PDF(Pubmed)
Abstract：
Plant virus nanoparticles can be used as drug carriers, imaging reagents, vaccine carriers, and immune adjuvants in the formulation of intratumoral in situ cancer vaccines. One example is the cowpea mosaic virus (CPMV), a nonenveloped virus with a bipartite positive-strand RNA genome with each RNA packaged separately into identical protein capsids. Based on differences in their densities, the components carrying RNA-1 (6 kb) denoted as the bottom (B) component or carrying RNA-2 (3.5 kb) denoted as the middle (M) component can be separated from each other and from a top (T) component, which is devoid of any RNA. Previous preclinical mouse studies and canine cancer trials used mixed populations of CPMV (containing B, M, and T components), so it is unclear whether the particle types differ in their efficacies. It is known that the CPMV RNA genome contributes to immunostimulation by activation of TLR7. To determine whether the two RNA genomes that have different sizes and unrelated sequences cause different immune stimulation, we compared the therapeutic efficacies of B and M components and unfractionated CPMV in vitro and in mouse cancer models. We found that separated B and M particles behaved similarly to the mixed CPMV, activating innate immune cells to induce the secretion of pro-inflammatory cytokines such as IFNα, IFNγ, IL-6, and IL-12, while inhibiting immunosuppressive cytokines such as TGF-β and IL-10. In murine models of melanoma and colon cancer, the mixed and separated CPMV particles all significantly reduced tumor growth and prolonged survival with no significant difference. This shows that the specific RNA genomes similarly stimulate the immune system even though B particles have 40% more RNA than M particles; each CPMV particle type can be used as an effective adjuvant against cancer with the same efficacy as native mixed CPMV. From a translational point of view, the use of either B or M component vs the mixed CPMV formulation offers the advantage that separated B or M alone is noninfectious toward plants and thus provides agronomic safety.
摘要：
植物病毒纳米颗粒可作为药物载体，成像试剂,疫苗携带者，瘤内原位癌疫苗制剂中的免疫佐剂。一个例子是cow豆花叶病毒（CPMV），一种无包膜病毒，具有二分正链RNA基因组，每种RNA分别包装到相同的蛋白质衣壳中。根据它们的密度差异，例如,携带RNA-1(6kb)的组分表示为底部(B)组分或携带RNA-2(3.5kb)表示为中间(M)组分可以彼此分离并与顶部(T)组分分离。没有任何RNA。以前的临床前小鼠研究和犬癌试验使用CPMV的混合群体(含有B，M,和T分量)，因此，目前尚不清楚粒子类型是否在其功效上有所不同。已知CPMVRNA基因组通过激活TLR7而有助于免疫刺激。为了确定具有不同大小和不相关序列的两个RNA基因组是否引起不同的免疫刺激，我们比较了B和M组分和普通CPMV在体外和小鼠癌症模型中的治疗效果。我们发现分离的B和M颗粒的行为与混合的CPMV相似，激活先天性免疫细胞以诱导促炎细胞因子如IFNα的分泌，IFNγ,IL-6和IL-12,同时抑制免疫抑制细胞因子如TGF-β和IL-10。在黑色素瘤和结肠癌的小鼠模型中，混合和分离的CPMV颗粒均显着降低了肿瘤的生长，延长了生存期，但没有显着差异。这表明,即使B颗粒具有比M颗粒多40%的RNA,特定RNA基因组也类似地刺激免疫系统;每种CPMV颗粒类型可以用作针对癌症的有效佐剂,具有与天然混合CPMV相同的功效。从平移的角度来看，B或M组分相对于混合CPMV制剂的使用提供了这样的优点,即单独分离的B或M对植物是非传染性的,因此提供了农艺安全性。
