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.

纳米药物制剂的性能取决于增强渗透性和保留 (EPR) 效应。基于纳米药物的原型药物递送系统，如脂质体、聚合物和胶束，旨在利用 EPR 效应在病理部位积累，从而改善药物疗效和毒性之间的平衡。然而，到目前为止，靶向肿瘤的纳米药物还没有取得令人信服的治疗结果，至少在大量患者中还没有。这可能主要是由于 EPR 的高患者间和患者内异质性。除了开发（成像）生物标志物来监测和预测 EPR，解决这种异质性的另一种策略是建立血管调节策略以均质化和改善 EPR。这些年来，已经评估了几种药理学和物理联合治疗以改善 EPR 介导的肿瘤靶向。这些包括药理学策略，例如血管通透性、正常化、破坏和促进，以及通过热疗、放射疗法、超声穿孔和光疗增强物理 EPR。在本手稿中，我们总结了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输送的示例性研究，并讨论了如何最佳地使用这些先进的组合方案来增强（预）临床表现肿瘤靶向纳米药物。以及通过热疗、放射疗法、声孔疗法和光疗增强物理 EPR。在本手稿中，我们总结了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输送的示例性研究，并讨论了如何最佳地使用这些先进的组合方案来增强（预）临床表现肿瘤靶向纳米药物。以及通过热疗、放射疗法、声孔疗法和光疗增强物理 EPR。在本手稿中，我们总结了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输送的示例性研究，并讨论了如何最佳地使用这些先进的组合方案来增强（预）临床表现肿瘤靶向纳米药物。