State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), College of Chemistry, Nankai University, Tianjin 300071, PR China.
Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, PR China.
Acta Biomater. 2018 Jan;65:339-348. doi: 10.1016/j.actbio.2017.10.034. Epub 2017 Oct 25.
Recently, zwitterionic materials have been developed as alternatives to PEG for prolonging the circulation time of nanoparticles without triggering immune responses. However, zwitterionic coatings also hindered the interactions between nanoparticles and tumor cells, leading to less efficient uptake of nanoparticles by cancer cells. Such effect significantly limited the applications of zwitterionic materials for the purposes of drug delivery and the development to novel therapeutic agents. To overcome these issues, surface-adaptive mixed-shell micelles (MSMs) with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)/poly(β-amino ester) (PAE) heterogeneous surfaces were constructed. Owing to the synergistic effect of zwitterionic coatings and micro-phase-separated surfaces, PMPC mixed-shell micelles exhibited the improved blood circulation time compared to single-PEG-shell micelles (PEGSMs) and single-PMPC-shell micelles (PMPCSMs). Moreover, such MSMs can convert their surface to positively charged ones in response to the acidic tumor microenvironment, leading to a significant enhancement in cellular uptake of MSMs by tumor cells. This strategy demonstrated a general approach to enhance the cellular uptake of zwitterionic nanoparticles without compromising their long circulating capability, providing a practical method for improving the tumor-targeting efficiency of particulate drug delivery systems.
Herein we demonstrate a general strategy to integrate non-fouling zwitterionic surface on the nanoparticles without compromising their capability of tumor accumulation, by constructing a surface-adaptive mixed-shell micelles (MSMs) with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)/poly(β-amino ester) (PAE) heterogeneous surfaces. At the blood pH (7.4), PAE chains collapsed to the inner of the shell due to the deprotonation, and the forming micro-phase separation structure was synergistic with zwitterionic surface to prolong the circulation time of MSMs in the blood. While at the tumor sites, PAE was protonated, and the positively charged surface of MSMs enhanced cellular uptake. This self-assembly-based strategy is compatible to other zwitterionic materials, endowing a great flexibility for the construction of responsive drug delivery systems particularly to the novel chemotherapeutic agents.
最近，两性离子材料已被开发为聚乙二醇的替代品，用于延长纳米粒子的循环时间而不引发免疫反应。然而，两性离子涂层也阻碍了纳米粒子与肿瘤细胞之间的相互作用，导致癌细胞对纳米粒子的摄取效率降低。这种效果显著限制了两性离子材料在药物输送和新型治疗剂开发方面的应用。为了克服这些问题，构建了具有聚（2-甲基丙烯酰氧基乙基磷酸胆碱）（PMPC）/聚（β-氨基酯）（PAE）异质表面的表面自适应混合壳胶束（MSMs）。由于两性离子涂层和微相分离表面的协同作用，与单 PEG 壳胶束（PEGSMs）和单 PMPC 壳胶束（PMPCSMs）相比，PMPC 混合壳胶束表现出改善的血液循环时间。此外，这种 MSM 可以在响应酸性肿瘤微环境时将其表面转化为正电性，从而显著增强肿瘤细胞对 MSM 的细胞摄取。该策略展示了一种在不损害其长循环能力的情况下增强两性离子纳米粒子细胞摄取的通用方法，为提高颗粒药物输送系统的肿瘤靶向效率提供了一种实用方法。
