Wagner Julia, Gößl Dorothée, Ustyanovska Natasha, Xiong Mengyao, Hauser Daniel, Zhuzhgova Olga, Hočevar Sandra, Taskoparan Betül, Poller Laura, Datz Stefan, Engelke Hanna, Daali Youssef, Bein Thomas, Bourquin Carole
Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland.
School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland.
ACS Nano. 2021 Mar 23;15(3):4450-4466. doi: 10.1021/acsnano.0c08384. Epub 2021 Mar 1.
Nanoparticle-based delivery systems for cancer immunotherapies aim to improve the safety and efficacy of these treatments through local delivery to specialized antigen-presenting cells (APCs). Multifunctional mesoporous silica nanoparticles (MSNs), with their large surface areas, their tunable particle and pore sizes, and their spatially controlled functionalization, represent a safe and versatile carrier system. In this study, we demonstrate the potential of MSNs as a pH-responsive drug carrier system for the anticancer immune-stimulant R848 (resiquimod), a synthetic Toll-like receptor 7 and 8 agonist. Equipped with a biotin-avidin cap, the tailor-made nanoparticles showed efficient stimuli-responsive release of their R848 cargo in an environmental pH of 5.5 or below. We showed that the MSNs loaded with R848 were rapidly taken up by APCs into the acidic environment of the lysosome and that they potently activated the immune cells. Upon subcutaneous injection into mice, the particles accumulated in migratory dendritic cells (DCs) in the draining lymph nodes, where they strongly enhanced the activation of the DCs. Furthermore, simultaneous delivery of the model antigen OVA and the adjuvant R848 by MSNs resulted in an augmented antigen-specific T-cell response. The MSNs significantly improved the pharmacokinetic profile of R848 in mice, as the half-life of the drug was increased 6-fold, and at the same time, the systemic exposure was reduced. In summary, we demonstrate that MSNs represent a promising tool for targeted delivery of the immune modulator R848 to APCs and hold considerable potential as a carrier for cancer vaccines.
用于癌症免疫治疗的基于纳米颗粒的递送系统旨在通过局部递送至专门的抗原呈递细胞（APC）来提高这些治疗的安全性和有效性。多功能介孔二氧化硅纳米颗粒（MSN）具有大的表面积、可调节的颗粒和孔径以及空间可控的功能化，是一种安全且通用的载体系统。在本研究中，我们证明了MSN作为抗癌免疫刺激剂R848（瑞喹莫德）的pH响应性药物载体系统的潜力，R848是一种合成的Toll样受体7和8激动剂。配备生物素-抗生物素蛋白帽的定制纳米颗粒在环境pH为5.5或更低时显示出其R848货物的有效刺激响应释放。我们表明，负载R848的MSN被APC迅速摄取到溶酶体的酸性环境中，并且它们有力地激活了免疫细胞。皮下注射到小鼠体内后，颗粒在引流淋巴结中的迁移树突状细胞（DC）中积累，在那里它们强烈增强了DC的激活。此外，MSN同时递送模型抗原OVA和佐剂R848导致增强的抗原特异性T细胞反应。MSN显著改善了R848在小鼠体内的药代动力学特征，因为药物的半衰期增加了6倍，同时全身暴露减少。总之，我们证明MSN是将免疫调节剂R848靶向递送至APC的有前途的工具，并且作为癌症疫苗的载体具有相当大的潜力。
