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.