Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu No. 17 Section, 3 Renmin South Rd, Chengdu, 610041, PR China.
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu No. 17 Section, 3 Renmin South Rd, Chengdu, 610041, PR China.
Biomaterials. 2017 Apr;122:105-113. doi: 10.1016/j.biomaterials.2017.01.010. Epub 2017 Jan 11.
It has been widely accepted that lymph nodes (LNs) are critical targets of cancer vaccines and particles sized between 10 and 100 nm with a neutral or negative surface charge are preferred for lymphatic transfer after subcutaneous or intradermal injection. However their limited uptake by antigen presenting cells (APCs) and inadequate retention within LNs undoubtedly restrains their strength on activating T cell immunity. Here, we address this issue by tailoring the physicochemical properties of polymeric hybrid micelles (HMs), which are self-assembled from two amphiphilic diblock copolymers, poly-(ethylene glycol) phosphorethanolamine (PEG-PE) and polyethylenimine-stearic acid conjugate (PSA) via hydrophobic and electrostatic interactions. We successfully encapsulate melanoma antigen peptide Trp2 and Toll-like receptor-9 (TLR-9) agonist CpG ODN into HMs with a size of sub-30 nm. Their surface characteristics which are found closely related to their in vivo kinetics can be modulated by simply adjusting the molar ratio of PEG-PE and PSA. Our results demonstrated the optimized HMs with an equal mol of PEG-PE and PSA can potently target proximal LNs where their cargos are efficiently internalized by DCs. Furthermore, HMs mediated Trp2/CpG delivery system greatly expands antigen specific cytotoxic T lymphocytes (CTLs) and offers a strong anti-tumor effect in a lung metastatic melanoma model.
人们普遍认为淋巴结（LNs）是癌症疫苗的关键靶点，并且粒径在 10 至 100nm 之间、表面带中性或负电荷的颗粒，经皮下或皮内注射后更有利于淋巴转移。然而，它们被抗原提呈细胞（APCs）摄取的能力有限，并且在 LNs 中的保留不足，这无疑限制了它们在激活 T 细胞免疫方面的效力。在这里，我们通过调整聚合物混合胶束（HM）的物理化学性质来解决这个问题，HM 是通过疏水和静电相互作用自两种两亲性嵌段共聚物聚（乙二醇）磷乙醇胺（PEG-PE）和聚乙二胺-硬脂酸缀合物（PSA）组装而成的。我们成功地将黑色素瘤抗原肽 Trp2 和 Toll 样受体-9（TLR-9）激动剂 CpG ODN 包封到尺寸小于 30nm 的 HM 中。它们的表面特性与体内动力学密切相关，可以通过简单地调整 PEG-PE 和 PSA 的摩尔比来调节。我们的结果表明，具有等摩尔 PEG-PE 和 PSA 的优化 HM 可以有效地靶向近端 LNs，其中其货物被 DC 有效内化。此外，HM 介导的 Trp2/CpG 递药系统大大扩增了抗原特异性细胞毒性 T 淋巴细胞（CTL），并在肺转移黑色素瘤模型中提供了强大的抗肿瘤作用。
