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Delivery of a Cancer-Testis Antigen-Derived Peptide Using Conformationally Restricted Dipeptide-Based Self-Assembled Nanotubes
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2021-09-09 , DOI: 10.1021/acs.molpharmaceut.1c00451
Priyanka Verma 1 , Saikat Biswas 1 , Nitin Yadav 1 , Anjali Khatri 1 , Hamda Siddiqui 1, 2 , Jiban Jyoti Panda 1, 3 , Bhupendra Singh Rawat 4 , Prafullakumar Tailor 4 , Virander Singh Chauhan 1
Affiliation  

Use of tumor-associated antigens for cancer immunotherapy is limited due to their poor in vivo stability and low cellular uptake. Delivery of antigenic peptides using synthetic polymer-based nanostructures has been actively pursued but with limited success. Peptide-based nanostructures hold much promise as delivery vehicles due to their easy design and synthesis and inherent biocompatibility. Here, we report self-assembly of a dipeptide containing a non-natural amino acid, α,β-dehydrophenylalanine (ΔF), into nanotubes, which efficiently entrapped a MAGE-3-derived peptide (M3). M3 entrapped in F-ΔF nanotubes was more stable to a nonspecific protease treatment and both F-ΔF and F-ΔF-M3 showed no cellular toxicity for four cancerous and noncancerous cell lines used. F-ΔF-M3 showed significantly higher cellular uptake in RAW 267.4 macrophage cells compared to M3 alone and also induced in vitro maturation of dendritic cells (DCs). Immunization of mice with F-ΔF-M3 selected a higher number of IFN-γ secreting CD8+ T cells and CD4+ T compared to M3 alone. On day 21, a tumor growth inhibition ratio (TGI, %) of 41% was observed in a murine melanoma model. These results indicate that F-ΔF nanotubes are highly biocompatible, efficiently delivered M3 to generate cytotoxic T lymphocytes responses, and able to protect M3 from degradation under in vivo conditions. The F-ΔF dipeptide-based nanotubes may be considered as a good platform for further development as delivery agents.

中文翻译:

使用基于构象限制的二肽的自组装纳米管递送癌症睾丸抗原衍生肽

肿瘤相关抗原在癌症免疫治疗中的应用受到限制,因为它们在体内较差稳定性和低细胞摄取。使用基于合成聚合物的纳米结构递送抗原肽已得到积极追求,但成功有限。基于肽的纳米结构由于其易于设计和合成以及固有的生物相容性而作为运载工具具有很大的前景。在这里,我们报告了一种含有非天然氨基酸 α,β-脱氢苯丙氨酸 (ΔF) 的二肽自组装成纳米管,该纳米管有效地包埋了 MAGE-3 衍生肽 (M3)。包埋在 F-ΔF 纳米管中的 M3 对非特异性蛋白酶处理更稳定,并且 F-ΔF 和 F-ΔF-M3 对所用的四种癌性和非癌性细胞系均无细胞毒性。与单独的 M3 相比,F-ΔF-M3 在 RAW 267.4 巨噬细胞中显示出显着更高的细胞摄取,并且还在体外诱导树突状细胞 (DC) 的成熟。与单独的 M3 相比,用 F-ΔF-M3 免疫小鼠选择了更多数量的分泌 IFN-γ 的 CD8 + T 细胞和 CD4 + T。在第 21 天,在小鼠黑色素瘤模型中观察到 41% 的肿瘤生长抑制率 (TGI, %)。这些结果表明,F-ΔF 纳米管具有高度的生物相容性,可有效递送 M3 以产生细胞毒性 T 淋巴细胞反应,并能够保护 M3在体内条件下免于降解。基于 F-ΔF 二肽的纳米管可被视为进一步开发作为递送剂的良好平台。
更新日期:2021-10-04
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