# Enhancement of EPR Effect for Passive Tumor Targeting: Current Status and Future Perspectives
## 4 The Use of EPR in Passive Tumor Targeting with Nanomedicines
### Hardness Dependence  
The rigidity of nanoparticles, defined as their ability to resist deformation, plays a crucial role in the accumulation of nanomedicines within tumors [5; 147]. Specifically, softer and more flexible nanoparticles exhibit greater surface contact with cancer cells without necessarily being internalized, making them useful for effective targeting [5]. Moreover, these nanoparticles are less readily absorbed by macrophages of the immune system and, due to their deformability, are not easily removed by the body's biological filtration systems. Consequently, nanoparticles made from soft materials demonstrate longer circulation times in the bloodstream and higher accumulation in tumor tissues compared to their harder counterparts [147]. Nanoparticles' Biocompatibility and Stability  
The bioavailability of a material refers to its ability to elicit an appropriate host response in a specific situation, impacting either locally or systemically within the organism. This means that the presence of a material in tissue should perform predicted functions, with the induced response being appropriate for the intended application. Additionally, the nature of the response to a specific material and its suitability may vary depending on the context [148]. A high degree of bioavailability is achieved when a material interacts with the organism without causing undesirable toxic, immunogenic, thrombogenic, or carcinogenic reactions. Biocompatibility is heavily influenced by anatomy, meaning that the same biomaterial can elicit different reactions depending on the tissue it appears in or the application it is used for. Moreover, the inherent characteristics of biomaterials, such as their stable physicochemical properties, regardless of external conditions, do not alone determine their biocompatibility [148]. Therefore, the selection of a biomaterial for optimal bioavailability should consider both its structure and composition as well as the intended application and target tissue [148]. Biodegradable nanoparticles, often used in the targeted delivery of drugs and biomolecules, can degrade internally and subsequently be excreted from the body. In contrast, non-biodegradable nanoparticles tend to accumulate in the body for extended periods and can remain in the mononuclear phagocyte system (MPS), such as in the liver and spleen, leading to potentially irreversible toxic side effects. Biodegradable nanoparticles are generally preferred over non-biodegradable ones because they do not require future removal and are made from proteins, polysaccharides, and composite biodegradable polymers [148]. Another key factor influencing the behavior of nanomedical formulations in living organisms, especially concerning the enhanced permeability and retention (EPR) effect, is biocompatibility. The nanocarri encapsulating the anticancer drug should be degradable and removable from the organism via filtration after releasing the therapeutic agent to be considered biodegradable and safe [144]. The reticuloendothelial system (RES) or mononuclear phagocyte system includes monocytes, macrophages, and other phagocytic cells in the liver and spleen [149]. This system filters and destroys non-natural or foreign particles, which are ultimately removed from the immune system via opsonization and phagocytosis. During intravenous infusion, nanoparticles are taken up by the RES and macrophages that are prominent in the liver and spleen. Non-biocompatible materials accumulate in the tissues of these organs, forming granulomas from macrophage fusion, which leads to tissue damage and malignancy [110; 143; 144]. Furthermore, their concentration in the plasma decreases rapidly (short half-life) [110; 143]. To avoid the removal of macromolecular drugs or nanoparticles by the RES, they must exhibit good biocompatibility. To achieve this, various biocompatible polymers, such as polyethylene glycol (PEG), are used. PEG is linked to the surface of nanoparticles, imparting both hydrophilicity and biocompatibility.