# Enhancement of EPR Effect for Passive Tumor Targeting: Current Status and Future Perspectives
## 4 The Use of EPR in Passive Tumor Targeting with Nanomedicines
### Significant Parameters  
The half-life (t\({}_{1/2}\)) of a nanomedicine in the bloodstream is crucial for the success of targeted drug delivery to tumors through the enhanced permeability and retention (EPR) effect. The half-life affects the stability of the nanomedicine and its ability to release the active pharmaceutical ingredients (APIs) appropriately. To achieve targeted drug delivery through the EPR effect, it is essential that the nanomedicine remains stable in the bloodstream with a long half-life, ideally over 8 h. A long half-life allows nanoparticles to remain in the plasma for a sufficient period, increasing the likelihood of accumulation in tumors via the EPR effect. The EPR effect exploits the increased permeability of tumor blood vessels and the reduced removal of nanoparticles, facilitating focused drug delivery [143; 123]. Furthermore, nanomedicines that persist in circulation for extended periods, such as liposomes and micelles, exhibit dose-independent, non-saturated, logarithmic linear kinetics, which contributes to increased bioavailability and efficiency in passive accumulation in tumors. This characteristic behavior of nanocarriers enhances their ability to accumulate in pathological areas with impaired vasculature via the EPR effect [151]. Effective internalization of nanoparticles (NPs) can improve their retention, the impact of the EPR effect, and therapeutic efficacy, as many nanoterapies target intracellular sites [145]. Nanoparticles approach the components of the plasma membrane or the extracellular matrix to enter cells through endocytosis [155]. To enhance cellular uptake, NPs can be decorated with targeting ligands that recognize specific receptors on the surface of cancer cells [145]. Endocytosis involves the passage of nanoparticles through membrane receptors, leading to the formation of intracellular vesicles which are then detached from the membrane. These vesicles are subsequently transported to their intended cellular compartments. Depending on the type of cell being targeted and the proteins, lipids, and molecules involved in endocytosis, the type of endocytosis is determined [156; 157]. Physical and chemical characteristics of nanoparticles selected for endocytosis play a significant role in effectiveness, reduced toxicity, and cellular uptake, with the most important being size, shape, material, and surface characteristics such as chemistry and charge [158]. For drugs conjugated with hydrophilic polymers, such as PEG, cellular uptake and cytotoxicity are lower. In contrast, the use of hydrophobic (or amphiphilic) polymers provides higher affinity with cellular membranes and improves drug cellular uptake [143]. As mentioned, the EPR effect is used in passive targeting due to the accumulation of the prodrug in the tumor resulting from reduced lymphatic drainage [130]. To achieve the desired therapeutic outcome, active pharmaceutical ingredients (APIs) need to enter cancer cells [146]. Therefore, after internalization, NPs must either release their therapeutic payload for diffusion through cellular compartments to reach the target or be directed through intracellular transport pathways for release at specific subcellular locations. Inaddition to cytoplasmic delivery, targeting may involve intracellular organelles such as the nucleus, mitochondria, endoplasmic reticulum, and Golgi apparatus. Nanoparticles (NPs) may release their therapeutic payload gradually during circulation in the human body, resulting in nanoparticles that circulate for an extended period, reaching the tumor with a reduced payload. Consequently, careful attention to drug release, NPs' pharmacokinetics, and NPs' extravasation is required for optimal outcomes [145]. The stability of the nanomedicine alone is not sufficient. If the nanomedicine is excessively stable and does not release the active substances within a reasonable time after reaching the tumor, its therapeutic efficacy may be limited.