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

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.

• Authors: Qiongming Xu, Lingchuan Guo, Xinhua Gu, Biao Zhang, Xin Hu, Jiajia Zhang, Jinghong Chen, Yi Wang, Cheng Chen, Bei Gao, Yuting Kuang, Shouli Wang
• Journal: Biomaterials (Biomaterials) Vol. 33 Issue 15 Pg. 3909-18 (May 2012) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 22374455 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Polyphosphates
• Interleukin-12
• Chitosan
• triphosphoric acid

Topics

• Animals
• Cell Line, Tumor
• Chemistry, Pharmaceutical
• Chitosan (chemistry)
• Colorectal Neoplasms (pathology)
• Injections, Intravenous
• Interleukin-12 (administration & dosage, pharmacology)
• Liver (drug effects, immunology, pathology)
• Liver Neoplasms (prevention & control, secondary)
• Lymphocytes, Tumor-Infiltrating (drug effects, pathology)
• Mice
• Mice, Inbred BALB C
• Nanoparticles (administration & dosage, chemistry, ultrastructure)
• Particle Size
• Polyphosphates (chemistry)
• Surface Properties (drug effects)
• Tissue Distribution (drug effects)
• Tumor Microenvironment (drug effects)