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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 °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 24 h, the diethylene glycol ester conjugate cleaved rapidly following pseudo first order kinetics (t1/2 = 51 min). G0 PAMAM dendrimer prodrugs with an appropriate linker (diethylene glycol) show good potential as carriers for oral delivery.