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

• Published in: Biomaterials 2012-05, Vol.33 (15), p.3909-3918
• Main Authors: Xu, Qiongming, Guo, Lingchuan, Gu, Xinhua, Zhang, Biao, Hu, Xin, Zhang, Jiajia, Chen, Jinghong, Wang, Yi, Chen, Cheng, Gao, Bei, Kuang, Yuting, Wang, Shouli
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Cell Line, Tumor; Chemistry, Pharmaceutical; Chitosan; Chitosan - chemistry; Colorectal cancer; Colorectal Neoplasms - pathology; Dentistry; IL-12; Injections, Intravenous; Interleukin-12 - administration & dosage; Interleukin-12 - pharmacology; Liver - drug effects; Liver - immunology; Liver - pathology; Liver Neoplasms - prevention & control; Liver Neoplasms - secondary; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - pathology; Metastasis; Mice; Mice, Inbred BALB C; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Particle Size; Polyphosphates - chemistry; Surface Properties - drug effects; Systemic delivery; Tissue Distribution - drug effects; Tumor Microenvironment - drug effects
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2012.02.014

Abstract 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.