Brückner Maximilian, Fichter Michael, da Costa Marques Richard, Landfester Katharina, Mailänder Volker
Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.
Pharmaceutics. 2022 Aug 2;14(8):1614. doi: 10.3390/pharmaceutics14081614.
Successful cell targeting depends on the controlled positioning of cell-type-specific antibodies on the nanocarrier's (NC) surface. Uncontrolled antibody immobilization results in unintended cell uptake due to Fc-mediated cell interaction. Consequently, precise immobilization of the Fc region towards the nanocarrier surface is needed with the Fab regions staying freely accessible for antigen binding. Moreover, the antibody needs to be a certain distance from the nanocarrier surface, influencing the targeting performance after formation of the biomolecular corona. This can be achieved by using PEG linker molecules. Here we demonstrate cell type-specific targeting for dendritic cells (DC) as cellular key regulators of immune responses. However, to date, dendritic cell targeting experiments using different linker lengths still need to be conducted. Consequently, we focused on the surface modification of nanocarriers with different molecular weight PEG linkers (0.65, 2, and 5 kDa), and their ability to reduce undesired cell uptake, while achieving efficient DC targeting via covalently immobilized antibodies (stealth targeting). Our findings demonstrate that the PEG linker length significantly affects active dendritic cell targeting from cell lines (DC2.4) to primary cells (BMDCs, splenocytic conventional DCs type 1 (cDC1)). While antibody-functionalized nanocarriers with a shorter PEG length (0.65 kDa) showed the best targeting in DC2.4, a longer PEG length (5 kDa) was required to specifically accumulate in BMDCs and splenocytic cDC1. Our study highlights that these crucial aspects must be considered when targeting dendritic cell subsets, which are of great importance in the fields of cancer immunotherapy and vaccine development.
成功的细胞靶向取决于细胞类型特异性抗体在纳米载体（NC）表面的可控定位。由于Fc介导的细胞相互作用，不受控制的抗体固定会导致意外的细胞摄取。因此，需要将Fc区域精确固定在纳米载体表面，同时使Fab区域保持可自由用于抗原结合。此外，抗体需要与纳米载体表面保持一定距离，这会影响生物分子冠形成后的靶向性能。这可以通过使用聚乙二醇（PEG）连接分子来实现。在此，我们展示了针对树突状细胞（DC）的细胞类型特异性靶向，树突状细胞是免疫反应的关键细胞调节因子。然而，迄今为止，仍需进行使用不同连接子长度的树突状细胞靶向实验。因此，我们专注于用不同分子量的PEG连接子（0.65、2和5 kDa）对纳米载体进行表面修饰，以及它们减少不必要细胞摄取的能力，同时通过共价固定抗体实现有效的DC靶向（隐形靶向）。我们的研究结果表明，PEG连接子长度显著影响从细胞系（DC2.4）到原代细胞（骨髓来源的树突状细胞、脾细胞常规1型树突状细胞（cDC1））的活性树突状细胞靶向。虽然PEG长度较短（0.65 kDa）的抗体功能化纳米载体在DC2.4中表现出最佳靶向效果，但需要更长的PEG长度（5 kDa）才能在骨髓来源的树突状细胞和脾细胞cDC1中特异性积累。我们的研究强调，在靶向树突状细胞亚群时必须考虑这些关键因素，这在癌症免疫治疗和疫苗开发领域非常重要。
