Enhancing the efficacy of Ara-C through conjugation with PAMAM dendrimer and linear PEG: a comparative study.
1β-d-Arabinofuranosylcytosine (Cytarabine, Ara-C) is a key drug in the treatment of acute myeloid leukemia. Ara-C has a number of limitations such as a rapid deactivation by cytidine deaminase leading to the formation of a biologically inactive metabolite, Ara-U (1β-d-arabinofuranosyluracil), a low lipophilicity, and fast clearance from the body. To address these problems, we developed a conjugate in which hydroxyl-terminated PAMAM dendrimer, G4-OH ["D"] and PEG were used as carriers for the drug (Ara-C). The conjugates were synthesized using an efficient multistep protection/deprotection method resulting in the formation of a covalent bond between the primary hydroxyl group of Ara-C and dendrimer/PEG. The structure, physicochemical properties, and drug release kinetics were characterized extensively. (1)H NMR and MALDI-TOF mass spectrometry suggested covalent attachment of 10 Ara-C molecules to the dendrimer. The release profile of Ara-C in human plasma and in PBS buffer (pH 7.4) showed that the conjugates released the drug over 14 days in PBS, with the release sped up in plasma. In PBS, while most of the drug is released from PEG-Ara-C, the dendrimer continues to release the drug in a sustained fashion. The results also suggested that the formation of the inactive form of Ara-C (Ara-U) was delayed upon conjugation of Ara-C to the polymers. The inhibition of cancer growth by the dendrimer-Ara-C and PEG-Ara-C conjugates was evaluated in A549 human adenocarcinoma epithelial cells. Both dendrimer- and PEG-Ara-C conjugates were 4-fold more effective in inhibition of A549 cells compared to free Ara-C after 72 h of treatment.
Departments of Chemical Engineering and Materials Science and Biomedical Engineering, Wayne State University, Detroit, MI 48202, USA.
Ugir Hossain
UH
Sk
Siva P
SP
Kambhampati
Manoj K
MK
Mishra
Wojciech G
WG
Lesniak
Fan
F
Zhang
Rangaramanujam M
RM
Kannan
D001086:Arabinofuranosyluracil / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D002851:Chromatography, High Pressure Liquid; D003561:Cytarabine / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D003564:Cytidine Deaminase / Q000378:metabolism; D050091:Dendrimers / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D050091:Dendrimers; C104700:PAMAM Starburst; D003561:Cytarabine; D001086:Arabinofuranosyluracil; D011092:Polyethylene Glycols; D003564:Cytidine Deaminase