# Enhancement of EPR Effect for Passive Tumor Targeting: Current Status and Future Perspectives
## 3 Morphological Characteristics of the Vascular Network
### Functional Characteristics of the Tumor Vascular System
#### 3.4.4 Decreased Lymphatic Drainage and Increased Interstitial Fluid Pressure (IFP)  
Transport of Dissolved Substances Through Vascular Walls  
An ideal vascular network enables sequential blood flow from arteries to veins via arterioles, capillaries, and venules, with capillaries and post-capillary venules serving as primary sites for fluid and solute exchange due to their thin walls and large surface area [106]. No molecule or cell reaches cancer cells without traversing the vascular and interstitial compartments. In normal tissues, solute transport occurs via diffusion, driven by concentration gradients, and convection, driven by pressure gradients. Small hydrophilic and lipophilic molecules primarily diffuse, whereas large molecules utilize both mechanisms. According to [PERSON]'s hypothesis, capillary hydrostatic and osmotic pressure gradients regulate movement through the vascular wall. While some interstitial fluid is reabsorbed by the microvasculature, the rest is cleared by the lymphatic system [106].  
High Interstitial Fluid Pressure (IFP)  
The tumor tissue exhibits increased stiffness due to increased interstitial fluid pressure (IFP), which remains high in the tumor core and decreases sharply at the periphery, driving the interstitial fluid flow (IFF) outwards. IFP in solid tumors ranges from 5 to 40 mm Hg, compared to 0-3 mm Hg in normal tissue [106; 107]. Elevated IFP prevents the penetration of therapeutic agents through the EPR effect, as drugs reaching the tumor periphery cannot diffuse centrally [106; 107; 108; 109]. However, macromolecular agents can be extruded and accumulate on the tumor surface. IFP at the tumor site is like the microvascular pressures of the surrounding capillaries, contributing to tumor cell migration and promoting tumor invasion and proliferation [106].  
The exact mechanisms underlying the increase in IFP remain unclear but likely include increased vascular permeability, ECM stiffness, increased blood influx, and inadequate lymphatic drainage [107; 109].  
Decreased Lymphatic Drainage  
The lymphatic system is vital for tissue fluid balance and immunity [110]. It parallels the vascular network, extends throughout the body, and drains the components of the interstitial fluid, especially lipids and plasma proteins [75; 111]. Under normal conditions, the initial lymphatic vessels collect extracellular fluids, which carry tissue waste, proteins, and antigens, which together with immune cells form the lymph. It is transported from the interstitial space into the bloodstream through a network of lymphatic vessels and lymph nodes, which filter and regulate immune responses. The movement of lymph is controlled by the contraction of smooth muscle cells and the direction of flow is determined by valves that prevent backflow. Because of the large gaps in endothelial cells and the absence of a basement membrane and pericytes, lymphatic vessels have increased permeability.  
In cancer, the obstruction or dysfunction of lymphatic vessels due to increased interstitial fluid pressure (IFP) leads to the accumulation of fluids in tissues, i.e., extracellular lipids and macromolecules, reduced immunity, and the migration of cancer cells into lymph nodes, causing immunosuppression [75; 110; 111; 112; 110; 111; 113; 114; 115; 116; 117; 118; 119; 120; 121; 122]. Lymphangiogenesis, induced by the binding of VEGF-C and VEGF-D to VEGFR-3 receptors, facilitates tumor drainage and cancer spread through the lymphatic system [75; 112].  
Increased vascular permeability in solid tumors allows the passage of liposomes, nanoparticles, and macromolecular drugs with pore sizes smaller than the pores, enhancing the phenomenon of increased permeability and retention. The lack of lymphatic drainage leads to the trapping and retention of anticancer agents in the tumor site. In addition to the unique characteristics of the cancer vascular network, the physicochemical properties of the administered nanomedicines play a crucial role in the effective targeting of tumors using the EPR effect [101].