Diclofenac derivatives as promising anticancer and anti-inflammatory drug: Synthesis, formulations, and pharmacokinetics

Diclofenac (DCF) is well-known non-steroidal anti-inflammatory drug used in the treatment of several cancer cell lines. DCF is derived from phenylacetic acid, and its pharmaceutical activity is attributed to the carboxylic acid moiety. The carboxylic acid group is also responsible for the DCF's side effects, which include gastrointestinal bleeding and ulceration. Therefore, researchers do vast efforts and proposed many strategies to reduce DCF hepatotoxicity. In this regard, the present review provides a comparison and insight into recent developments in DCF through structural modification, drug delivery carriers (multiparticles, microparticles, and nanoparticles), and pharmacokinetics to reduce the toxicity side effects while simultaneously enhancing sustained drug release and the pharmaceutical effect. The researchers demonstrated that the nature and quantity of polymeric drug vehicles (hydrophilic or hydrophobic polymers) have a profound effect on DCF release rate, encapsulation efficiency, and mechanism of action. Furthermore, masking the DCF carboxylic acid with certain moieties such as hydrazones or heterocyclics could substantially boost the pharmaceutical and anticancer activities with a significant reduction in ulcerogenic effect. In this review, comparisons between the published DCF prodrugs, commercial formulations, and parent drug DCF based on the pharmacokinetics (the area under the concentration-time curve from dosing time 0 to infinity, time to reach the maximum concentration, and concentration of the agent inhibiting cell growth by 50%) were also elucidated. It also briefly summarizes the synergistic interactions between DCF with some bio-enhancers. In the last section, we highlighted how the researchers incorporated artificial intelligence during the drug formulation to overcome hepatotoxicity and used it to predict its activity against cancer cell lines. In the last line, this review will serve as compilation of useful and recent sources, which are indexed in Scopus, PubMed, Academic Search Complete, and others, on how scientists created more efficient and sustained release DCF formulations, and how they made it safer with almost no side effects.