Polypeptide-based nanogels co-encapsulating a synergistic combination of doxorubicin with 17-AAG show potent anti-tumor activity in ErbB2-driven breast cancer models

Title
Polypeptide-based nanogels co-encapsulating a synergistic combination of doxorubicin with 17-AAG show potent anti-tumor activity in ErbB2-driven breast cancer models
Author(s)
김종오Swapnil S. Desale[Swapnil S. Desale]Srikumar M. Raja[Srikumar M. Raja]Bhopal Mohapatra[Bhopal Mohapatra]Kruti S. Soni[Kruti S. Soni]Haitao Luan[Haitao Luan]Stetson H.Williams[Stetson H.Williams]Timothy A. Bielecki[Timothy A. Bielecki]Dan Feng[Dan Feng]MatthewStorck[MatthewStorck]Vimla Band[Vimla Band]Samuel M. Cohen[Samuel M. Cohen]Hamid Band[Hamid Band]Tatiana K. Bronich[Tatiana K. Bronich]
Keywords
OVARIAN-CANCER; MONOCLONAL-ANTIBODY; HSP90 INHIBITION; DRUG-THERAPY; GELDANAMYCIN; EXPRESSION; TRASTUZUMAB; CELLS; HER2; THERAPEUTICS
Issue Date
201506
Publisher
ELSEVIER SCIENCE BV
Citation
JOURNAL OF CONTROLLED RELEASE, v.208, pp.59 - 66
Abstract
ErbB2-driven breast cancers constitute 20-25% of the cases diagnosed within the USA. The humanized anti-ErbB2 monoclonal antibody, Trastuzumab (Herceptin(TM); Genentech), with chemotherapy is the current standard of treatment. Novel agents and strategies continue to be explored, given the challenges posed by Trastuzumab-resistance development in most patients. The HSP90 inhibitor, 17-allylaminodemethoxygeldanamycin (17-AAG), which induces ErbB2 degradation and attenuates downstream oncogenic signaling, is one such agent that showed significant promise in early phase I and II clinical trials. Its low water solubility, potential toxicities and undesirable side effects observed in patients, partly due to the Cremophor-based formulation, have been discouraging factors in the advancement of this promising drug into clinical use. Encapsulation of 17-AAG into polymeric nanoparticle formulations, particularly in synergistic combination with conventional chemotherapeutics, represents an alternative approach to overcome these problems. Herein, we report an efficient co-encapsulation of 17-AAG and doxorubicin, a clinically well-established and effective modality in breast cancer treatment, into biodegradable and biocompatible polypeptide-based nanogels. Dual drug-loaded nanogels displayed potent cytotoxicity in a breast cancer cell panel and exerted selective synergistic anticancer activity against ErbB2-overexpressing breast cancer cell lines. Analysis of ErbB2 degradation confirmed efficient 17-AAG release from nanogels with activity comparable to free 17-AAG. Furthermore, nanogels containing both 17-AAG and doxorubicin exhibited superior antitumor efficacy in vivo in an ErbB2-driven xenograft model compared to the combination of free drugs. These studies demonstrate that polypeptide-based nanogels can serve as novel nanocarriers for encapsulating 17-AAG along with other chemotherapeutics, providing an opportunity to overcome solubility issues and thereby exploit its full potential as an anti-cancer agent. (C) 2015 Elsevier B.V. All rights reserved.
URI
http://hdl.handle.net/YU.REPOSITORY/32058http://dx.doi.org/10.1016/j.jconrel.2015.02.001
ISSN
0168-3659
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약학대학 > 약학부 > Articles
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