Institute of Organic Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 10-14, ,55128, Mainz, Germany.
Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Obere Zahlbacher Straße 63, ,55131, Mainz, Germany.
Macromol Biosci. 2019 Jun;19(6):e1800481. doi: 10.1002/mabi.201800481. Epub 2019 Apr 10.
The selective activation of the immune system using nanoparticles as a drug delivery system is a promising field in cancer therapy. Block copolymers from HPMA and laurylmethacrylate-co-hymecromone-methacrylate allow the preparation of multifunctionalized core-crosslinked micelles of variable size. To activate dendritic cells (DCs) as antigen presenting cells, the carbohydrates mannose and trimannose are introduced into the hydrophilic corona as DC targeting units. To activate DCs, a lipophilic adjuvant (L18-MDP) is incorporated into the core of the micelles. To elicit an immune response, a model antigen peptide (SIINFEKL) is attached to the polymeric nanoparticle-in addition-via a click reaction with the terminal azide. Thereafter, the differently functionalized micelles are chemically and biologically characterized. While the core-crosslinked micelles without carbohydrate units are hardly bound by DCs, mannose and trimannose functionalization lead to a strong binding. Flow cytometric analysis and blocking studies employing mannan suggest the requirement of the mannose receptor and DC-SIGN for effective micelle binding. It could be suppressed by blocking with mannan. Adjuvant-loaded micelles functionalized with mannose and trimannose activate DCs, and DCs preincubated with antigen-conjugated micelles induce proliferation of antigen-specific CD8+ T cells.
使用纳米粒子作为药物递送系统选择性激活免疫系统是癌症治疗中一个很有前途的领域。HPMA 和月桂基甲基丙烯酸酯-co-海克酮甲基丙烯酸酯的嵌段共聚物允许制备具有不同尺寸的多功能化核交联胶束。为了激活树突状细胞（DC）作为抗原提呈细胞，将碳水化合物甘露糖和三糖引入亲水性冠作为 DC 靶向单元。为了激活 DC，将脂溶性佐剂（L18-MDP）掺入胶束的核心。为了引发免疫反应，通过与末端叠氮化物的点击反应将模型抗原肽（SIINFEKL）附加到聚合物纳米颗粒上。此后，对不同功能化的胶束进行化学和生物学表征。虽然没有碳水化合物单元的核交联胶束几乎不与 DC 结合，但甘露糖和三糖的功能化导致强烈的结合。流式细胞术分析和使用甘露聚糖的阻断研究表明，有效胶束结合需要甘露糖受体和 DC-SIGN。它可以通过用甘露聚糖阻断来抑制。用甘露糖和三糖功能化的载有佐剂的胶束激活 DC，并且用抗原偶联的胶束预先孵育的 DC 诱导抗原特异性 CD8+T 细胞的增殖。
