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.
abstract: 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.
authors: Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, United States.
authors: Swapnil S
authors: SS
authors: Desale
authors: Eppley Institute for Research in Cancer and Allied Diseases, UNMC, United States. Electronic address: srikumar.raja@northwestern.edu.
authors: Srikumar M
authors: SM
authors: Raja
authors: Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, United States; College of Pharmacy, Yeungnam University, Gyeongsan 712-749, South Korea.
authors: Jong Oh
authors: JO
authors: Kim
authors: Eppley Institute for Research in Cancer and Allied Diseases, UNMC, United States.
authors: Bhopal
authors: B
authors: Mohapatra
authors: Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, United States.
authors: Kruti S
authors: KS
authors: Soni
authors: Eppley Institute for Research in Cancer and Allied Diseases, UNMC, United States.
authors: Haitao
authors: H
authors: Luan
authors: Eppley Institute for Research in Cancer and Allied Diseases, UNMC, United States.
authors: Stetson H
authors: SH
authors: Williams
authors: Eppley Institute for Research in Cancer and Allied Diseases, UNMC, United States.
authors: Timothy A
authors: TA
authors: Bielecki
authors: Eppley Institute for Research in Cancer and Allied Diseases, UNMC, United States.
authors: Dan
authors: D
authors: Feng
authors: Eppley Institute for Research in Cancer and Allied Diseases, UNMC, United States.
authors: Matthew
authors: M
authors: Storck
authors: Department of Genetics, Cell Biology and Anatomy, UNMC, United States.
authors: Vimla
authors: V
authors: Band
authors: Department of Pathology and Microbiology, UNMC, United States.
authors: Samuel M
authors: SM
authors: Cohen
authors: Eppley Institute for Research in Cancer and Allied Diseases, UNMC, United States. Electronic address: hband@unmc.edu.
authors: Hamid
authors: H
authors: Band
authors: Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, United States. Electronic address: tbronich@unmc.edu.
authors: Tatiana K
authors: TK
authors: Bronich
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D016227:Benzoquinones / Q000008:administration & dosage* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology*; D004339:Drug Compounding; D004357:Drug Synergism; D005260:Female; D005782:Gels; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D049329:Nanostructures / Q000737:chemistry*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000900:Anti-Bacterial Agents; D016227:Benzoquinones; D004317:Doxorubicin; D005782:Gels; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018719:Erb-b2 Receptor Tyrosine Kinases; C112765:tanespimycin; C508053:ERBB2 protein, human
keywords: 17-AAG; Block copolymers; Breast cancer; Doxorubicin; Drug combinations; ErbB2; HSP90; Her2/Neu; Nanogels