Folates are potential ligands for ruthenium compounds in vivo

Scrase, Tom G; Page, Simon M.; Barker, Paul D.; Boss, Sally R.

doi:10.1039/c4dt00081a

Cited by 3 publications

(2 citation statements)

References 33 publications

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“…Also, superior cancer cell recognition can be achieved using mAb, which, coupled to metallodrugs, amplifies their intracellular delivery. The biological carriers might be extended even further to include vitamin-mediated drug targeting [122,123] or steroid-conjugates [124]. These systems have the potential to evolve into highly efficacious metallodrug-based therapies.…”

Section: Discussionmentioning

confidence: 99%

Nano-Based Systems and Biomacromolecules as Carriers for Metallodrugs in Anticancer Therapy

2018

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Since the discovery of cisplatin and its potency in anticancer therapy, the development of metallodrugs has been an active area of research. The large choice of transition metals, oxidation states, coordinating ligands, and different geometries, allows for the design of metal-based agents with unique mechanisms of action. Many metallodrugs, such as titanium, ruthenium, gallium, tin, gold, and copper-based complexes have been found to have anticancer activities. However, biological application of these agents necessitates aqueous solubility and low systemic toxicity. This minireview highlights the emerging strategies to facilitate the in vivo application of metallodrugs, aimed at enhancing their solubility and bioavailability, as well as improving their delivery to tumor tissues. The focus is on encapsulating the metal-based complexes into nanocarriers or coupling to biomacromolecules, generating efficacious anticancer therapies. The delivery systems for complexes of platinum, ruthenium, copper, and iron are discussed with most recent examples. explored as possible alternatives, but none have yet entered the clinic. Importantly, high efficacy of platinum paved the way for the development of other transition metal complexes, many with outstanding cytotoxic properties against cancer cells.Transition metals form complexes of multiple geometries based on the number of coordination sites, offering a stereoisomeric diversity higher than carbon. In addition, a synthesis of metallodrugs requires fewer steps when compared to organic compounds. This is accompanied by a myriad choice of coordinating ligands [17] facilitating fine-tuning the properties of metal-based complexes [17,18]. The octahedral titanium species cis-diethoxy-bis(1-phenylbutane-1,3-dionato)titanium(IV) [(bzac) 2 Ti(OEt) 2 ] (budotitane), was the first non-Pt(II) metal compound that reached clinical trials [19]. Following this, ruthenium-based complexes were explored showing fewer side effects when compared to platinum-based agents and activity against Pt-resistant cancers [20][21][22]. Two ruthenium derivates, imidazolium trans-DMSO-imidazole-tetrachlororuthenate (NAMI-A) and imidazolium trans-[tetrachlorido(DMSO)(1H-imidazole)ruthenate(III)] (KP-1019), have been tested in clinical trials [22,23]. KP-1019 showed efficacy towards primary tumors, such as colon cancer, without triggering systemic toxicity, while NAMI-A was not cytotoxic but demonstrated activity against metastases. Moreover, NKP-1339 (the sodium salt analogue of KP1019, sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]) has successfully completed a phase I clinical trial [24]. NKP-1339 is Ru(III) that binds to serum proteins albumin and transferrin, which transport and deliver the metallodrug to the tumor tissue. Once inside endosomes, NKP-1339 reduces to Ru(II). Recently, new designs of ruthenium complexes are emerging that include Ru(η 5 -C 5 H 5 ) core. This class of Ru(II) compounds demonstrates enhanced selectivity and effectiveness, for example ruthenium pyridocarbazole (DW1/2...

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Section: Discussionmentioning

confidence: 99%

Nano-Based Systems and Biomacromolecules as Carriers for Metallodrugs in Anticancer Therapy

2018

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“…Some years later, Scrase et al demonstrated the coordination of the folate to the ruthenium core through the N^N (77-FA right). [127] The authors explored the synthesis of 77-FA at physiological conditions (37 ºC) and also at higher temperatures (65 ºC). In both cases, the NMR characterization revealed two set of signals, corresponding to the diastereomers (ΛS/ΔR:ΛR/ΔS).…”

Section: Vitaminsmentioning

confidence: 99%