title: Spiral assembly of amphiphilic cytarabine prodrug assisted by probe sonication: Enhanced therapy index for leukemia.
abstract: In order to overcome the drawbacks of cytarabine (Ara-C), such as low lipophilicity as well as short plasma half-life and rapid inactivation, a new derivative of Ara-C was designed by incorporation into the non-toxic material, oleic acid (OA), obtaining an amphiphilic small molecular weight prodrug (OA-Ara). By a simple amidation reaction, OA-Ara was synthesized successfully with a yield up to 61.32%. It was for the first time to see that the novel prodrug molecules could assemble into the unexpectedly spiral assembly under probe ultrasonication in aqueous solution. The oil/water partition coefficient (Ko/w) and the permeability of cell membrane of the prodrug were significantly increased compared with Ara-C molecules. In addition, OA-Ara molecules were stable in various pH solutions and artificial digestives, which indicated that it could be administrated orally. Cell viability assay showed that the prodrug displayed much higher antiproliferative effect against K562 and HL60 cells due to its improvement of the lipophilicity and penetrability of cell membrane. These findings demonstrate the feasibility of utilizing structural modification to broaden the clinic application of Ara-C and thus provide an effective new therapeutic alternative for leukemia.
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong Province 250012, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong Province 250012, PR China.
authors.forename: Naxin
authors.initials: N
authors.lastname: Ma
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong Province 250012, PR China.
authors.forename: Dujuan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Key Lab. of Colloid & Interface Chemistry, Shandong University, Ministry of Education, 250100, PR China.
authors.forename: Zhonghao
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong Province 250012, PR China. Electronic address: yuxialuan@sdu.edu.cn.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Luan
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D002942:Circular Dichroism; D003561:Cytarabine / Q000008:administration & dosage*; D006801:Humans; D020014:K562 Cells; D046529:Microscopy, Electron, Transmission; D011355:Prodrugs / Q000008:administration & dosage*; D066244:Proton Magnetic Resonance Spectroscopy; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D003561:Cytarabine
keywords: Cytarabine; Leukemia therapy; Prodrug; Spiral assembly