title: Effects of different carboxylic ester spacers on chemical stability, release characteristics, and anticancer activity of mono-PEGylated curcumin conjugates.
abstract: We investigated the effects of different carboxylic ester spacers of mono-PEGylated curcumin conjugates on chemical stability, release characteristics, and anticancer activity. Three novel conjugates were synthesized with succinic acid, glutaric acid, and methylcarboxylic acid as the respective spacers between curcumin and monomethoxy polyethylene glycol of molecular weight 2000 (mPEG(2000) ): mPEG(2000) -succinyl-curcumin (PSC), mPEG(2000) -glutaryl-curcumin (PGC), and mPEG(2000) -methylcarboxyl-curcumin (PMC), respectively. Hydrolysis of all conjugates in buffer and human plasma followed pseudo first-order kinetics. In phosphate buffer, the overall degradation rate constant and half-life values indicated an order of stability of PGC > PSC > PMC > curcumin. In human plasma, more than 90% of curcumin was released from the esters after incubation for 0.25, 1.5, and 2 h, respectively. All conjugates exhibited cytotoxicity against four human cancer cell lines: Caco-2 (colon), KB (oral cavity), MCF7 (breast), and NCI-H187 (lung) with half maximal inhibitory concentration (IC(50) ) values in the range of 1-6 µM, similar to that observed for curcumin itself. Our results suggest that mono-PEGylation of curcumin produces prodrugs that are stable in buffer at physiological pH, release curcumin readily in human plasma, and show anticancer activity.
authors.affiliation: Department of Pharmaceutical Technology (International) Program, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Wisut
authors.initials: W
authors.lastname: Wichitnithad
authors.forename: Ubonthip
authors.initials: U
authors.lastname: Nimmannit
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Callery
authors.forename: Pornchai
authors.initials: P
authors.lastname: Rojsitthisak
mesh_terms: D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D004952:Esters; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011092:Polyethylene Glycols / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism; D012995:Solubility; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D016588:Anticarcinogenic Agents; D002264:Carboxylic Acids; D004952:Esters; D011355:Prodrugs; D011092:Polyethylene Glycols; D003474:Curcumin