Antitumoral efficacy by systemic delivery of heparin conjugated polyethylenimine–plasmid interleukin‐15 complexes in murine models of lung metastasis

Gene therapy shows promising application in cancer therapy, but the lack of an ideal gene delivery system is still a tough challenge for cancer gene therapy. Previously, we prepared a novel cationic nanogel, heparin‐polyethylenimine (HPEI), which had potential application in gene delivery. In the present study, we constructed a plasmid with high expression efficiency of interleukin‐15 (IL15) and investigated the effects HPEI–plasmid IL15 (HPEI–pIL15) complexes on the distribution level of the lung. We then evaluated the anticancer effect of HPEI–pIL15 complexes on lung metastases of B16‐F10 melanoma and CT26 colon carcinoma. These results demonstrated that intravenous injection of the HPEI–pIL15 complex exhibited the highest plasmid distribution level in the lung compared with that of PEI2K–pIL15 and PEI25K–pIL15, and mice treated with HPEI–pIL15 had a lower tumor metastasis index compared with other treatment groups. Moreover, the number of natural killer cells, which were intermingled among the tumor cells, and the level of tumor necrosis factor‐α and interferon‐γ in the serum also increased in the pIL15‐treated mice. Furthermore, the cytotoxic activity of spleen cells also increased significantly in the HPEI–pIL15 group. In addition, induction of apoptosis and inhibition of cell proliferation in lung tumor foci in the HPEI–pIL15 group was observed. Taken together, treating lung metastasis cancer with the HPEI nanogels delivered by plasmid IL15 might be a new and interesting cancer gene therapy protocol. ( Cancer Sci 2011; 102: 1403–1409)