title: A novel approach to improve the pharmacokinetic properties of 8-chloro-adenosine by the dual combination of lipophilic derivatisation and liposome formulation.
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 100 nm and an entrapment efficiency of 69-86%. MTT assays showed that the cytotoxicity of 8CAS and its pegylated liposomes (8CAS-PL) were retained, with IC(50) values of 1.0 μM and 1.9 μM at 72 h on MCF-7 cells, respectively, slightly higher than that of 8CA (0.6 μM). Pharmacokinetic studies in rats after i.v. injection showed that both 8CAS and 8 CAS-PL had increased elimination half-lives (t(1/2), 128.4, 249.2 vs. 74.7 min), decreased clearance rates (Cl, 0.0135, 0.00875 vs. 0.2398 L/min/kg) and increased area under the concentration-time curve (AUC(0-∞), 741.4, 1163.6 vs. 42.0 mg min/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.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Jiao
authors.forename: Xue-Qing
authors.initials: XQ
authors.lastname: Wang
authors.forename: Wan-Liang
authors.initials: WL
authors.lastname: Lu
authors.forename: Zhen-Jun
authors.initials: ZJ
authors.lastname: Yang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D015762:2-Chloroadenosine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005227:Fatty Acids / Q000737:chemistry; D006801:Humans; D008081:Liposomes; D008297:Male; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D005227:Fatty Acids; D008081:Liposomes; D015762:2-Chloroadenosine; D011092:Polyethylene Glycols; C075440:8-chloroadenosine