title: 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.affiliation: Department of Pharmaceutical Chemistry, Soochow University College of Pharmaceutical Science, Suzhou 215123, China.
authors.forename: Qiongming
authors.initials: Q
authors.lastname: Xu
authors.forename: Lingchuan
authors.initials: L
authors.lastname: Guo
authors.forename: Xinhua
authors.initials: X
authors.lastname: Gu
authors.forename: Biao
authors.initials: B
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.forename: Jiajia
authors.initials: J
authors.lastname: Zhang
authors.forename: Jinghong
authors.initials: J
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.forename: Bei
authors.initials: B
authors.lastname: Gao
authors.forename: Yuting
authors.initials: Y
authors.lastname: Kuang
authors.forename: Shouli
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D048271:Chitosan / Q000737:chemistry*; D015179:Colorectal Neoplasms / Q000473:pathology*; D007275:Injections, Intravenous; D018664:Interleukin-12 / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D011122:Polyphosphates / Q000737:chemistry*; D013499:Surface Properties / Q000187:drug effects; D014018:Tissue Distribution / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D011122:Polyphosphates; D018664:Interleukin-12; D048271:Chitosan; C005692:triphosphoric acid