Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
Institute of Macromolecular Chemistry v.v.i, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Int J Nanomedicine. 2019 Aug 6;14:6269-6285. doi: 10.2147/IJN.S208938. eCollection 2019.
Reactive oxygen species (ROS), such as hydrogen peroxide and superoxide, trigger biodegradation of polymer-based nanoparticles (NPs) bearing pinacol-type boronic ester groups. These NPs may selectively release their cargo, in this case paclitaxel (PTX), at the high levels of ROS present in the intracellular environment of inflamed tissues and most tumors.
The main objective was to determine anti-tumor efficacy of PTX-loaded ROS-sensitive NPs and to examine whether macrophage infiltration had any impact on treatment efficacy.
NPs were synthesized and their characteristics in the presence of HO were demonstrated. Both confocal microscopy as well as flow cytometry approaches were used to determine degradation of ROS-sensitive NPs. HeLa cells were cultured in vitro and used to establish tumor xenografts in nude mice. In vivo experiments were performed to understand toxicity, biodistribution and anti-tumor efficacy of the NPs. Moreover, we performed immunohistochemistry on tumor sections to study infiltration of M1 and M2 subsets of macrophages.
We demonstrated that PTX delivered in NPs containing a ROS-sensitive polymer exhibits a better anti-tumor efficacy than PTX in NPs containing ROS-non-sensitive polymer, free PTX or Abraxane (nab-PTX). The biodistribution revealed that ROS-sensitive NPs exhibit retention in liver, spleen and lungs, suggesting a potential to target cancer metastasizing to these organs. Finally, we demonstrated a correlation between infiltrated macrophage subsets and treatment efficacy, possibly contributing to the efficient anti-tumor effects.
Treatment with ROS-sensitive NPs containing PTX gave an improved therapeutic effect in HeLa xenografts than their counterpart, free PTX or nab-PTX. Our data revealed a correlation between macrophage infiltration and efficiency of the different antitumor treatments, as the most effective NPs resulted in the highest infiltration of the anti-tumorigenic M1 macrophages.
活性氧（ROS），如过氧化氢和超氧自由基，可引发带有频哪醇型硼酸酯基团的聚合物纳米粒子（NPs）的生物降解。这些 NPs 可以在炎症组织和大多数肿瘤的细胞内环境中存在的高水平 ROS 存在的情况下选择性地释放其货物，在这种情况下是紫杉醇（PTX）。
主要目的是确定负载 ROS 敏感型 NPs 的紫杉醇的抗肿瘤功效，并研究巨噬细胞浸润对治疗效果的影响。
合成了 NPs，并证明了它们在 HO 存在下的特性。使用共聚焦显微镜和流式细胞术方法来确定 ROS 敏感型 NPs 的降解情况。在体外培养 HeLa 细胞，并将其用于在裸鼠中建立肿瘤异种移植。进行体内实验以了解 NPs 的毒性、生物分布和抗肿瘤功效。此外，我们对肿瘤切片进行免疫组织化学染色，以研究 M1 和 M2 巨噬细胞亚群的浸润情况。
我们证明了在包含 ROS 敏感型聚合物的 NPs 中递送的 PTX 比在包含 ROS 非敏感型聚合物、游离 PTX 或 Abraxane（nab-PTX）的 NPs 中递送的 PTX 具有更好的抗肿瘤功效。生物分布表明 ROS 敏感型 NPs 会在肝脏、脾脏和肺部滞留，表明它们有可能靶向转移到这些器官的癌症。最后，我们证明了浸润的巨噬细胞亚群与治疗效果之间存在相关性，这可能有助于实现有效的抗肿瘤作用。
与游离 PTX 或 nab-PTX 相比，用负载 PTX 的 ROS 敏感型 NPs 治疗 HeLa 异种移植瘤可获得更好的治疗效果。我们的数据揭示了巨噬细胞浸润与不同抗肿瘤治疗效果之间的相关性，因为最有效的 NPs 导致抗肿瘤 M1 巨噬细胞的浸润最高。
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