3.2. Delivery Systems

As such, the administration of metallodrugs can often be problematic, due to their rapid metabolism, difficulty in reaching the site of action, and high systemic toxicity. To overcome these limitations, research has turned to finding novel delivery systems that are capable of adequately transporting and protecting the drug. The most studied delivery systems are generally polymeric or inorganic nanoparticles (NPs) and liposomes (Figure 4, Pathway 2).

Studies in this area have focused mainly on Pt chemotherapeutics to overcome the drawbacks associated with the use of this class of drugs in clinical cancer chemotherapy. A liposomal formulation of cisplatin, called Lipoplatin, reached Phase III of clinical trials. Lipoplatin, which is a nanoparticle with an average diameter of 110 nm, composed of lipids and cisplatin, can evade immune surveillance so that it is not eliminated by macrophages and can extravasate into a tumor through the damaged endothelium of the vascular system [91,92].

Nanoparticle systems have also been developed for two Ru(III)-drugs, KP1019 and NAMI-A, which have reached clinical trials. A nanoscale drug conjugate of (NAMI-A)-block copolymer micelles showed an improved inhibition of cell invasion and migration while enhancing the antimetastatic activity compared to the metallodrug alone in pancreatic and ovarian cancer cells [93,94]. The encapsulation of KP1019 in poly(lactic acid) (PLA) nanoparticles containing Tween-80 resulted in higher cytotoxicity than KP1019 alone in hepatoma cell lines and colon carcinomas [95].

A recent study reported the design of diruthenium(II,III)-NSAID metallodrugs encapsulated in biocompatible terpolymer–lipid nanoparticles (TPLNs) to target glioblastoma cancer. The metal complex was formed with a Ru₂(II,III) mixed-valence metal–metal multiply bonded core linked to four carboxylate ibuprofen (Ibp) drug ligands, [Ru₂(Ibp)₄Cl]. Its encapsulation in TPLNs significantly enhanced the antiproliferative effect in two human glioblastoma cancer cells, U87MG and T98G, which are chemoresistant to cisplatin [96].

Since a perfect drug delivery system should be characterized by high biocompatibility, stability, and selectivity for a specific target site, research is moving towards the use of delivery systems composed of molecules that are already present in our bodies, such as ferritins (Fts). These are natural proteins that are involved in the storage and release of iron, can self-assemble into hollow, cage-like structures, and are recognized by receptors that are overexpressed on the surfaces of cancer cells. These proteins were recently selected to encapsulate a prototype of a new class of metallodrug with a PtAs(OH)₂ core, called Arsenoplatin-1(AP-1). Cellular experiments on human epidermoid carcinoma cell lines and human keratinocytes (A431 and HaCaT) showed significantly higher selectivity of AP-1-loaded Ft against cancer cells compared to normal cells [1].