PEGylated curcumin: A potent drug candidate

The biomedical applications of curcumin are due to its potent antioxidant actions, inhibition of cell signaling pathways, effects on cellular enzymes, ability to alter gene transcription, apoptosis induction or a combination of these. The pharmacokinetic (PK) and pharmacodynamic (PD) studies of curcumin in rodents and in humans (Clinical Phase I) following oral dose, has shown insufficient efficacious concentration of curcumin in tissues, to exert beneficial effects. The low bioavailability of curcumin is due to rapid metabolism, aqueous insolubility and some degree of intestinal metabolism, predominantly due to glucuronidation and sulfonation. Radiolabelled studies have revealed that most of the oral dose was excreted in feces and one third of it remained structurally unchanged. Development of curcumin-based novel drug molecules devoid of low aqueous solubility and poor bioavailability is an unmet challenge. Various efforts have been made in the recent past to address this issue in depth. The most common approach attempted, has been to encapsulate curcumin in liposome or polymer-based carrier molecules. This approach has shown some degree of improvement but does not provide a practical and easy solution to the existing problem. A recent approach has been developed to incorporate various sizes of the poly(ethylene glycol) (PEG) in the curcumin back bone to address the poor aqueous solubility and bioavailability issues. The in vitro and in vivo results of PEGylated curcumin in pancreatic cancer, ovarian cancer, 3T3-L1 cell lines (fibroblast) and as Nrf2 activator in human bronchial epithelial cells have shown several-fold enhancements in efficacy compared to the free curcumin. The enhanced effects are due to higher aqueous solubility and thereby improved membrane permeability, slower clearance, prolonged systemic exposure and reduced systemic toxicity - all attributed to the presence of poly(ethylene glycol). PEGylation modulates the balance between the PK and PD properties of curcumin, and the resulting change in the PK-PD profile provides an overall improved therapeutic efficacy. This review focuses on the prospects of PEGylated curcumin as a potent drug molecule.