country Rank (SJR)

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      pH-Responsive Artesunate Polymer Prodrugs with Enhanced Ablation Effect on Rodent Xenograft Colon Cancer

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          Abstract

          Purpose

          In this study, pH-sensitive poly(2-ethyl-2-oxazoline)-poly(lactic acid)-poly(β-amino ester) (PEOz-PLA-PBAE) triblock copolymers were synthesized and were conjugated with an antimalaria drug artesunate (ART), for inhibition of a colon cancer xenograft model.

          Methods

          The as-prepared polymer prodrugs are tended to self-assemble into polymeric micelles in aqueous milieu, with PEOz segment as hydrophilic shell and PLA-PBAE segment as hydrophobic core.

          Results

          The pH sensitivity of the as-prepared copolymers was confirmed by acid-base titration with p Kb values around 6.5. The drug-conjugated polymer micelles showed high stability for at least 96 h in PBS and 37°C, respectively. The as-prepared copolymer prodrugs showed high drug loading content, with 9.57%±1.24% of drug loading for PEOz-PLA-PBAE-ART4. The conjugated ART could be released in a sustained and pH-dependent manner, with 92% of released drug at pH 6.0 and 57% of drug released at pH 7.4, respectively. In addition, in vitro experiments showed higher inhibitory effect of the prodrugs on rodent CT-26 cells than that of free ART. Animal studies also demonstrated the enhanced inhibitory efficacy of PEOz-PLA-PBAE-ART2 micelles on the growth of rodent xenograft tumor.

          Conclusion

          The pH-responsive artesunate polymer prodrugs are promising candidates for colon cancer adjuvant therapy.

          Most cited references45

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          TPGS-Functionalized Polydopamine-Modified Mesoporous Silica as Drug Nanocarriers for Enhanced Lung Cancer Chemotherapy against Multidrug Resistance

          Lin Mei, Xiaowei Zeng, Xudong Zhang … (2017)
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            Mitochondrial gateways to cancer.

            Lorenzo Galluzzi, Eugenia Morselli, Oliver Kepp … (2010)
            Mitochondria are required for cellular survival, yet can also orchestrate cell death. The peculiar biochemical properties of these organelles, which are intimately linked to their compartmentalized ultrastructure, provide an optimal microenvironment for multiple biosynthetic and bioenergetic pathways. Most intracellular ATP is generated by mitochondrial respiration, which also represents the most relevant source of intracellular reactive oxygen species. Mitochondria participate in a plethora of anabolic pathways, including cholesterol, cardiolipin, heme and nucleotide biosynthesis. Moreover, mitochondria integrate numerous pro-survival and pro-death signals, thereby exerting a decisive control over several biochemical cascades leading to cell death, in particular the intrinsic pathway of apoptosis. Therefore, it is not surprising that cancer cells often manifest the deregulation of one or several mitochondrial functions. The six classical hallmarks of cancer (i.e., limitless replication, self-provision of proliferative stimuli, insensitivity to antiproliferative signals, disabled apoptosis, sustained angiogenesis, invasiveness/metastatic potential), as well as other common features of tumors (i.e., avoidance of the immune response, enhanced anabolic metabolism, disabled autophagy) may directly or indirectly implicate deregulated mitochondria. In this review, we discuss several mechanisms by which mitochondria can contribute to malignant transformation and tumor progression. 2009 Elsevier Ltd. All rights reserved.
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              Contribution of reactive oxygen species to ovarian cancer cell growth arrest and killing by the anti-malarial drug artesunate.

              Trevor Shepherd, Anna L Greenshields, David W. Hoskin (2017)
              Ovarian cancer is a leading cause of cancer-related death in women and the most lethal gynecological malignancy in the developed world. The morbidity and mortality of ovarian cancer underscore the need for novel treatment options. Artesunate (ART) is a well-tolerated anti-malarial drug that also has anti-cancer activity. In this study, we show that ART inhibited the in vitro growth of a panel of ovarian cancer cell lines, as well as the growth of ovarian cancer cells isolated from patients. Moreover, ART decreased tumor growth in vivo in a mouse model of ovarian cancer. ART-treated ovarian cancer cells showed a strong induction of reactive oxygen species (ROS) and reduced proliferation. ROS-dependent cell cycle arrest occurred in the G2/M phase whereas ROS-independent cell cycle arrest occurred in the G1 phase, depending on the concentration of ART to which ovarian cancer cells were exposed. The anti-proliferative effect of ART was associated with altered expression of several key cell cycle regulatory proteins, including cyclin D3, E2F-1, and p21, as well as inhibition of mechanistic target of rapamycin signaling. Exposure of ovarian cancer cells to higher concentrations of ART resulted in ROS-dependent DNA damage and cell death. Pretreatment of ovarian cancer cells with a pan-caspase inhibitor or ferroptosis inhibitor decreased but did not completely eliminate ART-mediated cytotoxicity, suggesting the involvement of both caspase-dependent and caspase-independent pathways of killing. These data show that ART has potent anti-proliferative and cytotoxic effects on ovarian cancer cells, and may therefore be useful in the treatment of ovarian cancer. © 2016 Wiley Periodicals, Inc.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Nanomedicine
                Journal ID (iso-abbrev): Int J Nanomedicine
                Journal ID (publisher-id): IJN
                Journal ID (pmc): intjnano
                Title: International Journal of Nanomedicine
                Publisher: Dove
                ISSN (Print): 1176-9114
                ISSN (Electronic): 1178-2013
                Publication date (Electronic): 16 March 2020
                Publication date Collection: 2020
                Volume: 15
                Pages: 1771-1786
                Affiliations
                [1 ]Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences , Beijing 100700, People’s Republic of China
                Author notes
                Correspondence: Qing-He Zhao; Yan-Jun Chen Tel/Fax +86-10-84036059 Email qhzhao@icmm.ac.cn; yjchen@icmm.ac.cn
                Author information
                http://orcid.org/0000-0001-6099-5052
                Article
                Publisher ID: 242032
                DOI: 10.2147/IJN.S242032
                PMC ID: 7083641
                PubMed ID: 32214810
                SO-VID: 6781ed01-0bf4-4c9a-a055-afbf063e0d5c
                Copyright © © 2020 Hao et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 12 December 2019
                Date accepted : 02 March 2020
                Page count
                Figures: 6, Tables: 4, References: 55, Pages: 16
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Molecular medicine
                Keywords: artesunate,micelles,ph responsive,polymer prodrug,poly(2-ethyl-2-oxazoline),poly(β-amino ester)
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: artesunate, micelles, ph responsive, polymer prodrug, poly(2-ethyl-2-oxazoline), poly(β-amino ester)

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