# Enhancement of EPR Effect for Passive Tumor Targeting: Current Status and Future Perspectives
###### Abstract
AgNPs, likewise, have been studied for their ability to inhibit neovascularization through the disruption of VEGF signaling and ROS production, making them suitable for applications in cancer therapy. Zinc oxide nanoparticles and their nanophysical forms (ZONFs) have also shown pro-angiogenic properties. Activation of the MAPK-Akt-eNOS pathway and the production of ROS and NO promotes neovascularization, making them useful for applications in ischemic diseases and tissue engineering [19]. Polymeric nanoparticles, such as PEG-, PLGA-, and PAMAM-based nanoparticles, are being investigated for their potential to enhance targeted drug delivery [20,21, 22]. PEG polymeric nanoparticles have been used for delayed drug release due to their ability to prolong drug release, enhancing the efficacy of treatments [23]. PLGA nanoparticles, on the other hand, have been developed for the local targeted delivery of anticancer drugs, such as paclitaxel, with the aim of prolonged action and enhancing therapeutic efficacy [23]. Moreover, polymeric dendrimers such as PAMAM, with their ability to incorporate multiple drug molecules, allow optimized targeted therapy in cancer [23]. Lipid nanoparticles, such as liposomes and solid lipid nanoparticles (SLNs), find applications in chemotherapy and hyperthermia, while nanostructured lipid nanoparticles (NLCs) improve drug bioavailability [24]. SLNs enhance the efficacy of chemotherapy through improved targeted drug release and bypassing resistance mechanisms, such as drug export from cancer cells via P-glycoprotein [25]. SLNs have also been found to be effective in inhibiting angiogenesis, limiting blood vessel growth and nutrient delivery to tumors [25]. The study by [PERSON] et al. demonstrated the combined administration of drugs, such as doxorubicin and curcumin via SLNs, which improved cytotoxicity and apoptosis in cancer cells while reducing toxicity in normal cells [26]. SLN/NLC drug delivery systems, through passive and active targeting, offer improved permeability and drug delivery to tumors. In a study by [PERSON] et al., SLNs/NLCs showed significant improvement in drug delivery to tumors through these mechanisms. Also, SLNs/NLCs improve permeability in the brain for central nervous system therapies, allowing for effective targeted therapy [27]. Finally, hybrid nanoparticles, such as polymer-structured nanoparticles (NCPs), nanoscale metal-organic frameworks (NMOFs), polysiloxanes (PSQs), porous-core nanoparticles (MSNs), and iron oxide nanoparticles (IONPs), have been developed to incorporate diagnostic and therapeutic functions. These hybrid systems enhance the application of nanomedicine through the EPR effect and the enhancement of cancer therapy via EPR [28]. A typical example of these hybrid nanoparticles is AGuIX (Activation and Guiding of Irradiation by X-ray) nanoparticles, which have a hydrodynamic diameter of 4 \(\pm\) 2 nm and are based on polysiloxane. They incorporate both diagnostic and therapeutic activities by using X-irradiation for their activation. These nanoparticles have the potential to exploit the EPR effect for the passive targeting of tumors, as their small size allows them to easily penetrate tumor vessels. The passive accumulation of nanoparticles in the tumor leads to an increased local concentration, while their elimination through the kidneys reduces the risk of toxicity. Furthermore, AGuIX NPs are activated by X-irradiation, enhancing tumor toxicity and providing effective radiotherapy even with low radiation doses. This approach was also verified in clinical studies, where the accumulation and persistence of AGuIX NPs in tumors in humans with brain metastases were monitored by MRI [29] (Figure 1). Figure 1: Schematic illustration of the different types of nanoparticles used for passive and active tumor targeting through the EPR effect (created with BioRender.com).