Zhang Cheng, Liu Tianqing, Wang Wenqian, Bell Craig A, Han Yanxiao, Fu Changkui, Peng Hui, Tan Xiao, Král Petr, Gaus Katharina, Gooding J Justin, Whittaker Andrew K
Materials Research Laboratory, University of California, Santa Barbara, California 93106, United States.
QIMR Berghofer Medical Research Institute, Brisbane, Qld 4006, Australia.
ACS Nano. 2020 Jun 23;14(6):7425-7434. doi: 10.1021/acsnano.0c02954. Epub 2020 May 18.
Incorporation of fluorinated moieties in polymeric nanoparticles has been shown in many instances to increase their uptake by living cells and, hence, has proven to be a useful approach to enhancing delivery to cells. However, it remains unclear how incorporation of fluorine affects critical transport processes, such as interactions with membranes, intracellular transport, and tumor penetration. In this study, we investigate the influence of fluorine on transport properties using a series of rationally designed poly(oligo(ethylene glycol) methyl ether acrylate)--perfluoropolyether (poly(OEGA)-PFPE) copolymers. Copolymers with different fluorine contents were prepared and exhibit aggregate in solution in a manner dependent on the fluorine content. Doxorubicin-conjugated poly(OEGA)-PFPE nanoparticles with lower fluorine content exist in solution as unimers, leading to greater exposure of hydrophobic PFPE segments to the cell surface. This, in turn, results in greater cellular uptake, deeper tumor penetration, as well as enhanced therapeutic efficacy compared to that with the micelle-state nanoaggregates (poly(OEGA)-PFPE and poly(OEGA)-PFPE) with higher fluorine content but with less PFPE exposed to the cell membranes. Our results demonstrate that the aggregation behavior of these fluorinated polymers plays a critical role in internalization and transport in living cells and 3D spheroids, providing important design criteria for the preparation of highly effective delivery agents.
在许多情况下，已表明在聚合物纳米颗粒中引入含氟部分可增加活细胞对它们的摄取，因此，已证明这是一种增强细胞递送的有用方法。然而，氟的引入如何影响关键的转运过程，如与膜的相互作用、细胞内转运和肿瘤渗透，仍不清楚。在本研究中，我们使用一系列合理设计的聚（寡聚（乙二醇）甲基醚丙烯酸酯）-全氟聚醚（聚（OEGA）-PFPE）共聚物研究氟对转运性质的影响。制备了具有不同氟含量的共聚物，其在溶液中的聚集方式取决于氟含量。氟含量较低的阿霉素缀合聚（OEGA）-PFPE纳米颗粒以单聚体形式存在于溶液中，导致疏水性PFPE链段更多地暴露于细胞表面。这反过来又导致更高的细胞摄取、更深的肿瘤渗透，以及与氟含量较高但暴露于细胞膜的PFPE较少的胶束态纳米聚集体（聚（OEGA）-PFPE和聚（OEGA）-PFPE）相比更高的治疗效果。我们的结果表明，这些含氟聚合物的聚集行为在活细胞和3D球体的内化和转运中起关键作用，为制备高效递送剂提供了重要的设计标准。
