Pancreatic cancer (PC) is one of the most lethal malignancies and represents an increasing and challenging threat, especially with an aging population. The identification of immunogenic PC‐specific upregulated antigens and an enhanced understanding of the immunosuppressive tumor microenvironment have provided opportunities to enable the immune system to recognize cancer cells. Due to its differential upregulation and functional role in PC, the transmembrane mucin MUC4 is an attractive target for immunotherapy. In the current study we characterized the antigen stability, antigenicity and release kinetics of a MUC4β‐nanovaccine to guide further optimization and, in vivo evaluation. Amphiphilic polyanhydride copolymers based on 20 mol % 1,8‐bis(p‐carboxyphenoxy)‐3,6‐dioxaoctane and 80 mol % 1,6‐bis(p‐carboxyphenoxy)hexane were used to synthesize nanoparticles. Structurally stable MUC4β protein was released from the particles in a sustained manner and characterized by gel electrophoresis and fluorescence spectroscopy. Modest levels of protein degradation were observed upon release. The released protein was also analyzed by MUC4β‐specific monoclonal antibodies using ELISA and showed no significant loss of epitope availability. Further, mice immunized with multiple formulations of combination vaccines containing MUC4β‐loaded nanoparticles generated MUC4β‐specific antibody responses. These results indicate that polyanhydride nanoparticles are viable MUC4β vaccine carriers, laying the foundation for evaluation of this platform for PC immunotherapy.

中文翻译：

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聚酐纳米粒子稳定胰腺癌抗原 MUC4β

胰腺癌 (PC) 是最致命的恶性肿瘤之一，代表着日益严重和具有挑战性的威胁，尤其是在人口老龄化的情况下。免疫原性 PC 特异性上调抗原的鉴定和对免疫抑制性肿瘤微环境的深入了解为使免疫系统识别癌细胞提供了机会。由于其在 PC 中的差异上调和功能作用，跨膜粘蛋白 MUC4 是免疫治疗的一个有吸引力的靶点。在目前的研究中，我们表征了 MUC4β-纳米疫苗的抗原稳定性、抗原性和释放动力学，以指导进一步优化和体内评估。基于 20 mol % 1,8-bis( p -carboxyphenoxy)-3,6-dioxaoctane 和 80 mol% 1,6-bis( p-羧基苯氧基）己烷用于合成纳米颗粒。结构稳定的 MUC4β 蛋白以持续的方式从颗粒中释放出来，并通过凝胶电泳和荧光光谱进行表征。释放后观察到适度水平的蛋白质降解。释放的蛋白质还通过 MUC4β 特异性单克隆抗体使用 ELISA 进行分析，没有显示表位可用性的显着损失。此外，用含有 MUC4β 负载纳米颗粒的多种联合疫苗制剂免疫的小鼠会产生 MUC4β 特异性抗体反应。这些结果表明聚酐纳米颗粒是可行的 MUC4β 疫苗载体，为评估该平台用于 PC 免疫治疗奠定了基础。