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.
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.
In this study, we present a convenient method for the labelling of tyrosine residues on bovine serum albumin (BSA) and human serum albumin (HSA) and report for the first time their subsequent bio‐orthogonal conjugation with porphyrins via “click” chemistry. We demonstrate that these serum proteins can be labelled with an alkyne‐diazonium heterobifunctional linker and can then undergo chemo‐selective bio‐orthogonal conjugation with a water‐soluble azido metalloporphyrin via “click” chemistry to yield protein‐conjugates that retain their photodynamic properties. In our hands, this method was found to be highly reproducible, scalable, and tuneable which allows for the production of bioconjugates where the porphyrin‐protein conjugate not only retains an ability to generate singlet oxygen but possess an enhanced relative singlet oxygen quantum yields relative to the porphyrin alone. Furthermore, we have investigated the photochemical properties of these conjugates through photospectrometric techniques and have determined that the porphyrin macrocycles remain appreciably photostable under light irradiation. Our phototoxic protein‐photosensitizer‐conjugates show excellent photodynamic activity against a human colorectal adenocarcinoma cancer cell line (HT‐29) with cell viabilities of 7.7±0.5 % (IC50 8.76±2.14 μM) and 1.7±1.9 % (IC50 8.48±5.11 μM) for BSA and HAS, respectively, when irradiated with 20 J cm−2 of white‐light. Importantly, neither of the conjugates was found to possess any significant “dark” toxicity even at concentrations of 100 μM. Furthermore, the natural fluorescent properties of the bioconjugates allowed for the determination of cellular uptake in vitro via fluorescence microscopy thus highlighting the potential theranostic applications of these unique protein‐drug‐conjugates.
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