# 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
A characteristic example of the surface modification of nanodrugs with polymers is the conjugation with polyethylene glycol (PEG) polymer chains, which protect nanocarriers from the reticuloendothelial system, preventing their removal. Due to the high molecular weight of PEG chains, the half-life of a drug in the body is prolonged, extending its activity and reducing its administration frequency for passive tumor targeting [127; 148]. Moreover, PEG-coated nanocarriers used in drug delivery applications reduce macrophage uptake, thereby increasing their circulation time. The increase in the half-life of nanocarriers with PEG coating is attributed to its physical properties, which can also reduce or prevent the adsorption of RES proteins on their surface and, consequently, their opsonization [21; 148]. Therefore, the use of PEG dramatically reduces the immune response to a substance's surface, including reduced protein adsorption, platelet aggregation, neutrophil activation, hemolytic activity, and coagulation [148]. PEG is commonly used for the design of biodegradable and biocompatible nanoparticles. The repeating ethylene glycol units form tight associations with water molecules, creating a hydration layer. As a result, it increases the solubility of water-soluble compounds, reduces drug toxicity, creates the desired pharmacokinetic profile, and enhances specific uptake at the target site [20]. Additionally, this polymer exhibits solubilization capability in both aqueous and organic environments, making it ideal for constructing drug carriers under mild physiological conditions [124]. A characteristic example is the PEG coating on liposomes containing the anticancer drug doxorubicin (DOX). These are successfully used to treat solid tumors in patients with metastatic breast carcinoma, showing high efficacy and reduced side effects [151]. Additionally, to predict therapeutic efficacy through the EPR effect, the mineral magnetite, with the chemical formula Fe\({}_{3}\)O\({}_{4}\), was conjugated with PEG, improving biocompatibility while reducing non-specific phagocytosis [152]. The strategies used for conjugating drugs or biomolecules with PEG involve the use of various coupling agents, such as dicyclohexylcarbodiimide (DCC) or N-hydroxysuccinimide (NHS) esters. During the conjugation process, stable covalent bonds, such as esters, amides, and disulfides, are formed to prevent the release of the drug during its transport to the target. The PEG-prodrug conjugate is expected to be stable during circulation and to degrade or hydrolyze upon arrival at the target site. Therefore, PEGconjugation assists in the release of the parent drug through activation by external or intracellular enzymes or by a change in pH [153]. Another class of biodegradable polymers used as drug carriers includes poly(amides), poly(amino acids), poly(alkyl \(\alpha\)-cyanoacrylates), poly(esters), poly(ortho esters), poly(urethanes), poly(acrylamides), N-(2-hydroxyethyl)methacrylamide (HPMA), soluble collagen, polylactic acid (PLA), polyglycolic acid (PGA), and poly(lactic-co-glycolic acid) (PLGA) [144; 149; 21]. However, nanoparticles modified with such polymers have been observed to remain in the bloodstream for extended periods but do not achieve satisfactory accumulation in tumors, with approximately 80% of the initial drug dose being removed within a few hours of administration [154; 133].