**3. Types of Nanoparticles and Materials Utilized for Targeted Drug Delivery—Focus on GAG-Based Nanoparticles**

The development of targeted delivery systems for anticancer drugs in the form of nanoparticles has been prioritized since classical methods, namely chemotherapy, radiation therapy, surgery, and their combination, still do not benefit a significant number of patients [83].

Micro- and nanoencapsulation [84–86], micellar [87,88], and liposomal [89] forms, dendrimers [90], mesoporous particles [91], and nanogels [92] are used most often for targeted drug delivery. A wide range of compounds, both synthetic [93,94] and natural [86,87,89,92], are used as materials, and each of the groups has several advantages and disadvantages (Table 1).

The delivery of nanoparticles to the tumors rests on a series of both specific and nonspecific interactions with cells. The specific interactions are based on functionalizing the surface of nanoparticles with ligands that are specific for the target tumor tissue, including tumor cells, intracellular targets, intratumoral and peritumoral blood vessels, and the ECM. The nonspecific nanoparticles are coated solely with stabilizing agents. Most of the studies suggest that the crossing of the tumor blood vessel barrier by nanoparticles is mostly perpetrated through intercellular gaps. Their restraint to the tumor site is dependent on the pressure produced by inadequate lymphatic drainage, commonly denominated as the enhanced permeability and retention (EPR) process [95]. Recent developments suggest that more than 90% of nanoparticles actively enter solid tumor tissue through endothelial cells, challenging the current rationale for nanomaterial synthesis [96]. Nanoparticles targeting specific tumor-associated antigens exhibit superior delivery and effects [96]. A new stage in developing nanomaterials is utilizing patient-derived macromolecules, as recently shown by Lazarovits et al. [97].

In common with others, GAG-based nanoparticles have to overcome the mononuclear phagocytic system's action, which attenuates their efficiency through sequestration and elimination. Notably, nanoparticles carrying a negative charge are more prone to phagocytosis than positive surface charge carrying nanoparticles. Thus, modulating CS charges with competent functionalization can attenuate their phagocytosis [98]. Renal excretion function is another obstacle as it can severely attenuate nanoparticles' actual delivery

efficiency. Indeed, renal excretion function seems to be facilitated by incorporating GAG components even though it does not seem to affect tumor accumulation [99]. Modification of the hydrodynamic diameter to the 5.5 nm–100 nm range minimizes kidney excretion and enhances delivery efficiency [100].

Nanocarriers obtained using biocompatible natural polymers such as GAGs do not exhibit adverse effects on cell viability in cell cultures. They show good biocompatibility in animal experiments [92,101,102]. In addition to biocompatibility and specificity, GAGbased nanocarriers, when their GAG components are specifically modified, exhibit other properties, such as high stability, adjustable particle size, and the ability to respond to external stimuli, such as temperature, light, pH, and ionic strength [103–105], enabling multifunctional utilization [106,107]. GAGs, such as CS and HA, have been utilized as therapeutic agents for various pathologies, including osteoarthritis [108,109], with no significant side effects, suggesting their long-term safety. The broad utilization of HA in dermatological clinical practice has not been associated with side effects [110].

The resulting nano-systems' properties depend on the type and concentration of polymer used for their production and the type and degree of intermolecular interaction or crosslinking. Thus, HA can generate self-assembling micelles with the ability to create amphiphilic nanocarriers. Indeed, HA micelles can effectively deliver hydrophobic drugs to target cancer cells while simultaneously facilitating bioavailability and the half-life of the utilized drugs [111]. Importantly, nanoparticles can be loaded with various types of drugs, both hydrophilic and lipophilic, as well as DNA, RNA, peptides, and proteins [85,88,112,113].


**Table 1.** Types of nanoparticles and materials utilized for targeted drug delivery.
