*3.4. Hyaluronic Acid-Based Nanoparticles for Controlled Drug Release in Cancer*

HA is an abundant GAG, deposited to most tissues' ECM [160]. Its properties, biodegradation, biocompatibility, water-solubility, non-toxicity, and non-immunogenicity and its chemical characteristics, enabling modifications with functional groups, define HA as a suitable molecule carrier to deliver low molecular weight drugs [161]. Furthermore, its specific ligation with cell surface receptors such as CD44 and RHAMM [111] enables HA-based nanoparticles to target diseased cells that express these receptors. Indeed, CD44 and RHAMM receptors are overexpressed by many tumor types [162–164]. High production of HA has been determined in many solid tumors, but it is the combination of HA production and Hyal overexpression that facilitate both carcinogenesis and metastasis [165]. In prostate cancer, the increased release of low molecular weight HA (LMWHA) due to Hyal1 overexpression and increased HASs activity results in enhanced autocrine proliferation [166]. The naked mole-rat example, the only mammal resistant to cancer, argues the importance of HA. This rodent produces high amounts of very high molecular weight HA and simultaneously exhibits low Hyals expression, correlated to the minuscule ability to cleave HA [167].

Therefore, the involvement of HA in tumorigenesis processes is of crucial significance. This finding has ignited vibrant research efforts directed at HA metabolism and focusing on the inhibition of HA degradation and on blocking HA-receptors interaction. The HAdegrading enzymes Hyals have been identified as attractive anticancer therapy targets due to their cell surface or extracellular deposition. HA localization enables their inhibition in the ECM [81].

The use of HA-based nanoparticles requires knowledge of HA pharmacokinetics. Thus, it is well established that blood and lymphatic transport system are responsible for HA distribution in the body [168,169]. The utilization of isotopes showed that high molecular weight HA (HMWHA) mainly accumulates in the liver, while LMWHA is secreted in urine [170]. Notably, many studies indicate that the differences in HA-based nanoparticles' targeting efficiency depend on their molecular weight. For example, HMWHA-coated lipid nanoparticles exhibited a stronger binding affinity to the CD44 receptor of murine melanoma cells in vitro than theLMWHA nanoparticles [162].

Different types of HA-based nanoparticles with discrete features have been used as drug carriers (summarized in Figure 1).

**Figure 1.** Mechanism of action of HA-based nanoparticles: HA (Hyaluronic acid)-based nanomedicines are used to mediate targeted delivery of therapeutic compounds (DRUGS or siRNA: small interfering RNA) in cancer cells. Nanoparticle targeting is enhanced by HA-specific interaction with CD44 or RHAMM, which are overexpressed in different cancer cell types. These receptors also mediate the internalization of the nanoparticles. After their uptake, each type of nanoparticle is degraded either by enzymatic lysis of HA by hyaluronidase (HYAL) action or by a pH-dependent mechanism.
