title: Polymer nanoparticles for enhanced immune response: combined delivery of tumor antigen and small interference RNA for immunosuppressive gene to dendritic cells.
abstract: In this study, we report on polymer nanoparticles (NPs) that can induce an enhanced immune response in dendritic cell (DC)-based cancer immunotherapy by the combined delivery of tumor antigen and small interference RNA (siRNA) for the immunosuppressive gene to DCs. DCs are specialized antigen-presenting cells (APCs) that capture, process and present antigens and induce an antigen-specific cytotoxic T lymphocyte response. Because the suppressor of cytokine signaling 1 (SOCS1) is a negative regulator of the APC-based immune response, the inhibition of SOCS1 gene expression is essential for DCs to enhance antigen-specific anti-tumor immunity. Multifunctional poly(lactide-co-glycolic acid) (PLGA) NPs that can deliver tumor antigen and siRNA for immunosuppressive SOCS1 genes to DCs simultaneously were fabricated by the emulsion solvent evaporation method. We have found that the encapsulation efficiency of small-sized and hydrophilic SOCS1 siRNA into hydrophobic PLGA matrix is drastically enhanced by the help of a tumor model antigen such as ovalbumin (OVA), and the encapsulation efficiency of siRNA in PLGA (SOCS1 siRNA only) NPs and PLGA (OVA/SOCS1 siRNA) NPs was ∼2% and 57.6%, respectively. PLGA (OVA/SOCS1 siRNA) NPs were efficiently taken up by bone-marrow-derived dendritic cells (BMDCs) and showed no detectable toxic effect. The knockdown of SOCS1 in BMDCs by PLGA (OVA/SOCS1 siRNA) NPs enhanced pro-inflammatory cytokine (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-12 and IL-2) expression. Additionally, PLGA (OVA/SOCS1 siRNA) NP-treated BMDCs could elicit an immune response through cross-presentation in OVA-specific CD8 T cells that express IL-2 cytokine. Taken together, the combined delivery of NPs that can deliver both tumor antigen and immunosuppressive gene siRNA to BMDCs simultaneously could be a potent strategy to enhance immunotherapeutic effects in BMDC-based cancer therapy.
authors.affiliation: Graduate School and Department of Analytical Science and Technology, Chungnam National University, Yuseong, Daejeon 305-764, Republic of Korea.
authors.forename: Min Beom
authors.initials: MB
authors.lastname: Heo
authors.affiliation: Graduate School and Department of Analytical Science and Technology, Chungnam National University, Yuseong, Daejeon 305-764, Republic of Korea.
authors.forename: Mi Young
authors.initials: MY
authors.lastname: Cho
authors.affiliation: SKKU Advanced Institute of Nanotechnology (SAINT), School of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: yongtaik@cnu.ac.kr.
authors.forename: Yong Taik
authors.initials: YT
authors.lastname: Lim
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002470:Cell Survival; D002645:Chickens; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D004705:Endocytosis; D005260:Female; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D007109:Immunity; D007165:Immunosuppression Therapy; D018836:Inflammation Mediators / Q000378:metabolism; D019344:Lactic Acid / Q000138:chemical synthesis / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010047:Ovalbumin / Q000378:metabolism; D010316:Particle Size; D011100:Polyglycolic Acid / Q000138:chemical synthesis / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D034741:RNA, Small Interfering / Q000378:metabolism*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D016207:Cytokines; D018836:Inflammation Mediators; D034741:RNA, Small Interfering; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D010047:Ovalbumin
keywords: Antigen delivery; Cancer vaccine; Dendritic cells; Nanoparticles; SOCS1