Impact of Zwitterionic Polymers on the Tumor Permeability of Molecular Bottlebrush-Based Nanoparticles
Impact of Zwitterionic Polymers on the Tumor Permeability of Molecular Bottlebrush-Based Nanoparticles
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DOI：
10.1021/acs.biomac.2c00216
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发表时间：
2022-04-29
影响因子：
6.2
通讯作者：
Sakurai, Kazuo
中科院分区：
文献类型：
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作者：
Fujii, Shota;Takano, Shin;Sakurai, Kazuo
具有生物分子防污特性的生物相容性聚合物必须与纳米颗粒结合用于癌症化疗，以改善其在血液中的保留和随后的肿瘤积聚。然而，这些特性同时导致其对细胞的亲和力较差，从而导致肿瘤组织的渗透性较低，这是实现有效抗癌功效的主要障碍之一。为了解决这个问题，我们试图用分子瓶刷（mb）作为由各种生物相容性聚合物组成的模型聚合物纳米颗粒来阐明纳米颗粒的肿瘤渗透性。由非离子型聚乙二醇甲基丙烯酸甲醚（PEGMA）组成的MB完全没有肿瘤渗透性，而由聚甲基丙烯酸磷酸甜菜碱（phosphobetaine methacrylate）、聚甲基丙烯酸亚砜甜菜碱（sulfobetaine methacrylate）或聚甲基丙烯酸羧甜菜碱（carboxybetaine methacrylate）组成的两性离子MB则能深入肿瘤组织。基于羧甜菜碱的MBs显示出有效的细胞摄取癌细胞，而其他MBs则没有，这使得它们能够通过胞吞途径渗透到肿瘤组织中。此外，它们的渗透性基于细胞间或细胞内途径，这可能与甜菜碱的两性离子特性有关，甜菜碱可以识别癌细胞上的蛋白质转运体。令人惊讶的是，仅将10mol %的两性离子甜菜碱聚合物加入到pegma基mb中，就能显著提高其组织渗透性。该平台技术使我们能够重新设计临床应用于癌症化疗的聚乙二醇基纳米颗粒。
Biocompatible polymers possessing antifouling properties for biomolecules are necessary to be combined with nanoparticles for cancer chemotherapy to improve their retention in blood and subsequent tumor accumulation. However, these properties simultaneously lead to poor affinity to cells, and low tumor tissue permeability subsequently, which is one of the major barriers in achieving efficient anticancer efficacy. To address this, we try to elucidate the tumor permeability of nanoparticles using molecular bottlebrushes (MBs) as model polymeric nanoparticles composed of various biocompatible polymers. An MB comprising nonionic poly[(ethylene glycol) methyl ether methacrylate] (PEGMA) shows no tumor permeability at all, whereas zwitterionic MBs composed of poly(phosphobetaine methacrylate), poly(sulfobetaine methacrylate), or poly(carboxybetaine methacrylate) penetrate deeply into tumor tissues. The carboxybetaine-based MBs showed an efficient cellular uptake into cancer cells while the other MBs did not, which enable them to penetrate into tumor tissues via the transcytosis pathway. Additionally, their permeability is based on intercellular or intracellular pathways, which might be related to the zwitterionic betaine properties that recognize protein transporters on cancer cells. Surprisingly, incorporating only 10 mol % of the zwitterionic betaine polymers into PEGMA-based MBs significantly enhances their tissue permeability. This platform technology enables us to redesign the PEG-based nanoparticles developed for cancer chemotherapy in clinical applications.