title: Synthesis, characterization and stability of dendrimer prodrugs.
abstract: The design, synthesis and characterization of a series of zero generation (G0) PAMAM dendrimer-based prodrugs for the potential enhancement of drug solubility and bioavailability are described. Naproxen, a poorly water-soluble drug, was conjugated to dendrimers either directly by an amide bond or by ester bonds using either L-lactic acid or diethylene glycol as a linker. All of the prodrugs were more hydrophilic than the parent drug, as evaluated by drug partitioning between 1-octanol and phosphate buffer (pH 7.4). Hydrolysis of the conjugates was measured at 37 degrees C in hydrochloric acid buffer (pH 1.2), phosphate buffer (pH 7.4), borate buffer (pH 8.5) and in 80% human plasma. The amide conjugate and both ester conjugates were chemically stable at all pHs over 48 h of incubation. Naproxen was enzymatically released from both ester conjugates in plasma; the lactic ester conjugate hydrolyzed slowly with only 25% of naproxen released after 24h, the diethylene glycol ester conjugate cleaved rapidly following pseudo first order kinetics (t(1/2) = 51 min). G0 PAMAM dendrimer prodrugs with an appropriate linker (diethylene glycol) show good potential as carriers for oral delivery.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Najlah
authors.forename: Sally
authors.initials: S
authors.lastname: Freeman
authors.forename: David
authors.initials: D
authors.lastname: Attwood
authors.forename: Antony
authors.initials: A
authors.lastname: D'Emanuele
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism; D002021:Buffers; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D004355:Drug Stability; D005026:Ethylene Glycols / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D019344:Lactic Acid / Q000737:chemistry; D009288:Naproxen / Q000737:chemistry / Q000378:metabolism; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002021:Buffers; D050091:Dendrimers; D005026:Ethylene Glycols; C104700:PAMAM Starburst; D011073:Polyamines; D011355:Prodrugs; D019344:Lactic Acid; D009288:Naproxen; C013484:diethylene glycol