Augmentation of the EPR effect by mild hyperthermia to improve nanoparticle delivery to the tumor

The clinical translation of the nanoparticle (NP)-based anticancer therapies is still unsatisfactory due to the heterogeneity of the enhanced permeability and retention (EPR) effect. Despite the promising preclinical outcome of the pharmacological EPR enhancers, their systemic toxicity can limit their clinical application. Hyperthermia (HT) presents an efficient tool to augment the EPR by improving tumor blood flow (TBF) and vascular permeability, lowering interstitial fluid pressure (IFP), and disrupting the structure of the extracellular matrix (ECM). Furthermore, the HT-triggered intravascular release approach can overcome the EPR effect. In contrast to pharmacological approaches, HT is safe and can be focused to cancer tissues. Moreover, HT conveys direct anti-cancer effects, which improve the efficacy of the anti-cancer agents encapsulated in NPs. However, the clinical application of HT is challenging due to the heterogeneous distribution of temperature within the tumor, the length of the treatment and the complexity of monitoring.