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

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• 作者：Xiao Zhao^a ; ^b ; ¹ ; Keni Yang^b ; ¹ ; Ruifang Zhao^b ; Tianjiao Ji^b ; Xiuchao Wang^a ; Xiao Yang^b ; Yinlong Zhang^b ; Keman Cheng^b ; Shaoli Liu^b ; Jihui Hao^a ; He Ren^a ; ^{renhe@tjmuch.com" class="auth_mail" title="E-mail the corresponding author} ; Kam W. Leong^c ; Guangjun Nie^b ; ^{niegj@nanoctr.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Nanocarriers ; Immunogenic cell death ; Dendritic cells ; Oxaliplatin ; Gemcitabine ; Pancreatic cancer
• 刊名：Biomaterials
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：102
• 期：Complete
• 页码：187-197
• 全文大小：2855 K

文摘

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.