The lanthanide toolbox as multi-modal, non-invasive tumor specific theranostic prodrug

Despite the clinical success of several anti-cancer prodrugs (pharmacologically inactive forms of drugs that can be subsequently activated through normal metabolic processes) with improved cancer selectivity, water solubility and cell permeability, there is an unmet need to achieve the desired pharmacokinetics with minimal adverse side effects, coupled with the ability to monitor in-vitro/in-vivo. Most anti-cancer pro-drugs are distributed non-specifically throughout the body and their most effective dosage is questionable. Given the recent development of theranostic technology, where therapeutics and diagnostics are combined, we envision that developing theranostic prodrugs with responsive signals in-vitro/in-vivo can afford a promising solution to address this issue. Recently, we reported a ‘proof-of-concept’, two-photon-induced cleavable platinum–europium complex (PtEuL) which holds great promises as a controlled delivery vehicle for the drug, cisplatin. It offers real-time monitoring of the therapeutic process and the long-lived lanthanide emission allows time-resolved imaging, free from autofluorescence.

We will use our experience and knowledge in peptide chemistry to trace the integrin avβ3 isoform in bladder cancer, thereby developing a route to bladder cancer-specific prodrug agents. Photo-triggered therapy coupled to optical imaging is most suitable for cancer cells located close to the skin surface/on exposed organs. Our design of multimodal theranostic prodrugs against bladder cancer encompasses three different synthetic approaches. It combines cancer specificity and permeability, with sufficient ‘dark stability’ and harnesses the two-photon-induced dissociation of the cisplatin coupled to responsive europium emission that permits imaging studies to enable quantitative evaluation of the time-dependent fate of the prodrug. Four key ‘proof-of-concept’ experiments have been undertaken done in support of this proposal: (i) two new europium complexes have been synthesized (peptide ligated in cis – N1 and trans-N7, N1-Pt-Eu-L1-P1 and N7-Pt-Eu-L1-P1) for evaluating the binding with the integrin avβ3; (ii) the design of each complex has been optimised following molecular docking simulations; (iii) binding between the designed prodrug and the integrin avβ3 isoform has been estimated via Western blots methods and selectivity towards bladder cancer confirmed by MTT assays/preliminary imaging studies; (iv) two photon-induced quantitative delivery assays have been carried out with the comparison of the light dosed-emission intensity-N1-Pt content, establishing the linearity of this relationship. Our goal is to develop a library of compounds with photo-dissociable prodrugs and target specificity by the use of different vectors for clinical application. We intend to translate our knowledge in chemical syntheses-biochemistry-lanthanide chemistry into practical and responsive biomedical probes, serving as a drug-delivery vehicle capable of being monitored in real-time.