Inducing enhanced immunogenic cell death with nanocarrier-based drug delivery systems for pancreatic cancer therapy

• Published in: Biomaterials 2016-09, Vol.102, p.187-197
• Main Authors: Zhao, Xiao, Yang, Keni, Zhao, Ruifang, Ji, Tianjiao, Wang, Xiuchao, Yang, Xiao, Zhang, Yinlong, Cheng, Keman, Liu, Shaoli, Hao, Jihui, Ren, He, Leong, Kam W, Nie, Guangjun
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Cancer; Cell death; Cell Death - drug effects; Cell Line, Tumor; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - pathology; Dentistry; Drug Delivery Systems; Encapsulation; Female; Gemcitabine; Humans; Immunogenic cell death; Immunotherapy - methods; Inducers; Interferon-gamma - analysis; Interferon-gamma - immunology; Mice; Mice, Inbred C57BL; Nanocarriers; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - therapeutic use; Nanostructure; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - therapeutic use; Oxaliplatin; Pancreas - drug effects; Pancreas - immunology; Pancreas - pathology; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - therapy; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - pathology; Tumors
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2016.06.032

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.