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

Xiao Zhao, Keni Yang, Ruifang Zhao, Tianjiao Ji, Xiuchao Wang, Xiao Yang, Yinlong Zhang, Keman Cheng, Shaoli Liu, Jihui Hao, He Ren, Kam W. Leong, Guangjun Nie

Research output: Contribution to journalArticle

81 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)187-197
Number of pages11
JournalBiomaterials
Volume102
DOIs
StatePublished - Sep 1 2016

Keywords

  • Dendritic cells
  • Gemcitabine
  • Immunogenic cell death
  • Nanocarriers
  • Oxaliplatin
  • Pancreatic cancer

ASJC Scopus subject areas

  • Biomaterials
  • Bioengineering
  • Ceramics and Composites
  • Mechanics of Materials
  • Biophysics

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