Cytotoxic T lymphocytes (CTLs) are an important tool for anticancer immunotherapy. To elicit powerful CTL activities, ultra-pH-sensitive nanoparticles (NPs) based on methoxy poly(ethylene glycol)-b-[poly(diisopropylamino)ethyl methacrylate] have been synthesized as a vaccine delivery platform. A representative CTL epitope, ovalbumin (OVA) peptide antigen, was covalently conjugated to the polymer backbone through an acid responsive carboxy-dimethylmaleic amide linker (CDM) resulting in polymer P-CDM-OVA. Interestingly, while the P-CDM-OVA released OVA peptide slowly in a pH 6.4 buffer, the addition of bovine serum albumin (BSA) mimicking proteins encountered in a cellular and/or in vivo environment significantly accelerated the release process. Successful cell surface presentation of OVA was observed when P-CDM-OVA based ultra-pH-sensitive particles were incubated with antigen presenting cells. These P-CDM-OVA NPs greatly enhanced CTL responses in vivo compared to the free peptide or the previously reported acetalated dextran particles encapsulating OVA. The P-CDM was also investigated for adjuvant conjugation, and the coadministration of P-CDM-OVA and the P-CDM-adjuvant conjugate NPs further improved CTL responses in vivo and effectively reduced tumor growth in mice. Thus, the CDM linked polymer presents a promising platform for anticancer immunotherapy.

中文翻译：

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用于增强抗肿瘤免疫治疗的基于羧基二甲基马来酰胺连接的聚合物偶联物的超 pH 敏感纳米颗粒的合成

细胞毒性 T 淋巴细胞 (CTL) 是抗癌免疫治疗的重要工具。为了激发强大的 CTL 活性，已经合成了基于甲氧基聚（乙二醇）-b- [聚（二异丙基氨基）乙基甲基丙烯酸酯]的超 pH 敏感纳米颗粒 (NPs)作为疫苗递送平台。代表性的 CTL 表位，卵清蛋白 (OVA) 肽抗原，通过酸响应性羧基-二甲基马来酰胺接头 (CDM) 与聚合物主链共价结合，产生聚合物 P-CDM-OVA。有趣的是，虽然 P-CDM-OVA 在 pH 6.4 的缓冲液中缓慢释放 OVA 肽，但添加牛血清白蛋白 (BSA) 模拟蛋白质在细胞和/或体内环境显着加快了发布过程。当基于 P-CDM-OVA 的超 pH 敏感颗粒与抗原呈递细胞一起孵育时，观察到 OVA 的细胞表面成功呈递。与游离肽或先前报道的封装 OVA 的缩醛化葡聚糖颗粒相比，这些 P-CDM-OVA NPs 大大增强了体内CTL 反应。还研究了 P-CDM 的佐剂缀合，P-CDM-OVA 和 P-CDM-佐剂缀合物 NP 的共同给药进一步改善了体内CTL 反应并有效减少了小鼠的肿瘤生长。因此，CDM 连接的聚合物为抗癌免疫治疗提供了一个有前景的平台。