# Enhancement of EPR Effect for Passive Tumor Targeting: Current Status and Future Perspectives
## 4 The Use of EPR in Passive Tumor Targeting with Nanomedicines
### Active and Passive Tumor Targeting  
Nanoparticles have been extensively studied as diagnostic and therapeutic agents for tumor targeting, either passively through the EPR phenomenon or actively through receptor targeting, or with a strategy combining both to enhance accumulation and retention [125; 126]. The goal of these strategies is the effective delivery of nanoparticles and their therapeutic payloads, preferably to diseased tissues, while minimizing their accumulation in healthy organs and cells [123].  
Nanoparticles designed for active tumor targeting carry specific surface ligands (targeting ligands), which are biomolecules that recognize and bind to specific cell surface receptors on cancer cells with high affinity. The rationale for using these strategies over passive targeting is twofold: (a) improving the retention of passively accumulated nanopar  
\begin{table}
\begin{tabular}{p{113.8 pt} p{113.8 pt} p{113.8 pt}} \hline \hline
**Section** & \multicolumn{1}{c}{**Details**} & **References** \\ \hline Positive Regulators of Angiogenesis & VEGF family (VEGF-A, B, C, D), PlGF, angiopoietins, CXC chemokines, TGF-alpha, PDGF-BB, and others stimulate endothelial proliferation and migration. & [77; 94; 98] \\ \hline Negative Regulators of Angiogenesis & Inhibitors like angiostatin, interleukin, and other cytokines suppress angiogenesis and prevent tumor growth. & [77; 94; 78] \\ \hline Permeability and Fluid Diffusion & Tumor permeability is altered due to ECM changes and is regulated by EC junctions (TJs, AJs, GJs), whose disruption in cancer leads to endothelial barrier breakdown. This increases vascular permeability and facilitates molecular diffusion and transport. & [72; 73; 75; 85; 99; 100] \\ \hline Lymphatic Drainage and Interstitial Fluid Pressure & Decreased lymphatic drainage leads to increased interstitial fluid pressure (IFP) and cancer tissue stiffness. IFP ranges from 5 to 40 mm Hg in tumors. & [72; 73; 75; 85; 99; 100] \\ \hline \hline \end{tabular}
\end{table}
Table 2: _Cont._ticles in diseased areas due to the specific interaction between surface ligands and cell surface receptors, and (b) increasing the specific interaction of nanoparticles with the targeted diseased cells while minimizing interactions of the nanoparticle with other non-target cells [123].  
Passive tumor targeting is closely associated with the enhanced permeability and retention phenomenon [123]. Passive targeting deposits the drug or drug-carrier complex at a specific site because of physicochemical or pharmacological factors [127]. Specifically, the intravenous administration of nanoscale materials, first reported by [PERSON] and [PERSON] in 1986, leads to the spontaneous accumulation of administered macromolecular drugs in areas of solid tumors with leaky vessels and the retention of nanoparticles within the tumor due to reduced lymphatic drainage [123; 127]. The synthesis of therapeutic molecules in nanocariers has been significantly developed to produce anticancer nanomedicines and their targeted delivery to solid tumors and hematologic cancers, exploiting the EPR phenomenon [125].