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      Enhancing Therapeutic Effects of Docetaxel-Loaded Dendritic Copolymer Nanoparticles by Co-Treatment with Autophagy Inhibitor on Breast Cancer

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          Abstract

          Dendrimers are synthetic nanocarriers that comprise a highly branched spherical polymer as new, efficient tools for drug delivery. However, the fate of nanocarriers after being internalized into cells has seldom been studied. Docetaxel loaded dendritic copolymer H40-poly(D,L-lactide) nanoparticles, referred to as “DTX-H40-PLA NPs”, were prepared and used as a model to evaluate whether the NPs were sequestered by autophagy and fused with lysosomes. Besides being degraded through the endolysosomal pathway, the DTX-loaded H40-PLA NPs were also sequestered by autophagosomes and degraded through the autolysosomal pathway. DTX-loaded H40-PLA NPs may stop exerting beneficial effects after inducing autophagy of human MCF-7 cancer cells. Co-delivery of autophagy inhibitor such as chloroquine and chemotherapeutic drug DTX by dendritic copolymer NPs greatly enhanced cancer cell killing in vitro, and decreased both the volume and weight of the tumors in severe combined immunodeficient mice. These findings provide valuable evidence for development of nanomedicine such as dendritic copolymer NPs for clinical application.

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          Mediating tumor targeting efficiency of nanoparticles through design.

          Steven Perrault, Carl Walkey, Travis Jennings … (2009)
          Here we systematically examined the effect of nanoparticle size (10-100 nm) and surface chemistry (i.e., poly(ethylene glycol)) on passive targeting of tumors in vivo. We found that the physical and chemical properties of the nanoparticles influenced their pharmacokinetic behavior, which ultimately determined their tumor accumulation capacity. Interestingly, the permeation of nanoparticles within the tumor is highly dependent on the overall size of the nanoparticle, where larger nanoparticles appear to stay near the vasculature while smaller nanoparticles rapidly diffuse throughout the tumor matrix. Our results provide design parameters for engineering nanoparticles for optimized tumor targeting of contrast agents and therapeutics.
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            Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2.

            Maria Høyer-Hansen, Lone Bastholm, Piotr Szyniarowski … (2007)
            Macroautophagy is an evolutionary conserved lysosomal pathway involved in the turnover of cellular macromolecules and organelles. In spite of its essential role in tissue homeostasis, the molecular mechanisms regulating mammalian macroautophagy are poorly understood. Here, we demonstrate that a rise in the free cytosolic calcium ([Ca(2+)](c)) is a potent inducer of macroautophagy. Various Ca(2+) mobilizing agents (vitamin D(3) compounds, ionomycin, ATP, and thapsigargin) inhibit the activity of mammalian target of rapamycin, a negative regulator of macroautophagy, and induce massive accumulation of autophagosomes in a Beclin 1- and Atg7-dependent manner. This process is mediated by Ca(2+)/calmodulin-dependent kinase kinase-beta and AMP-activated protein kinase and inhibited by ectopic Bcl-2 located in the endoplasmatic reticulum (ER), where it lowers the [Ca(2+)](ER) and attenuates agonist-induced Ca(2+) fluxes. Thus, an increase in the [Ca(2+)](c) serves as a potent inducer of macroautophagy and as a target for the antiautophagy action of ER-located Bcl-2.
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              Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy.

              Gareth J. Morgan, Jacqueline Thorburn, Andrew Thorburn … (2012)
              Chloroquine (CQ) is a 4-aminoquinoline drug used for the treatment of diverse diseases. It inhibits lysosomal acidification and therefore prevents autophagy by blocking autophagosome fusion and degradation. In cancer treatment, CQ is often used in combination with chemotherapeutic drugs and radiation because it has been shown to enhance the efficacy of tumor cell killing. Since CQ and its derivatives are the only inhibitors of autophagy that are available for use in the clinic, multiple ongoing clinical trials are currently using CQ or hydroxychloroquine (HCQ) for this purpose, either alone, or in combination with other anticancer drugs. Here we show that in the mouse breast cancer cell lines, 67NR and 4T1, autophagy is induced by the DNA damaging agent cisplatin or by drugs that selectively target autophagy regulation, the PtdIns3K inhibitor LY294002, and the mTOR inhibitor rapamycin. In combination with these drugs, CQ sensitized to these treatments, though this effect was more evident with LY294002 and rapamycin treatment. Surprisingly, however, in these experiments CQ sensitization occurred independent of autophagy inhibition, since sensitization was not mimicked by Atg12, Beclin 1 knockdown or bafilomycin treatment, and occurred even in the absence of Atg12. We therefore propose that although CQ might be helpful in combination with cancer therapeutic drugs, its sensitizing effects can occur independently of autophagy inhibition. Consequently, this possibility should be considered in the ongoing clinical trials where CQ or HCQ are used in the treatment of cancer, and caution is warranted when CQ treatment is used in cytotoxic assays in autophagy research.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Theranostics
                Journal ID (iso-abbrev): Theranostics
                Journal ID (publisher-id): thno
                Title: Theranostics
                Publisher: Ivyspring International Publisher (Sydney )
                ISSN (Electronic): 1838-7640
                Publication date Collection: 2014
                Publication date (Electronic): 15 August 2014
                Volume: 4
                Issue: 11
                Pages: 1085-1095
                Affiliations
                1. School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China;
                2. The Shenzhen Key Lab of Gene and Antibody Therapy, Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, P.R. China;
                3. Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, University of Chinese Academy of Sciences, Guangzhou, Guangdong, 510530, P.R. China;
                4. Institute of Allergy and Immunology, School of Medicine, Shenzhen University, Shenzhen 518060, P.R. China.
                Author notes
                ✉ Corresponding authors: Lin Mei: Tel/Fax: +86 75526036736, E-mail: mei.lin@ 123456sz.tsinghua.edu.cn . Or Laiqiang Huang: Tel/Fax: +86 75526036052, E-mail: huanglq@ 123456sz.tsinghua.edu.cn .

                * These authors contributed equally to this work.

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                Publisher ID: thnov04p1085
                DOI: 10.7150/thno.9933
                PMC ID: 4173759
                PubMed ID: 25285162
                SO-VID: 18c4acfd-3d63-4326-93ca-14f0f411364c
                Copyright © © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
                History
                Date received : 18 June 2014
                Date accepted : 30 July 2014
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Molecular medicine
                Keywords: nanomedicine,endocytosis,autophagy,docetaxel,chloroquine,dendrimers.
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: nanomedicine, endocytosis, autophagy, docetaxel, chloroquine, dendrimers.

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