title: CpG expedites regression of local and systemic tumors when combined with activatable nanodelivery.
abstract: Ultrasonic activation of nanoparticles provides the opportunity to deliver a large fraction of the injected dose to insonified tumors and produce a complete local response. Here, we evaluate whether the local and systemic response to chemotherapy can be enhanced by combining such a therapy with locally-administered CpG as an immune adjuvant. In order to create stable, activatable particles, a complex between copper and doxorubicin (CuDox) was created within temperature-sensitive liposomes. Whereas insonation of the CuDox liposomes alone has been shown to produce a complete response in murine breast cancer after 8 treatments of 6 mg/kg delivered over 4 weeks, combining this treatment with CpG resolved local cancers within 3 treatments delivered over 7 days. Further, contralateral tumors regressed as a result of the combined treatment, and survival was extended in systemic disease. In both the treated and contralateral tumor site, the combined treatment increased leukocytes and CD4+ and CD8+ T-effector cells and reduced myeloid-derived suppressor cells (MDSCs). Taken together, the results suggest that this combinatorial treatment significantly enhances the systemic efficacy of locally-activated nanotherapy.
authors.affiliation: University of California, Davis, Department of Biomedical Engineering, 451 East Health Sciences Drive, Davis, CA 95616, USA.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Kheirolomoom
authors.affiliation: University of California, Davis, Department of Biomedical Engineering, 451 East Health Sciences Drive, Davis, CA 95616, USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Ingham
authors.affiliation: University of California, Davis, Department of Biomedical Engineering, 451 East Health Sciences Drive, Davis, CA 95616, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Mahakian
authors.affiliation: University of California, Davis, Department of Biomedical Engineering, 451 East Health Sciences Drive, Davis, CA 95616, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Tam
authors.affiliation: University of California, Davis, Department of Biomedical Engineering, 451 East Health Sciences Drive, Davis, CA 95616, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Silvestrini
authors.affiliation: University of California, Davis, Department of Biomedical Engineering, 451 East Health Sciences Drive, Davis, CA 95616, USA.
authors.forename: Spencer K
authors.initials: SK
authors.lastname: Tumbale
authors.affiliation: University of California, Davis, Department of Biomedical Engineering, 451 East Health Sciences Drive, Davis, CA 95616, USA.
authors.forename: Josquin
authors.initials: J
authors.lastname: Foiret
authors.affiliation: University of California, Davis, Center for Comparative Medicine, Davis, CA 95616, USA.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Hubbard
authors.affiliation: University of California, Davis, Center for Comparative Medicine, Davis, CA 95616, USA.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Borowsky
authors.affiliation: University of California, Davis, Department of Dermatology, 2921 Stockton Blvd., Institute for Regenerative Cures, Suite 1630, Sacramento, CA 95817, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
authors.affiliation: University of California, Davis, Department of Biomedical Engineering, 451 East Health Sciences Drive, Davis, CA 95616, USA. Electronic address: kwferrara@ucdavis.edu.
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Ferrara
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D003131:Combined Modality Therapy; D004247:DNA / Q000008:administration & dosage* / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D004339:Drug Compounding; D005260:Female; D007167:Immunotherapy / Q000379:methods*; D008081:Liposomes; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D053758:Nanoparticles; D036103:Nanotechnology; D009942:Organometallic Compounds / Q000008:administration & dosage* / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment; D014464:Ultrasonic Therapy / Q000379:methods*
chemical_list: D000276:Adjuvants, Immunologic; D000903:Antibiotics, Antineoplastic; C525069:CpG phosphorothioate ODN 1826-S; D008081:Liposomes; D009942:Organometallic Compounds; C053169:doxorubicin-copper(II) complex; D004317:Doxorubicin; D004247:DNA
keywords: CpG; Doxorubicin; Immunotherapy; Temperature-sensitive liposome; Ultrasound