# 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
Low-molecular-weight prodrug release drug molecules slowly from the high-molecular-weight carriers to which they are covalently bonded, providing high bioavailability and low systemic toxicity [153]. Active substances that are non-covalently encapsulated may be separated from nanoparticles due to the presence of counterions, such as plasma proteins, before reaching the tumor, thus reducing therapeutic effectiveness and making their results like those of free low-molecular-weight drugs. For drugs conjugated with hydrophilic polymers, such as PEG, cellular uptake and cytotoxicity are lower. Conversely, the use of hydrophobic (or amphiphilic) polymers provides higher affinity with cellular membranes and improves drug cellular uptake [143]. Drugs formulated in polymeric platforms are released either through dilution via the polymeric barrier, the erosion of the polymer material, or a combination of these mechanisms [21]. In summary, the ideal balance between drug stability and release is critical for the success of nanomedicines. A long half-life helps maintain high drug concentrations in the blood, while the effective release of APIs is essential for achieving adequate therapeutic results [123; 143; 151]. For precise controlled drug release, various stimuli-sensitive nanoparticles have been developed that recognize changes in the tumor environment and are activated by external stimuli, such as heat, light, magnetic fields, or ultrasound. Thermal-sensitive nanoparticles are designed to release APIs when exposed to heat through mechanisms such as the thermal degradation of heat-sensitive linkers, phase transitions in lipid-based nanoparticles, or thermal expansion that alters the nanoparticle structure. For example, liposomes with gel-to-liquid crystalline transition temperatures release drugs more efficiently when heated. Light-sensitive nanoparticles, on the other hand, employ photothermal or photochemical processes to facilitate drug release. These include the photothermal effect, where light-absorbing materials like gold nanorods convert light into heat, and photoinduced degradation, where light activates photosensitive linkers or coatings. Reactive oxygen species (ROS) generation through photosensizers also contributes to nanoparticle disruption and drug release. Magnetic nanoparticles respond to magnetic fields through hyperthermia induced by alternating magnetic fields, controlled movement via static fields, or magnetostriction effects, which result in deformation and drug release. For instance, iron oxide nanoparticles coated with temperature-sensitive polymers can release drugs under magnetic hyperthermia. Finally, ultrasound waves trigger drug release through cavitation, where microbubbles collapse to disrupt nanoparticles, acoustic streaming that enhances drug transport, and thermal effects due to ultrasound-induced localized heating. An example is the enhanced drug release from polymeric nanoparticles through cavitation effects. These mechanisms highlight the versatility of external stimuli in controlling drug delivery systems and improving targeted therapy [145; 158; 159; 160; 161; 162; 163]. Another promising strategy to improve targeted drug delivery and their therapeutic efficacy is the use of pH-responsive chemical bonds, such as hydrazone bonds, to link polymers with APIs. Tumors often exhibit a hypoxic environment with low pH, which induces anaerobic glycolysis. By using bonds that break down in acidic pH, APIs can be released inside tumors, while these bonds must remain stable in neutral pH to ensure stability during circulation. Additionally, the use of peptide linkers that are degraded by proteases abundant in tumor tissues represents an alternative strategy to enhance targeted therapy [143].