Raphas R&D Center/Raphas Co., Ltd. , Seoul 07793 , Republic of Korea.
ACS Nano. 2018 Oct 23;12(10):9702-9713. doi: 10.1021/acsnano.8b04146. Epub 2018 Sep 4.
Efficient delivery of tumor antigens and immunostimulatory adjuvants into lymph nodes is crucial for the maturation and activation of antigen-presenting cells (APCs), which subsequently induce adaptive antitumor immunity. A dissolving microneedle (MN) has been considered as an attractive method for transcutaneous immunization due to its superior ability to deliver vaccines through the stratum corneum in a minimally invasive manner. However, because dissolving MNs are mostly prepared using water-soluble sugars or polymers for their rapid dissolution in intradermal fluid after administration, they are often difficult to formulate with poorly water-soluble vaccine components. Here, we develop amphiphilic triblock copolymer-based dissolving MNs in situ that generate nanomicelles (NMCs) upon their dissolution after cutaneous application, which facilitate the efficient encapsulation of poorly water-soluble Toll-like receptor 7/8 agonist (R848) and the delivery of hydrophilic antigens. The sizes of NMCs range from 30 to 40 nm, which is suitable for the efficient delivery of R848 and antigens to lymph nodes and promotion of cellular uptake by APCs, minimizing systemic exposure of the R848. Application of MNs containing tumor model antigen (OVA) and R848 to the skin of EG7-OVA tumor-bearing mice induced a significant level of antigen-specific humoral and cellular immunity, resulting in significant antitumor activity.
高效地将肿瘤抗原和免疫佐剂递送至淋巴结对于抗原呈递细胞（APC）的成熟和激活至关重要，这会继而诱导适应性抗肿瘤免疫。由于溶解微针（MN）具有通过角质层以微创方式递送疫苗的卓越能力，因此被认为是一种有吸引力的经皮免疫方法。然而，由于溶解 MN 主要是使用水溶性糖或聚合物来制备的，以便在给药后在皮内液中快速溶解，因此它们通常难以与水溶性差的疫苗成分形成配方。在这里，我们开发了基于两亲性嵌段共聚物的原位溶解 MN，其在经皮应用后会形成纳米胶束（NMC），这有利于高效包封水溶性差的 Toll 样受体 7/8 激动剂（R848）和亲水性抗原。NMC 的大小在 30 至 40nm 之间，这适合 R848 和抗原向淋巴结的高效递送，并促进 APC 的细胞摄取，从而使 R848 的全身暴露最小化。将含有肿瘤模型抗原（OVA）和 R848 的 MN 应用于 EG7-OVA 荷瘤小鼠的皮肤，可诱导显著水平的抗原特异性体液和细胞免疫，从而产生显著的抗肿瘤活性。
