# Enhancement of EPR Effect for Passive Tumor Targeting: Current Status and Future Perspectives
## 6 Clinical Trials and Limitations  
Nanomedicine has made significant strides in cancer treatment by leveraging the enhanced permeability and retention (EPR) effect of the tumor microenvironment to facilitate drug delivery. The EPR effect allows nanoparticles to accumulate in tumors due to the leaky nature of tumor vasculature, which is particularly advantageous for nanocarries like liposomes and micelles. These nanoparticles passively target tumors, enhancing the delivery and effectiveness of chemotherapeutic agents. However, translating the EPR effect from preclinical models to clinical applications remains challenging [198]. A major limitation is tumor heterogeneity, which refers to variations in vascular permeability and interstitial pressure between tumor types. Such differences restrict the effectiveness of the EPR effect across various cancer types. Research by [PERSON] et al. emphasizes that the tumor microenvironment, including factors like blood flow and pressure, significantly influences nanoparticle delivery [11]. Thus, modulating these factors is crucial to optimizing nanoparticle distribution and therapeutic outcomes.  
Moreover, human and animal models differ considerably in tumor architecture and immune responses, further complicating clinical translation [199]. These disparities in tumor biology lead to variability in how nanoparticles accumulate and function within different individuals. Several strategies have been proposed to enhance the EPR effect in cancer therapy. One approach involves the use of nitric oxide donors to improve blood flow, while another uses enzyme-based methods, such as matrix metalloproteinase, to increase nanoparticle penetration through the tumor stroma [200,201]. Additionally, functionalized nanoparticles targeting specific tumor receptors, alongside external stimuli like hyperthermia and ultrasound, have shown promise in boosting drug delivery and therapeutic efficacy [202,203].  
Despite these advances, clinical translation remains inconsistent. Variability in tumor vascularization, immune infiltration, and extracellular matrix (ECM) composition affects the accumulation of nanoparticles in tumors. Even in cases where EPR conditions appear favorable, therapeutic efficacy can be unpredictable. Furthermore, factors such as nanoparticle size, surface properties, and circulation time impact biodistribution and clearance, introducing challenges like off-target delivery and rapid clearance by the immune system [180]. To address these issues, several clinical trials are underway to optimize the EPR effect in cancer therapy. Notable trials include the use of ThermoDox(r), a thermosensitive liposomal doxorubicin formulation, in combination with radiofrequency ablation (RFA) to enhance vascular permeability and improve drug delivery in hepatocellular carcinoma (HCC) [204]. Another trial explores sonoporation, using ultrasound and microbubbles to create temporary pores in tumor vasculature, enhancing nanoparticle delivery in pancreatic cancer [205]. In glioblastoma multiforme, magnetic nanoparticles are directed by external magnetic fields to improve tumor targeting and accumulation [206]. Other trials are investigating doxorubicin-loaded nanoparticles combined with vascular-modulating agents in breast cancer, as well as liposomal irinotecan (Onivyde(r)) in metastatic pancreatic cancer, which aim to increase drug retention through the EPR effect [207,208]. Table 3 summarizes the primary information on the clinical trials referred to above.  
In conclusion, while the EPR effect remains a cornerstone of cancer nanomedicine, its clinical application faces limitations due to tumor heterogeneity and the variability of patient responses. Current strategies, such as tumor microenvironment modulation, ligand-targeted nanoparticles, and external physical stimuli, hold promise for enhancing therapeutic outcomes. Nevertheless, continued refinement and better patient stratification are essential for the successful clinical translation of EPR-based therapies.