Advantageous Reactivity of Unstable Metal Complexes: Potential Applications of Metal-Based Anticancer Drugs for Intratumoral Injections

Abstract

Injections of highly cytotoxic or immunomodulating drugs directly into the inoperable tumor is a procedure that is increasingly applied in the clinic and uses established Pt-based drugs. It is advantageous for less stable anticancer metal complexes that fail administration by the standard intravenous route. Such hydrophobic metal-containing complexes are rapidly taken up into cancer cells and cause cell death, while the release of their relatively non-toxic decomposition products into the blood has low systemic toxicity and, in some cases, may even be beneficial. This concept was recently proposed for V(V) complexes with hydrophobic organic ligands, but it can potentially be applied to other metal complexes, such as Ti(IV), Ga(III) and Ru(III) complexes, some of which were previously unsuccessful in human clinical trials when administered via intravenous injections. The potential beneficial effects include antidiabetic, neuroprotective and tissue-regenerating activities for V(V/IV); antimicrobial activities for Ga(III); and antimetastatic and potentially immunogenic activities for Ru(III). Utilizing organic ligands with limited stability under biological conditions, such as Schiff bases, further enhances the tuning of the reactivities of the metal complexes under the conditions of intratumoral injections. However, nanocarrier formulations are likely to be required for the delivery of unstable metal complexes into the tumor.

Controversial Role of Transferrin in the Transport of Ruthenium Anticancer Drugs

“…As has been reported previously [ 36 ] and confirmed in this work (conditions B1 and B2 in Table 3 ), decomposition of KP1019 in cell culture medium occurred within several hours at 310 K and led to a dramatic decrease in cellular Ru(III) uptake and cytotoxicity. Recently, limited stability of typical transition metal complexes in biological media has been considered as a potential advantage for direct injections into tumors that are widely trialed for the treatment of inoperable cancers [ 14 , 76 ]. These applications rely on the ability of metal complexes with lipophilic organic ligands to enter cells rapidly via passive diffusion and cause high cytotoxicity, while their decomposition products, such as metal–protein complexes, are much less toxic and can have beneficial effects [ 14 , 76 ].…”

“…Recently, limited stability of typical transition metal complexes in biological media has been considered as a potential advantage for direct injections into tumors that are widely trialed for the treatment of inoperable cancers [ 14 , 76 ]. These applications rely on the ability of metal complexes with lipophilic organic ligands to enter cells rapidly via passive diffusion and cause high cytotoxicity, while their decomposition products, such as metal–protein complexes, are much less toxic and can have beneficial effects [ 14 , 76 ]. Potential beneficial effects of Ru(III)–protein adducts [ 14 ] can include antimetastatic [ 16 , 77 ], immunomodulatory [ 8 , 9 , 19 ], and antimicrobial [ 78 ] activities [ 14 ].…”

“…These applications rely on the ability of metal complexes with lipophilic organic ligands to enter cells rapidly via passive diffusion and cause high cytotoxicity, while their decomposition products, such as metal–protein complexes, are much less toxic and can have beneficial effects [ 14 , 76 ]. Potential beneficial effects of Ru(III)–protein adducts [ 14 ] can include antimetastatic [ 16 , 77 ], immunomodulatory [ 8 , 9 , 19 ], and antimicrobial [ 78 ] activities [ 14 ]. The development of these novel applications is particularly attractive for KP1019 and other anticancer metal complexes that have passed extensive animal testing but failed in human clinical trials [ 1 ] because of unfavorable pharmacokinetic properties for the traditional intravenous chemotherapy [ 14 ].…”

“…Potential beneficial effects of Ru(III)–protein adducts [ 14 ] can include antimetastatic [ 16 , 77 ], immunomodulatory [ 8 , 9 , 19 ], and antimicrobial [ 78 ] activities [ 14 ]. The development of these novel applications is particularly attractive for KP1019 and other anticancer metal complexes that have passed extensive animal testing but failed in human clinical trials [ 1 ] because of unfavorable pharmacokinetic properties for the traditional intravenous chemotherapy [ 14 ]. Development of suitable nanoformulations for controlled Ru release [ 79 ] is likely to be the key to success of this approach [ 14 ].…”

“…One of the main problems for medicinal applications of Ru complexes and metal-based drugs in general is their complicated and unpredictable reactivity in biological media both extra- and intra-cellularly [ 10 , 11 , 12 , 13 , 14 ]. For instance, NAMI-A ((ImH)[Ru III Cl 4 (Im)( S -dmso)], where Im = imidazole and S -dmso is S -bound dimethyl sulfoxide) showed great promise as a selective antimetastatic drug in preclinical studies but failed in phase I/II human clinical trials [ 15 ], probably due to non-specific binding to extracellular targets [ 16 ].…”