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Abstract: 8-Chloro-adenosine (8CA) has shown promise in hematologic and solid tumor models and is in a phase I clinical trial. However, 8CA is intensively metabolized shortly after i.v. administration, with a t 1/2β of approximately 1h. Many carriers have failed to encapsulate 8CA efficiently. To improve its pharmacokinetic properties, 8-chloro-adenosine-5′-O-stearate (8CAS), a lipophilic octadecanoyl analogue of 8CA, was synthesized and incorporated into pegylated liposomes. The liposomes, comprising egg phosphatidylcholine, cholesterol and poly (ethylene glycol) 2000-distearoyl phosphatidylethanolamine (PEG-DSPE), had mean diameters of approximately 100nm and an entrapment efficiency of 69–86%. MTT assays showed that the cytotoxicity of 8CAS and its pegylated liposomes (8CAS-PL) were retained, with IC50 values of 1.0μM and 1.9μM at 72h on MCF-7 cells, respectively, slightly higher than that of 8CA (0.6μM). Pharmacokinetic studies in rats after i.v. injection showed that both 8CAS and 8CAS-PL had increased elimination half-lives (t 1/2, 128.4, 249.2 vs. 74.7min), decreased clearance rates (Cl, 0.0135, 0.00875 vs. 0.2398L/min/kg) and increased area under the concentration–time curve (AUC0−∞, 741.4, 1163.6 vs. 42.0mgmin/L) compared to 8CA. No obvious hematological toxicity was seen for Kunming mice receiving i.v. 8CA or 8CAS-PL at a dosage of 10mg/kg daily. These results indicate that the lipophilic derivation of 8CA and the incorporation of 8CAS is an effective strategy to improve the bioavailability of 8CA. [Copyright &y& Elsevier]