Prevention of colorectal cancer liver metastasis by exploiting liver immunity via chitosan-TPP/nanoparticles formulated with IL-12

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• 作者：Qiongming Xu^a ; ¹ ; Lingchuan Guo^b ; ¹ ; Xinhua Gu^c ; Biao Zhang^b ; Xin Hu^b ; Jiajia Zhang^b ; Jinghong Chen^b ; Yi Wang^b ; Cheng Chen^b ; Bei Gao^b ; Yuting Kuang^d ; ^{hongwens@126.com} ; Shouli Wang^b ; ^{wangsoly112@hotmail.com}
• 关键词：Chitosan ; IL-12 ; Nanoparticles ; Colorectal cancer ; Metastasis ; Systemic delivery
• 刊名：Biomaterials
• 出版年：2012
• 期刊代码：7_01429612
• 类别：ms
• 出版时间：May, 2012
• 卷：33
• 期：15
• 页码：3909-3918
• 文件大小：1508 K

摘要

The development of effective therapies for the prevention of colorectal cancer (CRC) liver metastasis is of great importance. Recently, chitosan (CS) nanoparticles have been utilized as carriers of interluekin-12 (IL-12) administered locally to deliver therapeutic proteins and genes. In this study, we encapsulated IL-12 by incorporation using tripolyphosphate (TPP) as the coacervated crosslinking agent to form CS-TPP/IL-12 nanoparticles. We further characterized the association efficiency, rate of release, liver-targeting, and toxicity, which were predominantly dependent on the factors of particle size, zeta potential, pH of solution, and whether or not modified with TPP. Systemic delivery of CS-TPP/IL-12 nanoparticles significantly reduced the number and volume of CRC liver metastasis foci compared to the CS-TPP treated mouse group. Although delivery of IL-12 alone also inhibited the number of CRC liver metastasis observed, further study of the change in hepatic metastasis volume demonstrated no significant differences between the groups treated with CS-TPP or IL-12 alone. Mechanistically, CS-TPP nanoparticles blocked the toxicity of IL-12 and induced infiltration of NK cells and some T cells, which are most likely the effector cells that mediate tumor metastasis inhibition during CS-TPP/IL-12 immunotherapy. The results obtained from this study demonstrate the potential benefit of using chitosan modification technology as a cytokine delivery system for the successful prevention of CRC liver metastasis by exploiting liver immunity.