Therapeutical agents, with precise treatment in a spatiotemporal manner, and real-time evaluation of drug uptake, distribution, cellular localization, and clearance, have attracted considerable interest from researchers and pharmaceutical industries. While many new compounds are highly successful during in vitro and preclinical studies, half of all drug candidates that enter clinical trials fail due to problems such as poor bioavailability, low efficacy, and severe side effects. A common solution is to deliver the drug with a chaperone that encapsulates or complexes the drug. It is an effective means of improving the pharmacokinetic and pharmacodynamic properties of the parent drug. An ideal prodrug should take the drugs to their targets and release them at demanded periods. The prodrug should have low toxicity before its release and can be monitored through responsive signals. Several stimuli can trigger the drug release process such as temperature, a specific enzyme, pH, redox state, ultrasound, and light. Coordination complexes are effective platforms for selective drug delivery by virtue of their unique properties, such as environmentally responsive ligand exchange kinetics, different photochemical and photophysical properties, and the ability to form specific interactions with biomolecules.
- Enhancing solubility and bioavailability
Some of the drug candidates have poor water solubility, which may affect the efficacy of the drug or interfere with the metabolism of the drug in the body. In many cases, the coordination of drugs with positively charged coordination complexes has been shown to greatly increase water solubility. In addition, coordination of a metal to negatively-charged groups such as carboxylates and phosphates can reduce the negative charge of the drug and enhance the passive uptake and absorption by cells.
- Reducing systemic toxicity
Coordination complexes can be converted into prodrug complexes with inert properties, which appear inert under normal physiological conditions but become unstable with environmental changes such as redox state, pH, or locally applied light. By deactivating a drug before it reaches its target, side reactions and premature metabolism that can lead to undesirable side effects can be reduced.
- Increasing potency with multiple modes of action
There are some coordination complexes that are inherently bioactive. By generating an active coordination complex and active organic molecule from a single prodrug, multiple means of acting upon a target can be achieved. Dual-action drugs may be more potent than the parent organic drug and be able to reduce drug resistance.
Coordination complexes have been extensively explored as the most promising candidate in drug delivery systems for targeted chemotherapy. These complexes experience dissociation when exposed to light of a certain wavelength. This feature facilitates remote control of drug release. Recently, an Eu-Pt complex has been reported to function as a prodrug, releasing a Pt (II) drug in a controlled manner. Furthermore, dissociation of the PtGdL complex under single- or two-photon excitation can also be used to release the anticancer cisplatin species. It is also not necessarily Pt-based drugs that are released during drug delivery, but also other species. For example, the europium complex EuL was designed as a drug carrier for the delivery of Ru anticancer drugs . EuL was coordinated with the transition metal drug to form lanthanide-transition metal prodrug complexes (RuEuL). It can achieve two important tasks, photoactivated drug delivery, and quantitative monitoring via two different excitation wavelengths. Under irradiation at 488 nm, the dark-inactive prodrug undergoes photodissociation, releasing the DNA-damaging ruthenium species. Under evaluation-window irradiation, the drug delivery process can be quantitatively monitored in real-time because of the long-lived red europium emission.
Figure 1. Schematic illustration of light-triggered drug release of RuEuL complex
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- Wong, K. L.; et al. A smart europium-ruthenium complex as anticancer prodrug: controllable drug release and real-time monitoring under different light excitations. J. Med. Chem. 2017, 60: 8923-8932.