Alpha 1,3 Gal/pVEGF-hIFN-γ纳米脂质体的制备及其逆转TAMs的促肿瘤作用

Eradication of the tumor associated macrophage (TAMs) within the tumor microenvironment or reprogramming of TAMs toward proimmunogenic type refered to as the promising strategies in tumor immunotherapy is now attracting more and more attentions. Among these strategies, Utilizing TAMs as vehicles to deliver the exogenous gene in cancer gene therapy is regarded as an important approach. However, this approach is established to confront some limitations, such as the low transfection ratio of exogenous gene, considerable toxicity of the viral vector and lackage of selectivity to TAMs. Therefore, it is neccesary to expore the other novel strategy for tumor immunotherapy. A xenoantigen between human being and some inferior mammals, termed alpha 1，3 Gal glycolipid, is inset in the surface of nano-lipid and constitute a nanoparticle which can be specifically uptaked by TAMs for gene delivery. This nanoparticle is then used to load a hypoxia-responsible human interferon-γ construct pVEGF-hIFN-γ which becomes active in expression of hIFN-γ under hypoxic conditions to generate a nano-lipid gene delivery system alpha 1，3 Gal/pVEGF-hIFN-γ NP; Thereafter, the alpha 1，3 Gal/pVEGF-hIFN-γ NP is confirmed to be effective in faciliating the target of pVEGF-hIFN-γ to TAMs; Finally, the pVEGF-hIFN-γ gene-modified TAMs is tested in the capacity of highly producing hIFN-γ which synergize with the alpha1，3 Gal glycolipid to promote the reprogramming of TAMs toward M1 phenotype, to suppress the protumoral activities of TAMs and to inhibit the neovascularization of tumor under the hypoxic conditions. The alpha 1，3 Gal/pVEGF-hIFN-γ NP may presumably represent a novel approach and holds some promise in the tumor immunotherapy.

清除肿瘤间质内的肿瘤相关巨噬细胞（TAMs）或重塑其表型作为一种抗肿瘤免疫治疗的新策略备受关注。其中，利用TAMs作为基因载体是一种重要手段。但该策略存在外源基因转染效率低、病毒载体毒性大及对TAMs缺乏靶向性等问题。因此，有必要探索新的治疗策略。本研究拟将一种人与某些哺乳动物间的异种属抗原alpha 1,3 Gal糖脂引入到纳米脂质体表面，制备一种被TAMs靶向摄取的纳米基因载体系统；利用该系统荷载受缺氧调控表达人干扰素-γ（hIFN-γ）的载体pVEGF-hIFN-γ，制备TAMs靶向性的纳米基因脂质体alpha 1,3 Gal/pVEGF-hIFN-γ NP；证实该脂质体可增强TAMs对pVEGF-hIFN-γ的摄取，经缺氧诱导TAMs可持续表达hIFN-γ，alpha 1,3 Gal糖脂和hIFN-γ可协同抑制TAMs的促肿瘤作用和促肿瘤新生血管形成，为抗肿瘤免疫治疗探索新的思路。