Taking Artemisinin to Clinical Anticancer Applications: Design, Synthesis and Characterization of pH-responsive Artemisinin Dimer Derivatives in Lipid Nanoparticle

Qinghaosu or Artemisinin is an active sesquiterpene lactone isolated from Artemisia annua L. The natural product and its derivatives are known as a first line treatment for malaria. Investigations have also reported that the compound exhibits anti-cancer activities both on cell lines and in animal models. The remarkably stable endoperoxide bridge under ambient conditions is believed to be responsible for the selectivity as well as potency against cells that are rich in iron content. Dimeric derivatives where two artemisinin units are covalently bonded through lactone carbon (C10) show superior efficacies against both malaria parasites and cancer cells. Artemisinin dimer succinate derivative demonstrates a 100-fold enhancement in potency, compared to the natural product, with IC50 values in the low micromolar range.;This work focuses on the development of artemisinin dimer derivatives to facilitate their clinical development. Novel pH-responsive artemisinin dimers were synthesized to enhance the aqueous solubility of the pharmacophore motif. Compounds with promising potency against human breast cancer cell lines were selected for lipid and protein based nanoparticle formulations for delivery of the derivatives without the need of organic co-solvents into animal models. To improve the efficiency in designing appropriate lipid-nanoparticles as drug delivery systems, a geometrical flit model based on the drug binding pocket hypothesis was introduced. Finally, to lay a foundation for understanding in vivo behaviors of artemisinin dimer derivatives and their nanoparticle formulations, the first analytical method for preparation of biological tissue samples and quantification of artemisinin dimer derivative using liquid chromatography-tandem mass spectrometry was developed.