# Enhancement of EPR Effect for Passive Tumor Targeting: Current Status and Future Perspectives
## 4 The Use of EPR in Passive Tumor Targeting with Nanomedicines
### Biological Barriers Encountered by Nanoparticles
#### 4.2.1 Nanocarrier Specifications  
Nanoparticles used in the administration of nanomedicines to tumors via the EPR phenomenon should possess certain physicochemical characteristics, the most important of which are size, shape, and surface charge, to achieve prolonged circulation time, high penetration rate, intracellular internalization, and, consequently, high extravasation and accumulation within the tumor [72; 127]. Furthermore, nanoparticles should have a high drug-loading capacity and exhibit a very low probability of the immediate release of the therapeutic agent. They should also have the potential to be combined with ligands for targeted drug delivery. The therapeutic agents should be fully released from the nanoparticles at an optimal rate based on the design of the formulation. Additionally, nanoparticles should be biocompatible, biodegradable, and non-immunogenic, while organic solvents and toxic components should be excluded from the manufacturing process. All formulation components of the formulation should be safe, affordable, and commercially available, and the manufacturing process should be characterized by simplicity, cost-effectiveness, and ease of scaling up. The nanoparticle system should be able to participate in various processes during production, such as lyophilization, sterilization, drying, mixing, granulation, compression, capsule filling, and packaging [132; 133]. Another parameter that should be considered is the concentration of nanomedicines in the bloodstream, as this affects the forces of diffusion and convection, which are necessary for their extravasation into the interstitium. Specifically, higher concentrations in the bloodstream can impede the outflow of nanoparticles from the tumor [72]. Finally, nanoparticles should be stable both in the bloodstream and during storage. The stability of nanoparticles is crucial to ensure they can traverse biological barriers, considering their physicochemical properties, such as size, size distribution, and zeta potential [132; 133]. Utilized Materials  
The materials used as drug carriers in cancer therapy must be biocompatible and biodegradable to avoid toxicity and adverse side effects, stable in blood circulation, have appropriate size and shape, controllable surface properties, and achieve targeted delivery. Below are the main categories of these materials and their key characteristics. One type of nanoparticles used in cancer therapy is polymeric nanoparticles (PNPs), which offer controlled drug diffusion at neutral pH and high stability. PNPs can passively target tumors through the enhanced permeability and retention (EPR) effect but also actively through functionalized surfaces with specific target molecules. Their structure and characteristics affect their interaction with serum proteins, body distribution, and tumor penetration. They offer drugs protection from hepatic inactivation, enzymatic degradation, and rapid clearance, improving their pharmacological properties without requiring modifications to the drug molecule [134; 135; 136; 137]. Additionally, monoclonal antibody nanoparticles are utilized for targeted therapy, as they use monoclonal antibodies (mAbs), which are specifically designed to recognize and bind to specific antigens on the surface of cancer cells [134; 137]. A fundamental material in the construction of lipid-based nanocariers is liposomes, which exhibit prolonged drug release in acidic environments while being stable, biocompatible, and capable of carrying both hydrophobic and hydrophilic drugs [132; 134; 138]. Furthermore, nanogels and dendrimers are classes of carriers characterized by pulsatile drug distribution in acidic and basic environments, respectively [134]. Other inorganic materials, such as metals, metal oxides, and carbon-based materials, include gold nanoparticles, which release the drug through a photo-thermally activated mechanism at neutral pH, as well as mesoporous silica nanoparticles, which possess high drug-loading capacity and controlled release.