Department of Biomedical Engineering, Translational Tissue Engineering Center, and Institute for NanoBioTechnology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Department of Biomedical Engineering, Translational Tissue Engineering Center, and Institute for NanoBioTechnology, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Departments of Oncology, Materials Science and Engineering, Chemical and Biomolecular Engineering, Ophthalmology, and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Mol Immunol. 2018 Jun;98:13-18. doi: 10.1016/j.molimm.2018.02.016. Epub 2018 Mar 7.
Exciting developments in cancer nanomedicine include the engineering of nanocarriers to deliver drugs locally to tumors, increasing efficacy and reducing off-target toxicity associated with chemotherapies. Despite nanocarrier advances, metastatic cancer remains challenging to treat due to barriers that prevent nanoparticles from gaining access to remote, dispersed, and poorly vascularized metastatic tumors. Instead of relying on nanoparticles to directly destroy every tumor cell, immunotherapeutic approaches target immune cells to train them to recognize and destroy tumor cells, which, due to the amplification and specificity of an adaptive immune response, may be a more effective approach to treating metastatic cancer. One novel technology for cancer immunotherapy is the artificial antigen presenting cell (aAPC), a micro- or nanoparticle-based system that mimics an antigen presenting cell by presenting important signal proteins to T cells to activate them against cancer. Signal 1 molecules target the T cell receptor and facilitate antigen recognition by T cells, signal 2 molecules provide costimulation essential for T cell activation, and signal 3 consists of secreted cues that further stimulate T cells. Classic microscale aAPCs present signal 1 and 2 molecules on their surface, and biodegradable polymeric aAPCs offer the additional capability of releasing signal 3 cytokines and costimulatory molecules that modulate the T cell response. Although particles of approximately 5-10 μm in diameter may be considered the optimal size of an aAPC for ex vivo cellular expansion, nanoscale aAPCs have demonstrated superior in vivo pharmacokinetic properties and are more suitable for systemic injection. As sufficient surface contact between T cells and aAPCs is essential for activation, nano-aAPCs with microscale contact surface areas have been created through engineering approaches such as shape manipulation and nanoparticle clustering. These design strategies have demonstrated greatly enhanced efficacy of nano-aAPCs, endowing nano-aAPCs with the potential to be among the next generation of cancer nanomedicines.
癌症纳米医学的令人兴奋的发展包括工程纳米载体将药物局部递送到肿瘤，提高疗效并减少与化疗相关的脱靶毒性。尽管纳米载体取得了进展，但转移性癌症仍然难以治疗，因为存在阻止纳米颗粒进入远程、分散和血管不良的转移性肿瘤的障碍。免疫治疗方法不是依赖纳米颗粒直接破坏每个肿瘤细胞，而是靶向免疫细胞以训练它们识别和破坏肿瘤细胞，由于适应性免疫反应的放大和特异性，这可能是治疗转移性癌症的更有效方法。癌症免疫治疗的一种新的技术是人工抗原呈递细胞（aAPC），这是一种基于微或纳米颗粒的系统，通过向 T 细胞呈递重要的信号蛋白来模拟抗原呈递细胞，从而激活它们对抗癌症。信号 1 分子靶向 T 细胞受体并促进 T 细胞对抗原的识别，信号 2 分子提供 T 细胞激活所必需的共刺激，信号 3 由进一步刺激 T 细胞的分泌线索组成。经典的微尺度 aAPCs 在其表面呈现信号 1 和 2 分子，可生物降解的聚合物 aAPCs 提供了释放信号 3 细胞因子和共刺激分子的额外能力，这些细胞因子和共刺激分子调节 T 细胞反应。虽然直径约为 5-10μm 的颗粒可以被认为是用于体外细胞扩增的 aAPC 的最佳尺寸，但纳米级 aAPCs 已证明具有优越的体内药代动力学特性，更适合全身注射。由于 T 细胞和 aAPCs 之间的充分表面接触对于激活至关重要，因此通过形状操纵和纳米颗粒聚类等工程方法已经创建了具有微尺度接触表面积的纳米 aAPCs。这些设计策略已经证明了纳米 aAPCs 的功效大大增强，使纳米 aAPCs 有可能成为下一代癌症纳米医学的一部分。
