title: Marked enhancement of lysosomal targeting and efficacy of ErbB2-targeted drug delivery by HSP90 inhibition.
abstract: Targeted delivery of anticancer drugs to tumor cells using monoclonal antibodies against oncogenic cell surface receptors is an emerging therapeutic strategy. These strategies include drugs directly conjugated to monoclonal antibodies through chemical linkers (Antibody-Drug Conjugates, ADCs) or those encapsulated within nanoparticles that in turn are conjugated to targeting antibodies (Antibody-Nanoparticle Conjugates, ANPs). The recent FDA approval of the ADC Trastuzumab-TDM1 (Kadcyla; Genentech; San Francisco) for the treatment of ErbB2-overexpressing metastatic breast cancer patients has validated the strong potential of these strategies. Even though the activity of ANPs and ADCs is dependent on lysosomal traffic, the roles of the endocytic route traversed by the targeted receptor and of cancer cell-specific alterations in receptor dynamics on the efficiency of drug delivery have not been considered in these new targeted therapies. For example, constitutive association with the molecular chaperone HSP90 is thought to either retard ErbB2 endocytosis or to promote its recycling, traits undesirable for targeted therapy with ANPs and ADCs. HSP90 inhibitors are known to promote ErbB2 ubiquitination, targeting to lysosome and degradation. We therefore hypothesized that ErbB2-targeted drug delivery using Trastuzumab-conjugated nanoparticles could be significantly improved by HSP90 inhibitor-promoted lysosomal traffic of ErbB2. Studies reported here validate this hypothesis and demonstrate, both in vitro and in vivo, that HSP90 inhibition facilitates the intracellular delivery of Trastuzumab-conjugated ANPs carrying a model chemotherapeutic agent, Doxorubicin, specifically into ErbB2-overexpressing breast cancer cells, resulting in improved antitumor activity. These novel findings highlight the need to consider oncogene-specific alterations in receptor traffic in the design of targeted drug delivery strategies. We suggest that combination of agents that enhance receptor endocytosis and lysosomal routing can provide a novel strategy to significantly improve therapy with ANPs and ADCs.
authors: Eppley Institute for Research in Cancer and Allied Diseases, Omaha, Nebraska, USA.|Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.
authors: Srikumar M
authors: SM
authors: Raja
authors: Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, Omaha, Nebraska, USA.
authors: Swapnil S
authors: SS
authors: Desale
authors: Eppley Institute for Research in Cancer and Allied Diseases, Omaha, Nebraska, USA.
authors: Bhopal
authors: B
authors: Mohapatra
authors: Eppley Institute for Research in Cancer and Allied Diseases, Omaha, Nebraska, USA.
authors: Haitao
authors: H
authors: Luan
authors: Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, Omaha, Nebraska, USA.
authors: Kruti
authors: K
authors: Soni
authors: Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, Omaha, Nebraska, USA.
authors: Jinjin
authors: J
authors: Zhang
authors: Eppley Institute for Research in Cancer and Allied Diseases, Omaha, Nebraska, USA.
authors: Matthew A
authors: MA
authors: Storck
authors: Eppley Institute for Research in Cancer and Allied Diseases, Omaha, Nebraska, USA.
authors: Dan
authors: D
authors: Feng
authors: Eppley Institute for Research in Cancer and Allied Diseases, Omaha, Nebraska, USA.
authors: Timothy A
authors: TA
authors: Bielecki
authors: Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors: Vimla
authors: V
authors: Band
authors: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors: Samuel M
authors: SM
authors: Cohen
authors: Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, Omaha, Nebraska, USA.
authors: Tatiana K
authors: TK
authors: Bronich
authors: Eppley Institute for Research in Cancer and Allied Diseases, Omaha, Nebraska, USA.|Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, Omaha, Nebraska, USA.|Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.|Departments of Biochemistry and Molecular Biology, Pathology and Microbiology and Pharmacology and Neuroscience, College of Medicine, Omaha, Nebraska, USA.
authors: Hamid
authors: H
authors: Band
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D008453:Maytansine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004317:Doxorubicin; D018841:HSP90 Heat-Shock Proteins; D018796:Immunoconjugates; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: ErbB2; HSP90; Trastuzumab; breast cancer; targeted drug delivery