This Review aims to highlight key aspects of tetrapyrrole-based antibody–drug conjugates (ADCs) and significant developments in the field since 2010. Many new conjugation methods have been developed and employed in the past decade, and associated with this, there has been a rising interest in theranostic conjugates. We have investigated the physicochemical properties that tetrapyrroles need to possess in order to be viable photosensitizers for conjugation to antibodies. Differences in conjugation strategies are discussed, and structure–activity relationships of tetrapyrrole–antibody conjugates are reported, where available. As the elegance of bioconjugation techniques has increased, it has paved the way for exceptionally phototoxic, yet highly selective, tetrapyrrole–antibody conjugates, with photocytotoxicities in the nanomolar range, to be synthesized and biologically evaluated.

In this study we report the synthesis and biological evaluation of a novel cationic porphyrin-[Ru(η 6 -arene)(C2O4)PTA] (RAPTA) conjugate with potential as a multimodal dual-therapeutic agent. In the absence of high intensity light, relative to untreated cells our conjugate resulted in a 83% decrease in viable human adenocarcinoma cells at a concentration of 10 μM, which is significantly more active than the 57% decrease achieved with the same concentration of the unconjugated RAPTA complex alone. With a light dose of 20 J cm -2 (400 -1200 nm) a reduction 2 of 98% of viable cells was observed for the same concentration of conjugate. The conjugate is internalized by HT-29 cancer cells as proven by ICP-MS analysis and fluorescence microscopy: the latter result suggesting that the conjugate has applications as a multimodal agent by acting as a fluorophore to obtain in vivo biodistribution data. Furthermore, the conjugate has an excellent relative singlet oxygen quantum yield, and the tetrapyrollic unit was found to be photostable under irradiation by either white light or red light.

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Dinuclear metallodrugs offer much potential in the development of novel anticancer chemotherapeutics as a result of the distinct interactions possible with bio‐macromolecular targets and the unique biological activity that can result. Herein, we describe the development of isostructural homo‐dinuclear OsII–OsII and hetero‐dinuclear OsII–RuII organometallic complexes formed from linking the arene ligands of [M(η6‐arene)(C2O4)(PTA)] units (M=Os/Ru; PTA=1,3,5‐triaza‐7‐phosphaadamantane). Using these complexes together with the known RuII–RuII analogue, a chromatin‐modifying agent, we probed the impact of varying the metal ions on the structure, reactivity and biological activity of these complexes. The complexes were structurally characterised by X‐ray diffraction experiments, their stability and reactivity were examined by using 1H and 31P NMR spectroscopy, and their biological activity was assessed, alongside that of mononuclear analogues, through MTT assays and cell‐cycle analysis (HT‐29 cell line). The results revealed high antiproliferative activity in each case, with cell‐cycle profiles of the dinuclear complexes found to be similar to that for untreated cells, and similar but distinct profiles for the mononuclear complexes. These results indicate these complexes impact on cell viability predominantly through a non‐DNA‐damaging mechanism of action. The new OsII–OsII and OsII–RuII complexes reported here are further examples of a family of compounds operating via mechanisms of action atypical of the majority of metallodrugs, and which have potential as tools in chromatin research.

In this study, we report the first successful immobilisation of a known cytoactive [Ru(η6‐arene)(C2O4)PTA] (RAPTA) complex to a biologically inert polyacrylamide nanoparticle support. The nanoparticles have been characterised by zetasizer analysis, UV/Vis, ATR‐FTIR, TGA and ICP‐MS to qualitatively and quantitatively confirm the presence of the metallodrug on the surface of the carrier. The native RAPTA complex required a concentration of 50 μM to produce a cell viability of 47.1±2.1 % when incubated with human Caucasian colorectal adenocarcinoma cells for 72 h. Under similar conditions a cell viability of 45.1±1.9 % was obtained with 0.5 μM of RAPTA complex in its immobilised form. Therefore, conjugation of the RAPTA metallodrug to our nanoparticle carriers resulted in a significant 100‐fold decrease in effective concentration of ruthenium required for a near identical biological effect on cell viability.