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Article
Combination of Dendrimer Nanovector Mediated Small Interfering RNA Delivery to Target Akt with Clinical Anticancer Drug Paclitaxel for Effective and Potent Anticancer Activity in Treating Ovarian Cancer Shashwati Kala, Abby S. C. Mak, Xiaoxuan Liu, Paola Posocco, Sabrina Pricl, Ling Peng, and Alice S. T. Wong J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/jm401907z • Publication Date (Web): 04 Mar 2014 Downloaded from http://pubs.acs.org on March 13, 2014
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of Medicinal Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
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Journal of Medicinal Chemistry
Combination of Dendrimer Nanovector Mediated Small Interfering RNA Delivery to Target Akt with Clinical Anticancer Drug Paclitaxel for Effective and Potent Anticancer Activity in Treating Ovarian Cancer
Shashwati Kala,† Abby Mak,† Xiaoxuan Liu,‡ Paola Posocco,€ Sabrina Pricl,€,O Ling Peng,‡,* and Alice Wong†,*
†
School of Biological Sciences, University of Hong Kong, Pokfulam Road, Hong
Kong ‡
Aix-Marseille University, CNRS, Centre Interdisciplinaire de Nanoscience de
Marseille, CINaM UMR 7325, Marseille Cedex 09, France €
Molecular Simulation Engineering Laboratory (MOSE), Department of Engineering
and Architecture (DEA), University of Trieste, Via Valerio 10, 34127 Trieste, Italy O
National Interuniversity Consortium for Material Science and Technology (INSTM),
Research Unit MOSE-DEA, University of Trieste, 34127 Trieste, Italy
Keywords: ovarian cancer; dendrimers; siRNA; Akt; gene silencing; combination therapy
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Journal of Medicinal Chemistry
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ABSTRACT: The recently discovered small-interfering RNA (siRNA) holds great promise in cancer therapy. However, efficient and safe delivery systems are required for the development of new therapeutic paradigms. Ovarian cancer has the highest mortality of all gynecologic tumors, and there is an urgent need for specific and effective therapies. The phosphatidylinositol 3-kinase/Akt pathway, which is strongly implicated in the biology of ovarian cancer, constitutes an attractive therapeutic target. In this study, we described a triethanolamine-core poly(amidoamine) (PAMAM) dendrimer, which formed stable nanoparticles with the Akt siRNA, protected against RNase digestion and was highly effective for initiating Akt targetgene silencing both in vitro and in vivo, while being minimally toxic. Most importantly, it could potentiate the antitumor effect of anticancer drug paclitaxel. These results represent the proof-of-concept, demonstrating that dendrimer-mediated Akt siRNA delivery, in combination with chemotherapeutic regimen, may constitute a promising nanomedicine approach in cancer therapy.
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Journal of Medicinal Chemistry
INTRODUCTION Ovarian cancer is the leading cause of death of all gynecologic tumors. Although surgical resection could cure early stage ovarian cancer, most (~70%) patients present with advanced disease at diagnosis. Chemotherapy is the mainstay of treatment for metastatic ovarian cancer. However, commonly used cytotoxic chemotherapeutic agents often have narrow therapeutic indices due to highly nonspecific cytotoxicity and undesirable side effects. Furthermore, their applications are limited by both intrinsic and acquired chemoresistance, and in most making the disease incurable (5year survival
Article
Combination of Dendrimer Nanovector Mediated Small Interfering RNA Delivery to Target Akt with Clinical Anticancer Drug Paclitaxel for Effective and Potent Anticancer Activity in Treating Ovarian Cancer Shashwati Kala, Abby S. C. Mak, Xiaoxuan Liu, Paola Posocco, Sabrina Pricl, Ling Peng, and Alice S. T. Wong J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/jm401907z • Publication Date (Web): 04 Mar 2014 Downloaded from http://pubs.acs.org on March 13, 2014
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of Medicinal Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 32
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Journal of Medicinal Chemistry
Combination of Dendrimer Nanovector Mediated Small Interfering RNA Delivery to Target Akt with Clinical Anticancer Drug Paclitaxel for Effective and Potent Anticancer Activity in Treating Ovarian Cancer
Shashwati Kala,† Abby Mak,† Xiaoxuan Liu,‡ Paola Posocco,€ Sabrina Pricl,€,O Ling Peng,‡,* and Alice Wong†,*
†
School of Biological Sciences, University of Hong Kong, Pokfulam Road, Hong
Kong ‡
Aix-Marseille University, CNRS, Centre Interdisciplinaire de Nanoscience de
Marseille, CINaM UMR 7325, Marseille Cedex 09, France €
Molecular Simulation Engineering Laboratory (MOSE), Department of Engineering
and Architecture (DEA), University of Trieste, Via Valerio 10, 34127 Trieste, Italy O
National Interuniversity Consortium for Material Science and Technology (INSTM),
Research Unit MOSE-DEA, University of Trieste, 34127 Trieste, Italy
Keywords: ovarian cancer; dendrimers; siRNA; Akt; gene silencing; combination therapy
1
ACS Paragon Plus Environment
Journal of Medicinal Chemistry
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ABSTRACT: The recently discovered small-interfering RNA (siRNA) holds great promise in cancer therapy. However, efficient and safe delivery systems are required for the development of new therapeutic paradigms. Ovarian cancer has the highest mortality of all gynecologic tumors, and there is an urgent need for specific and effective therapies. The phosphatidylinositol 3-kinase/Akt pathway, which is strongly implicated in the biology of ovarian cancer, constitutes an attractive therapeutic target. In this study, we described a triethanolamine-core poly(amidoamine) (PAMAM) dendrimer, which formed stable nanoparticles with the Akt siRNA, protected against RNase digestion and was highly effective for initiating Akt targetgene silencing both in vitro and in vivo, while being minimally toxic. Most importantly, it could potentiate the antitumor effect of anticancer drug paclitaxel. These results represent the proof-of-concept, demonstrating that dendrimer-mediated Akt siRNA delivery, in combination with chemotherapeutic regimen, may constitute a promising nanomedicine approach in cancer therapy.
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ACS Paragon Plus Environment
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Journal of Medicinal Chemistry
INTRODUCTION Ovarian cancer is the leading cause of death of all gynecologic tumors. Although surgical resection could cure early stage ovarian cancer, most (~70%) patients present with advanced disease at diagnosis. Chemotherapy is the mainstay of treatment for metastatic ovarian cancer. However, commonly used cytotoxic chemotherapeutic agents often have narrow therapeutic indices due to highly nonspecific cytotoxicity and undesirable side effects. Furthermore, their applications are limited by both intrinsic and acquired chemoresistance, and in most making the disease incurable (5year survival
