title: Inducing enhanced immunogenic cell death with nanocarrier-based drug delivery systems for pancreatic cancer therapy.
abstract: Immunogenic cell death (ICD) occurs when apoptotic tumor cell elicits a specific immune response, which may trigger an anti-tumor effect, via the release of immunostimulatory damage-associated molecular patterns (DAMPs). Hypothesizing that nanomedicines may impact ICD due to their proven advantages in delivery of chemotherapeutics, we encapsulated oxaliplatin (OXA) or gemcitabine (GEM), an ICD and a non-ICD inducer respectively, into the amphiphilic diblock copolymer nanoparticles. Neither GEM nor nanoparticle-encapsulated GEM (NP-GEM) induced ICD, while both OXA and nanoparticle-encapsulated OXA (NP-OXA) induced ICD. Interestingly, NP-OXA treated tumor cells released more DAMPs and induced stronger immune responses of dendritic cells and T lymphocytes than OXA treatment in vitro. Furthermore, OXA and NP-OXA exhibited stronger therapeutic effects in immunocompetent mice than in immunodeficient mice, and the enhancement of therapeutic efficacy was significantly higher in the NP-OXA group than the OXA group. Moreover, NP-OXA treatment induced a higher proportion of tumor infiltrating activated cytotoxic T-lymphocytes than OXA treatment. This general trend of enhanced ICD by nanoparticle delivery was corroborated in evaluating another pair of ICD inducer and non-ICD inducer, doxorubicin and 5-fluorouracil. In conclusion, although nanoparticle encapsulation did not endow a non-ICD inducer with ICD-mediated anti-tumor capacity, treatment with a nanoparticle-encapsulated ICD inducer led to significantly enhanced ICD and consequently improved anti-tumor effects than the free ICD inducer. The proposed nanomedicine approach may impact cancer immunotherapy via the novel cell death mechanism of ICD.
authors.affiliation: Department of Pancreatic Carcinoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhao
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Keni
authors.initials: K
authors.lastname: Yang
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Zhao
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Tianjiao
authors.initials: T
authors.lastname: Ji
authors.affiliation: Department of Pancreatic Carcinoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Xiuchao
authors.initials: X
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Yinlong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Keman
authors.initials: K
authors.lastname: Cheng
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Shaoli
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Pancreatic Carcinoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Jihui
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Pancreatic Carcinoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: renhe@tjmuch.com.
authors.forename: He
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, USA.
authors.forename: Kam W
authors.initials: KW
authors.lastname: Leong
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing 100190, China. Electronic address: niegj@nanoctr.cn.
authors.forename: Guangjun
authors.initials: G
authors.lastname: Nie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000032:analysis / Q000276:immunology; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage / Q000627:therapeutic use*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D000077150:Oxaliplatin; D010179:Pancreas / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D007371:Interferon-gamma
keywords: Dendritic cells; Gemcitabine; Immunogenic cell death; Nanocarriers; Oxaliplatin; Pancreatic cancer