Department of Nanomedicines and Theranostics, Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Clinic, 52074 Aachen, Germany; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, 3584 CG, Utrecht, The Netherlands.
Department of Nanomedicines and Theranostics, Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Clinic, 52074 Aachen, Germany.
Adv Drug Deliv Rev. 2017 Sep 15;119:44-60. doi: 10.1016/j.addr.2017.07.007. Epub 2017 Jul 8.
The performance of nanomedicine formulations depends on the Enhanced Permeability and Retention (EPR) effect. Prototypic nanomedicine-based drug delivery systems, such as liposomes, polymers and micelles, aim to exploit the EPR effect to accumulate at pathological sites, to thereby improve the balance between drug efficacy and toxicity. Thus far, however, tumor-targeted nanomedicines have not yet managed to achieve convincing therapeutic results, at least not in large cohorts of patients. This is likely mostly due to high inter- and intra-patient heterogeneity in EPR. Besides developing (imaging) biomarkers to monitor and predict EPR, another strategy to address this heterogeneity is the establishment of vessel modulation strategies to homogenize and improve EPR. Over the years, several pharmacological and physical co-treatments have been evaluated to improve EPR-mediated tumor targeting. These include pharmacological strategies, such as vessel permeabilization, normalization, disruption and promotion, as well as physical EPR enhancement via hyperthermia, radiotherapy, sonoporation and phototherapy. In the present manuscript, we summarize exemplary studies showing that pharmacological and physical vessel modulation strategies can be used to improve tumor-targeted drug delivery, and we discuss how these advanced combination regimens can be optimally employed to enhance the (pre-) clinical performance of tumor-targeted nanomedicines.
纳米医学制剂的性能取决于增强型通透性和保留（EPR）效应。典型的基于纳米医学的药物递送系统，如脂质体、聚合物和胶束，旨在利用 EPR 效应在病理部位积累，从而提高药物疗效和毒性之间的平衡。然而，到目前为止，肿瘤靶向纳米药物尚未能够取得令人信服的治疗效果，至少在大量患者中没有。这可能主要是由于 EPR 存在高度的个体间和个体内异质性。除了开发（成像）生物标志物来监测和预测 EPR 外，另一种解决这种异质性的策略是建立血管调节策略，使 EPR 均匀化和改善。多年来，已经评估了几种药理学和物理联合治疗方法来改善 EPR 介导的肿瘤靶向。这些方法包括药理学策略，如血管通透性、正常化、破坏和促进，以及通过热疗、放疗、声孔和光疗来增强 EPR。在本手稿中，我们总结了一些示例研究，表明药理学和物理血管调节策略可用于改善肿瘤靶向药物递送，并讨论了如何优化这些先进的联合方案来增强肿瘤靶向纳米药物的（临床前）性能。
