TY - JOUR
T1 - Polypeptide-based nanogels co-encapsulating a synergistic combination of doxorubicin with 17-AAG show potent anti-tumor activity in ErbB2-driven breast cancer models
AU - Desale, Swapnil S.
AU - Raja, Srikumar M.
AU - Kim, Jong Oh
AU - Mohapatra, Bhopal
AU - Soni, Kruti S.
AU - Luan, Haitao
AU - Williams, Stetson H.
AU - Bielecki, Timothy A.
AU - Feng, Dan
AU - Storck, Matthew
AU - Band, Vimla
AU - Cohen, Samuel M.
AU - Band, Hamid
AU - Bronich, Tatiana K.
N1 - Funding Information:
This work was supported by the DOD Breast Cancer Research Program (grant W81XWH-11-1-0166 grant to HB and TB), the Nebraska DHHS LB506 and the National Institutes of Health (grants CA116552 , CA99163 , CA87986 and CA105489 to HB, CA96844 to VB; CA 116590 to TB). SMR acknowledges support from Nebraska Department of Health and Human Services and Center for Biomedical Research Excellence (CoBRE), Nebraska Center for Nanomedicine (COBRE-NCN; seed grant). We acknowledge the assistance of the Nanomaterials Core Facility of the COBRE-NCN supported by the Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the NIH grant number P20GM103480 . We would like to thank the NMR and Confocal Microscopy Core Facilities at UNMC (supported by the NCI Cancer Center Support Grant to Buffett Cancer Center) for excellent technical assistance.
Publisher Copyright:
© 2015 Elsevier B.V.
PY - 2015/6/28
Y1 - 2015/6/28
N2 - ErbB2-driven breast cancers constitute 20-25% of the cases diagnosed within the USA. The humanized anti-ErbB2 monoclonal antibody, Trastuzumab (Herceptin™; 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.
AB - ErbB2-driven breast cancers constitute 20-25% of the cases diagnosed within the USA. The humanized anti-ErbB2 monoclonal antibody, Trastuzumab (Herceptin™; 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.
KW - Block copolymers
KW - Breast cancer
KW - Doxorubicin
KW - Drug combinations
KW - ErbB2
KW - HSP90 17-AAG
KW - Her2/Neu
KW - Nanogels
UR - http://www.scopus.com/inward/record.url?scp=84939948741&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84939948741&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2015.02.001
DO - 10.1016/j.jconrel.2015.02.001
M3 - Article
C2 - 25660204
AN - SCOPUS:84939948741
SN - 0168-3659
VL - 208
SP - 59
EP - 66
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -