title: Biodegradable microparticles loaded with doxorubicin and CpG ODN for in situ immunization against cancer.
abstract: In situ immunization is based on the concept that it is possible to break immune tolerance by inducing tumor cell death in situ in a manner that provides antigen-presenting cells such as dendritic cells (DCs) with a wide selection of tumor antigens that can then be presented to the immune system and result in a therapeutic anticancer immune response. We designed a comprehensive approach to in situ immunization using poly(lactic-co-glycolic acid) (PLGA)-biodegradable microparticles (MPs) loaded with doxorubicin (Dox) and CpG oligodeoxynucleotides (CpG) that deliver Dox (chemotherapy) and CpG (immunotherapy) in a sustained-release fashion when injected intratumorally. Dox induces immunogenic tumor cell death while CpG enhances tumor antigen presentation by DCs. PLGA MPs allow their safe co-delivery while evading the vesicant action of Dox. In vitro, we show that Dox/CpG MPs can kill B and T lymphoma cells and are less toxic to DCs. In vivo, Dox/CpG MPs combined with antibody therapy to enhance and maintain the T cell response generated systemic immune responses that suppressed injected and distant tumors in a murine B lymphoma model, leading to tumor-free mice. The combination regimen was also effective at reducing T cell lymphoma and melanoma tumor burdens. In conclusion, Dox/CpG MPs represent an efficient and safe tool for in situ immunization that could provide a promising component of immunotherapy for patients with a variety of types of cancer.
authors.affiliation: Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, 52242, USA.
authors.forename: Amani
authors.initials: A
authors.lastname: Makkouk
authors.forename: Vijaya B
authors.initials: VB
authors.lastname: Joshi
authors.forename: Amaraporn
authors.initials: A
authors.lastname: Wongrakpanich
authors.forename: Caitlin D
authors.initials: CD
authors.lastname: Lemke
authors.forename: Brett P
authors.initials: BP
authors.lastname: Gross
authors.forename: Aliasger K
authors.initials: AK
authors.lastname: Salem
authors.forename: George J
authors.initials: GJ
authors.lastname: Weiner
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D003692:Delayed-Action Preparations; D003713:Dendritic Cells / Q000276:immunology; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D007167:Immunotherapy / Q000379:methods; D019344:Lactic Acid / Q000737:chemistry*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008863:Microspheres; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer
chemical_list: D000276:Adjuvants, Immunologic; D000903:Antibiotics, Antineoplastic; C408982:CPG-oligonucleotide; D003692:Delayed-Action Preparations; D009838:Oligodeoxyribonucleotides; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D004317:Doxorubicin