Local delivery of superagonist gene based on polymer nanoparticles for cancer immunotherapy

Cancer is the leading cause that threatens human life expectancy due to the lack of effective therapies.Cancer immunotherapy has been explored to improve the body's immune system against cancer and accompanied by promising results in recent years.Interleukin 15(IL-15),a pleiotropic immunomodulator,is critical for immune cells development and displays great anti-tumor potential in both preclinical and clinical trials.In this study,superagonist IL-15 plasmid(psIL-15)consisting of IL-15Rα-sushi-linker-IL-15 was constructed in order to secret superagonist IL-15(sIL-15)in tumor site.A gene delivery system through self-assembly by methylated polyethylene glycol-b-polylactic acid-b-methylated polyethylene glycol(m PEG-PLA-m PEG)and 1,2-dioleoyl-3-trimethylammonium-propane(DOTAP),named DMAM,was designed to deliver psIL-15.Further study showed that DMAM/psIL-15 could successfully deliver psIL-15 to tumor cells and the supernatants of the tumor cells could further stimulate lymphocytes proliferation as well as activation in vitro.Local delivery of DMAM/psIL-15 in animal models demonstrated significant tumor inhibition through enhancing immune cells responses,reducing angiogenesis,promoting tumor cell apoptosis and inhibiting proliferation,with no evidence of system toxicities.These results indicate that DMAM/psIL-15 may be a promising strategy for cancer immunotherapy.

pIL-12 delivered by polymer based nanovector for anti-tumor genetherapy

Finding more effective and safe non-viral vectors to transfer genes into cancer cells has become the key of immune gene therapy for cancer.Herein a triblock compound MPEG_(2000)-PDLLA_(4000)-MPEG_(2000) modified by cationic liposome DOTAP was used as a non-viral vector DOTAP/MPEG_(2000)-PDLLA_(4000)-MPEG_(2000)(DMPM)to effectively transfer interleukin(IL)-12 plasmid(pIL-12)into tumor tissue.IL-12 produced by transfected tumor cells successfully inducing lymphocyte proliferation and promoting interferon-γ(IFN-γ)secretion,which resulted in tumor cells death.The ability of DMPM to transfer pIL-12 and the immune effect induced by IL-12 in cells had been explored.The anti-tumor effect,mechanism and safety of pIL-12/DMPM in mice cancer model were investigated in this study.Our results showed that the pIL-12 transferred by DMPM was highly expressed both in CT26 cells and B16-F10 cells.IL-12 expressed in the culture supernatant of transfected tumor cells stimulated lymphocyte proliferation and promoted IFN-γsecretion.The experimental result confirmed that pIL-12/DMPM therapy significantly reduced tumor growth in mice model.We designed the nanocomposite DMPM to deliver pIL-12 for cancer treatment and explored its therapeutic efficacy and the underlying anti-tumor mechanism.Our study suggested pIL-12 loaded by DMPM complex would be an effective strategy for cancer treatment.