Themed collection Metallodrugs: Activation, Targeting, and Delivery

Welcome to this themed issue of Dalton Transactions entitled “Metallodrugs: Activation, Targeting and Delivery”.

This tribute to Dr Rosenberg is especially fitting, as an introduction to this themed issue, since the discovery of Cisplatin has not only had an enormous impact on the practice of modern day cancer chemotherapy, it has also promoted the explosive growth and maturity of the field of contemporary bioinorganic chemistry.

In this review, we discuss the attempts made by our lab to develop Pt(IV) prodrugs that can be activated and delivered using targeted nanodelivery systems.

Do we really know how “dual action” Pt(IV) work?

The rich chemical and structural versatility of transition metal complexes provides numerous novel paths to be pursued in the design of molecules that exert particular chemical or physicochemical effects that could operate over specific biological targets.

The article highlights the emergent use of upconverting nanoparticles as tools for the near infrared photoactivation of transition metal complexes.

Today, it is not sufficient to conceive an efficient drug, its mechanism of action have to be understood. To tackle this issue, trackable therapeutic agents are an interesting solution.

A novel self-quenched phthalocyanine tetramer has been prepared which can be activated in acidic environments, resulting in enhanced fluorescence emission and singlet oxygen production.

Herein we report the synthesis and anti-cancer activity of buforin IIb, its novel malonate derivative malBuf and its Pt(II) complex cis-[Pt(NH₃)₂(malBuf_–2H)].

We report the synthesis and characterisation of the nitroxide spin-labelled photoactivatable Pt(IV) prodrug trans,trans,trans-[Pt(N₃)₂(OH)(OCOCH₂CH₂CONH-TEMPO)(Py)₂] (Pt-TEMPO).

^99mTc and Re conjugates of Doxorubicin accumulate in the nucleus, bind tightly to DNA and retain hTopoII inhibition.

Photoactivation of cytotoxic Re(I) complexes by using lanthanide doped upconversion nanoparticles upon near infrared illumination was demonstrated to selectively activate Re(I) complexes in tumor cells for enhanced anti-cancer effect.

Cyclometallated platinum(II) β-diketonates show significant photocytotoxicity in skin-keratinocyte HaCaT cells [IC₅₀: ∼10 μM (visible light, 400–700 nm), ≥60 μM (dark)].

Careful design of the coligand of the photoCORM [MnBr(CO)₃(pyTAm)] makes it highly stable and soluble in aqueous media and allows light-induced CO release to biological targets.

Although carbon monoxide (CO) delivery materials (CORMAs) have been generated, remote-controlled delivery with light-activated CORMAs at a local site has not been achieved.

Combined photodynamic therapy and Pt chemotherapy based on upconversion nanoparticles are very effective in killing cisplatin-resistant cancer cells.

Guest encapsulation can modulate the cytotoxicity of anthracene-based nano-capsules and broaden their applications from metallodrugs to biocompatible delivery systems.

This report presents the first known p-cymene ruthenium quinaldamide complexes stabilised by a hydrogen-bridging atom, which are cytotoxic and show induced cancer cell death by apoptosis.

Synthetic hydroxyapatite nanocrystals are proposed as a pH-sensitive carrier capable to release an antitumor platinum-drug selectively at the tumor site.

Photoinduced DNA damage by trans-[PtCl₂(NH₃)(1-methyl-7-azaindole)] is related to its photocytotoxic activity.

In an attempt to combine the antimicrobial properties of Ga³⁺ and quinolone antimicrobial agents, tris(quinolono)gallium(III) complexes were prepared. In the style of the Ga³⁺vs. Fe³⁺ “Trojan Horse” hypothesis, the bactericidal efficacy of these gallium(III) complexes was evaluated in direct comparison to their iron(III) analogs.

A platinum(IV) complex was prepared as a prodrug of cisplatin and co-loaded with α-tocopheryl succinate into the galactosamine-modified PLGA nanoparticle for combinational chemotherapy of liver cancer.

A rhodium(I) and a ruthenium(II) complex with a caffeine derived N-heterocyclic carbene (NHC) ligand were biologically investigated as organometallic conjugates consisting of a metal center and a naturally occurring moiety.

[n]Ferrocenophane and [n]ruthenocenophane derivatives have been synthesized and their antiproliferative activity evaluated against MDA-MB-231 cells.

A versatile modular-synthetic scheme based on cleavable amide–ester linkers allows incorporation of platinum–acridines into multifunctional and targeted anticancer agents.

[Ru(tpy)(N^N)Cl]⁺ were synthesized for anticancer evolution. Ru2–Ru4 were dual-mode DNA-binding complexes and exhibited higher DNA binding affinity, better cellular uptake efficiency and higher anticancer activity than Ru1.

The antitumour activity of Ru^II arene complexes with N-donor ligands is realised through inhibition of cell division accompanied by caspase-dependent apoptosis.

2-Hydroxy-[1,4]-naphthoquinone-derived ligands and their Ru^II(η⁶-p-cymene)Cl complexes were prepared with the aim to obtain multimodal anticancer agents.

Hexadentate acyclic chelate H₂CHXdedpa and related N,N′-alkylated ligands are radiolabeled with radioactive ⁶⁴Cu(II) under mild conditions forming kinetically inert complexes.

Three phosphorescent cyclometalated iridium(III) complexes with mitochondria-specific localization and apoptosis-inducing capability have been explored as the theranostic anticancer agents.

PLGA-PEG nanoparticles loaded with Pt(IV) prodrugs of kiteplatin boost the antitumor effect of the drug and reduce its toxicity.

Recently, incorporating multiple components into one nanostructured matrix to construct a multifunctional nanomedical platform has attracted more and more attention for simultaneous anticancer diagnosis and therapy.