## 3 Results
### Targeted Drug Delivery
#### 3.2.2 Passive Targeting: The Enhanced Permeability and Retention Effect  
Passive targeting exploits the unique physiological properties of the tumor vasculature through the Enhanced Permeability and Retention effect, first described by Prof. [PERSON]'s group in 1986 [57]. The EPR effect is central to the passive targeting of nanoparticles in cancer therapy, as it allows for the preferential accumulation of drug carriers in the tumor [58],without the need for specific targeting ligands. The EPR effect arises from the distinct differences in vascular structure between normal and cancerous tissues. Tumor blood vessels are often disorganized and dilated, with larger and irregular fenestrations, allowing for easier penetration and retention of nanoparticles within the tumor. Additionally, impaired lymphatic drainage in tumor tissues helps retain these particles longer, resulting in a higher local concentration of therapeutic agents compared to normal tissues. This can be particularly advantageous for hepatocellular carcinoma, where systemic treatments often have limited efficacy and high toxicity [59]. Furthermore, high interstitial fluid pressure is common in HCC tumors, influencing drug distribution within the tumor tissue and contributing to the retention of larger molecules. This effect, while beneficial in retaining drugs within the tumor, can also present a barrier to uniform drug distribution, which is being addressed through innovative drug delivery systems. The literature has demonstrated that several physicochemical properties of nanocarriers--such as particle size, molecular weight, surface charge, hydrophobicity, and hydrophilicity--are critical for effective passive targeting in drug delivery systems. These features influence how nanocarriers interact with biological environments, enabling improved retention and accumulation in target tissues. The optimal size range for these nanostructures is generally considered to be between 50 and 200 nm, which helps avoid rapid renal clearance (as occurs with smaller particles) and uptake by the reticuloendothelial system (common with larger particles). For instance, stealth liposomes with sizes around 100-150 nm have shown efficient retention in tumor tissues due to this favorable size window [60]. Moreover, nanoparticles with surface modifications such as PEGylation have shown improved drug delivery performance in hepatocellular carcinoma. PEGylation, in particular, increases circulation time and enhances uptake within the liver tumor microenvironment. As a result of the EPR effect, these modified nanoparticles accumulate more effectively in HCC tissues and have demonstrated better therapeutic outcomes in animal models [61]. In addition to surface modifications, the nature of the nanocarrier itself plays a key role in passive targeting efficiency. pH-sensitive liposomes, polymeric micelles, and solid lipid nanoparticles have each shown specific advantages, such as enhanced stability, controlled drug release, and responsiveness to the acidic tumor environment. Studies indicate that dioleoylphosphatidylylethanolamine (DOPE)- and cholesteryl hemisuccinate (CHEMS)-based formulations, modified with polyethylene glycol, exhibit superior pharmacokinetics and significantly greater tumor accumulation than free drug formulations. Morphology also influences targeting performance. Spherical structures are most commonly used due to their stability and efficient extravasation. However, other shapes--such as nanorods or flexible particles--may offer additional benefits in certain tumor types by improving retention or prolonging circulation time [60]. Studies have shown that nanoparticles that rely on the EPR effect can enhance the concentration of chemotherapeutic agents within tumors, improving therapeutic outcomes compared to free drugs [62]. However, the efficiency of the EPR effect can vary significantly between patients and even within different regions of the same tumor, due to factors such as tumor size, type, and location.