Chitosan nanoparticle-based delivery of fused NKG2D–IL-21 gene suppresses colon cancer growth in mice

Abstract

Nanoparticles can be loaded with exogenous DNA for the potential expression of cytokines with immune-stimulatory function. NKG2D identifies major histocompatibility complex class I chain-related protein in human and retinoic acid early induced transcript-1 in mouse, which acts as tumor-associated antigens. Biologic agents based on interleukin 21 (IL-21) have displayed antitumor activities through lymphocyte activation. The NKG2D–IL-21 fusion protein theoretically identifies tumor cells through NKG2D moiety and activates T cells through IL-21 moiety. In this study, double-gene fragments that encode the extracellular domains of NKG2D and IL-21 genes were connected and then inserted into the pcDNA3.1(−) plasmid. PcDNA3.1–dsNKG2D–IL-21 plasmid nanoparticles based on chitosan were generated. Tumor cells pretransfected with dsNKG2D–IL-21 gene nanoparticles can activate natural killer (NK) and CD8 + T cells in vitro. Serum IL-21 levels were enhanced in mice intramuscularly injected with the gene nanoparticles. DsNKG2D–IL-21 gene nanoparticles accumulated in tumor tissues after being intravenously injected for ~4–24 h. Treatment of dsNKG2D–IL-21 gene nanoparticles also retarded tumor growth and elongated the life span of tumor-bearing mice by activating NK and T cells in vivo. Thus, the dsNKG2D–IL-21 gene nanoparticles exerted efficient antitumor activities and would be potentially used for tumor therapy.

Sterically stabilized liposomes targeting P21 (RAC1) activated kinase‑1 and secreted phospholipase A₂ suppress prostate cancer growth and metastasis

“…Several laboratories have utilized nanoparticles for targeted drug delivery in various types of cancer, including breast, lung, colon, and gastric cancers, which is similar to our approach, where these nanoparticles were enriched in tumors thus, delivering small molecule inhibitors specifically at the tumor site ( 52 – 56 ). To the best of our knowledge, these data are the first to demonstrate the ability of liposomal formulations of IPA3 to inhibit the lung metastasis of PCa.…”

Fusion Proteins of NKG2D/NKG2DL in Cancer Immunotherapy

“…Viral (including lentiviral [ 107 ] and adenoviral [ 108 ]) delivery systems and nanoparticles [ 109 ] are available delivery methods so far. The chitosan nanoparticle is a popularly used vehicle and shows great potential in cancer therapy, because of its capability of tumor targeting and releasing drugs or genes automatically in tumor tissues [ 80 ]. However, this is still far from perfect.…”

“…IL-21/IL-21R signal pathway regulates both innate and adaptive immune systems, and is significant in inflammatory responses, the development of autoimmune diseases and inflammatory disorders, anti-tumor and antiviral response [ 78 , 79 ]. Tan et al [ 80 ] fused two copies of NKG2D extracellular domain cDNA with IL-21 gene in a vector, and used chitosan nanoparticles to deliver this fusion gene vector into tumor cells. Tumor cells treated with the nanoparticles secreted the fusion protein, which activated NK and CD8+ cells to lyse tumor cell in co-culture.…”

Nanovectors Design for Theranostic Applications in Colorectal Cancer

“…Similarly, a recent study focused on the delivery of a peculiar fusion plasmid containing DNA for IL-21 and the tumor antigen NKG2D using chitosan-based nanoparticles [64]. IL-21 is considered a highly pro-inflammatory cytokine expressed by a wide array of immune cells.…”