Cancer therapy often relies on the combined action of different molecules to overcome drug resistance and enhance patient outcome. Combined strategies relying on molecules with different pharmacokinetics often fail due to the lack of concomitant tumor accumulation and, thus, in the loss of synergistic effect. Due to their ability to enhance treatment efficiency, improve drug pharmacokinetics, and reduce adverse effects, polymer nanoparticles (PNPs) have been widely investigated as co-delivery vehicles for cancer therapies. However, co-encapsulation of different drugs and probes in PNPs requires a flexible polymer platform and a tailored particle design, in which both the bulk and surface properties of the carriers are carefully controlled.

In this work, we propose a core-shell PNP design based on a polyurethane (PUR) core and a phospholipid external surface. The modulation of the hydrophilic/hydrophobic balance of the PUR core enhanced the encapsulation of two chemotherapeutics with dramatically different water solubility (Doxorubicin hydrochloride, DOXO and Docetaxel, DCTXL) and of Iron Oxide Nanoparticles for MRI imaging. The outer shell remained unchanged among the platforms, resulting in un-modified cellular uptake and in vivo biodistribution. We demonstrate that the choice of PUR core allowed a very high entrapment efficiency of all drugs, superior or comparable to previously reported results and that higher core hydrophilicity enhances the loading efficiency of the hydrophilic Doxorubicin and the MRI contrast. Moreover, we show that changing the PUR core did not alter the surface properties of the carriers, since all particles showed a similar behavior in terms of cell internalization and in vivo biodistribution. We also show that PUR PNPs have very high passive tumor accumulation and that they can efficient co-deliver the 2 drugs to the tumor, reaching an 11-fold higher DOXO/DCTXL ratio in tumor as compared to free drugs.

Statement of significance

Exploiting the synergistic action of multiple chemotherapeutics is a promising strategy to improve the outcome of cancer patients, as different agents can simultaneously engage different features of tumor cells and/or their microenvironment. Unfortunately, the choice is limited to drugs with similar pharmacokinetics that can concomitantly accumulate in tumors. To expand the spectrum of agents that can be delivered in combination, we propose a multi-compartmental core-shell nanoparticle approach, in which the core is made of biomaterials with high affinity for drugs of different physical properties. We successfully co-encapsulated Doxorubicin Hydrochloride, Docetaxel, and contrast agents and achieved a significantly higher concomitant accumulation in tumor versus free drugs, demonstrating that nanoparticles can improve synergistic cancer chemotherapy.

中文翻译：

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交替使用基于嵌段共聚物的纳米颗粒作为调节多种化学疗法和成像探针负载的工具

癌症疗法通常依靠不同分子的联合作用来克服耐药性并提高患者预后。依赖于具有不同药代动力学的分子的联合策略常常由于缺乏伴随的肿瘤积累而失败，因此失去了协同作用。由于它们具有提高治疗效率，改善药物药代动力学和减少不良影响的能力，因此聚合物纳米颗粒（PNP）已被广泛研究为癌症治疗的共同给药载体。然而，将不同药物和探针共封装在PNP中需要一个灵活的聚合物平台和一个定制的颗粒设计，在该设计中，必须仔细控制载体的体积和表面性质。

在这项工作中，我们提出了一种基于聚氨酯（PUR）核和磷脂外表面的核-壳PNP设计。PUR核的亲水/疏水平衡的调节增强了两种化学疗法的包封性，这些化学疗法的水溶性大大不同（盐酸阿霉素，DOXO和多西他赛，DCTXL）和氧化铁纳米颗粒用于MRI成像。平台之间的外壳保持不变，导致未改变的细胞吸收和体内生物分布。我们证明，PUR核心的选择允许所有药物具有非常高的包封效率，优于或可与先前报道的结果相提并论，更高的核心亲水性可增强亲水性阿霉素和MRI造影剂的加载效率。而且，我们表明改变PUR核心不会改变载体的表面性能，因为所有颗粒在细胞内在化和体内生物分布方面均表现出相似的行为。我们还显示，PUR PNP具有很高的被动肿瘤蓄积性，并且它们可以有效地将2种药物共递送至肿瘤，与游离药物相比，其在肿瘤中的DOXO / DCTXL比高11倍。

重要声明

利用多种化学疗法的协同作用是改善癌症患者预后的有前途的策略，因为不同的药物可以同时参与肿瘤细胞和/或其微环境的不同特征。不幸的是，选择仅限于具有类似药代动力学的药物，这些药物会同时在肿瘤中蓄积。为了扩大可以组合使用的药剂的范围，我们提出了一种多隔室的核-壳纳米颗粒方法，其中的核是由对不同物理性质的药物具有高亲和力的生物材料制成。我们成功地将阿霉素盐酸盐，多西紫杉醇和造影剂共囊化，与游离药物相比，肿瘤中伴随的累积明显增加，