# Enhancement of EPR Effect for Passive Tumor Targeting: Current Status and Future Perspectives
###### Abstract  
The Enhanced Permeability and Retention (EPR) effect is a key mechanism for passive tumor targeting, which involves the selective accumulation of therapeutic nanoparticles in tumors due to their unique vascular characteristics. While previous reviews have explored this phenomenon, the present review offers a comprehensive, multidisciplinary approach, highlighting recent advancements in strategies to enhance the EPR effect, as well as novel insights into the role of tumor microenvironment heterogeneity and the multifaceted approaches to overcome EPR-related challenges. This review provides a detailed analysis of the latest developments in nanocarriers' design, including size, shape, and surface modifications, as well as cutting-edge multi-stage drug delivery systems. Furthermore, the integration of physical, pharmacological, and combinatory therapies to optimize the EPR effect is also discussed, aiming to improve the clinical translation of nanomedicines. Unlike other reviews, this work emphasizes the dynamic interaction between the tumor microenvironment and the vascular network, which remains underexplored in the current literature. In addition, specific clinical trials' outcomes are highlighted and future directions to address existing limitations are proposed, offering a clearer roadmap regarding clinical applications in cancer therapy. 2020 IEEE/RSJ International Conference on Biomedical Research (IEEE)
reduced lymphatic drainage, increased stiffness of the extracellular matrix (ECM), and high interstitial fluid pressure (IFP) in tumors [2]. Specifically, solid tumors exhibit increased angiogenesis driven by cancer cells, resulting in the mass development of abnormal, structurally, and functionally impaired blood vessels [3]. This angiogenesis leads to the hyperproliferation, migration, and rearrangement of endothelial cells to meet their energy demands for oxygen and nutrients [4; 5]. Consequently, endothelial cells can exhibit low density, creating large gaps between them and increased vascular permeability to macromolecules and nanoparticles, with pore sizes in the interstitial spaces ranging from 100 to 780 nm [3; 5; 6]. Additionally, abnormal lymphangiogenesis is observed, leading to ineffective lymphatic drainage in the tissues of solid tumors, which further contributes to the prolonged retention of extracellular macromolecules [5; 6]. Finally, tissues express high levels of inflammatory factors and mediators that sustain the EPR phenomenon, such as prostaglandandins, bradykinin, nitric oxide, proteases, interferon gamma, angiotensin-converting enzyme (ACE) inhibitors, and vascular permeability factor (VPF) or vascular endothelial growth factor (VEGF), among others [6; 7; 8]. Theoretically, enhanced permeability and retention (EPR) allows for the development of various nanomedicines, which reduce systemic toxicity and remain in the target area to exert their therapeutic effect [7]. However, targeting using the EPR phenomenon requires assumptions that are not guaranteed in real conditions, such as mass transfer exclusively towards cancer cells regardless of concentration gradients, interstitial fluid pressure (IFP) variations due to leakage from blood vessels, transport resistance, and selective application of IFP to lymphatics rather than blood vessels [9; 10; 11]. Moreover, some drugs do not distribute effectively, and controlling the mechanism remains challenging [12]. Over the past decades, EPR has been a recognized mechanism for the selective entry of nanoparticles, successful in preclinical models. However, few nanomedicines have transitioned to clinical therapy, as most achieve low toxicity but do not improve the clinical outcomes for patients [3; 7]. In this context, both the characteristics of nanomedicine itself and those of the target site play crucial roles.