Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal; Louvain Drug Research Institute, Advanced Drug Delivery & Biomaterials, Université Catholique de Louvain, 1200 Brussels, Belgium.
Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
J Control Release. 2015 Jan 28;198:91-103. doi: 10.1016/j.jconrel.2014.11.033. Epub 2014 Dec 5.
We hypothesized that the co-entrapment of melanoma-associated antigens and the Toll-like receptor (TLR) ligands Poly(I:C) and CpG, known to be Th1-immunopotentiators, in mannose-functionalized aliphatic polyester-based nanoparticles (NPs) could be targeted to mannose receptors on antigen-presenting cells and induce anti-tumor immune responses. High entrapment efficiencies of antigens and immunopotentiators in 150nm NPs were obtained. The co-entrapment of the model antigen ovalbumin and the TLR ligands was crucial to induce high IgG2c/IgG1 ratios and high levels of IFN-γ and IL-2. Mannose-functionalization of NPs potentiated the Th1 immune response. The nanoparticulate vaccines decreased the growth rate of murine B16F10 melanoma tumors in therapeutic and prophylatic settings. The combination of mannose-functionalized NPs containing MHC class I- or class II-restricted melanoma antigens and the TLR ligands induced the highest tumor growth delay. Overall, we demonstrate that the multifunctional properties of NPs in terms of targeting and antigen/adjuvant delivery have high cancer immunotherapeutic potential.
我们假设将黑色素瘤相关抗原与 Toll 样受体 (TLR) 配体 Poly(I:C) 和 CpG 共同包封在甘露糖功能化的脂肪族聚酯基纳米颗粒 (NPs) 中,已知这些配体具有 Th1 免疫增强作用,能够靶向抗原呈递细胞上的甘露糖受体,并诱导抗肿瘤免疫反应。我们获得了 150nm NPs 中抗原和免疫增强剂的高包封效率。模型抗原卵清蛋白和 TLR 配体的共同包封对于诱导高 IgG2c/IgG1 比值和高水平 IFN-γ 和 IL-2 至关重要。NPs 的甘露糖化增强了 Th1 免疫反应。纳米颗粒疫苗在治疗和预防设置中降低了小鼠 B16F10 黑色素瘤肿瘤的生长速度。含有 MHC Ⅰ类或Ⅱ类限制性黑色素瘤抗原和 TLR 配体的甘露糖功能化 NPs 的组合诱导了最高的肿瘤生长延迟。总的来说,我们证明了 NPs 在靶向和抗原/佐剂递送上的多功能特性具有很高的癌症免疫治疗潜力。