3.1.3. Heparin Nanogels

Delivery systems based on liposomes, micelles, and magnetic nanoparticles are relatively well-studied systems for which specific rules and dependencies have already been developed, but depot forms based on nanogels represent a new milestone in this field [136]. Most scientific research, in this area, is devoted to creating matrices based on natural polymers, including Hep, chitosan, alginic acid salts, and others.

The majority of the studies were dedicated to delivering genes and proteins. There are also several reports in which Hep nanogels have been developed for the targeted delivery of anticancer drugs [100]. A polymer matrix is typically produced by covalent crosslinking to form strong and stable structures. Due to the polymer's properties, the delivery system can be sensitive to a wide range of external factors, and thus, fine-tuned release of the drug load can be accomplished [124]. Melanoma is characterized by a high metastatic potential of the transformed melanocytes, which also become "invisible" to the immune cells. This "invisibility" is sustained by many mechanisms, one of them being the formation of a platelet cloak. The heterogeneous mixture of GAGs can inhibit this process by blocking P-selectin-mediated intercellular adhesion. LMWHep-coated with Dox and loaded in liposomes (LMWHep-Dox-Lip) was studied in the B16F10 melanoma cell line. This nanomaterial exerted both a cytotoxic effect and inhibited the adhesion between tumor cells and platelets mediated by P-selectin. It was demonstrated in vivo that the pulmonary metastases of melanoma are prevented by LMWHep-Dox-Lip treatment [137].

This type of drug-delivery system can be utilized for combination chemotherapy, where more than two drugs with different properties and mechanisms of action are applied to boost the cancer treatment. Thus, Joung et al.produced Hep-Pluronic (Hep-Pr) nanogel loaded with paclitaxel and DNAase [138]. The nanogel allowed robust intracellular delivery to facilitate these drugs' synergistic effects in a dose-dependent manner and inhibited tumor cells' growth. Notably, the synthesized matrix can bind to high concentrations of both hydrophilic and hydrophobic drugs. Nanogels exhibit some disadvantages due to their high polydispersity, hence the uneven distribution of the active substance in the volume [139].

Some approaches utilize HS for nanoparticle preparation. A recent drug delivery strategy conjugated the chemotherapeutic agent, docetaxel, onto HS. Due to its antimetastatic and T cells infiltration enhancing properties, Aspirin (ASP) was encapsulated into the HS-docetaxel micelle followed by the cationic polyethyleneimine (PEI)-polyethylene glycol (PEG) copolymer binding to HS via electrostatic force. This approach results in an ASPloaded HS-docetaxel micelle (AHD)/PEI-PEG nanocomplex (PAHD). PAHD exhibits a long half-life in the blood due to the PEG shell. As TME is characterized by weakly acidic pH, the PEI-PEG polymers detach from AHD and increase tumor cells' permeability due to their positive charge. Heparanase, overexpressed by tumor cells, degrades HS, thus delivering the active ASP and docexatel to tumor cells. Indeed, PAHD exhibits targeted toxicity toward tumor cells but not normal cells and is bestowed with superior ability to suppress tumor growth and lung metastasis in 4T1 breast cancer tumor-bearing mice [140].
