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. 2017 May 1;14(5):1760-1770.
doi: 10.1021/acs.molpharmaceut.7b00015. Epub 2017 Mar 28.

A Light Responsive Nanoparticle-Based Delivery System Using Pheophorbide A Graft Polyethylenimine for Dendritic Cell-Based Cancer Immunotherapy

Chuangnian Zhang  1 , Ju Zhang  2 , Gaona Shi  1 , Huijuan Song  1 , Shengbin Shi  1 , Xiuyuan Zhang  1 , Pingsheng Huang  1 , Zhihong Wang  1 , Weiwei Wang  1 , Chun Wang  1   3 , Deling Kong  1   4 , Chen Li  1
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A Light Responsive Nanoparticle-Based Delivery System Using Pheophorbide A Graft Polyethylenimine for Dendritic Cell-Based Cancer Immunotherapy

Chuangnian Zhang et al. Mol Pharm. .

Abstract

In this study, the photochemical internalization (PCI) technique was adopted in a nanoparticle-based antigen delivery system to enhance antigen-specific CD8+ T cell immune response for cancer immunotherapy. Pheophorbide A, a hydrophobic photosensitizer, grafted with polyethylenimine (PheoA-PEI) with endosome escape activity and near-infrared imaging capability was prepared. A model antigen ovalbumin (OVA) was then complexed with PheoA-PEI to form PheoA-PEI/OVA nanoparticles (PheoA-PEI/OVA NPs) that are responsive to light. Flow cytometry analysis revealed increased endocytosis in a murine dendritic cell line (DC2.4) that was treated with PheoA-PEI/OVA NPs compared to free OVA. Generation of reactive oxygen species (ROS) in DC2.4 cells was also confirmed quantitatively and qualitatively using 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA). Confocal laser scanning microscopy (CLSM) further demonstrated that the PheoA-PEI/OVA NPs enhanced cytosolic antigen release after light stimulation. Moreover, PheoA-PEI/OVA NP treated DC2.4 cells exhibited enhanced cross-presentation to B3Z T cell hybridoma in vitro after light irradiation, substantially increased compared to those treated with free OVA. Consistently, in vivo results revealed upregulation of CD3+CD8+T lymphocytes in tumors of mice treated with dendritic cells plus PheoA-PEI/OVA NPs and light irradiation. The activated T cell response is partly responsible for the inhibitory effect on E.G7 tumor growth in mice immunized with dendritic cells plus PheoA-PEI/OVA NPs and light irradiation. Our results demonstrate the feasibility to enhance antigen-specific CD8+ T cell immune response by light-responsive nanoparticle-based vaccine delivery for cancer immunotherapy.

Keywords: antigen delivery; cross-presentation; endosome escape; immunotherapy; photochemical internalization.

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