A versatile prodrug approach for liposomal core-loading of water-insoluble camptothecin anticancer drugs.
We describe a versatile prodrug strategy for loading the liposomal lumen with water-insoluble camptothecins. The procedure involves conversion of an active camptothecin analogue to a 20-OR omega-aminoalkanoanic ester prodrug in which R = CO[CH(2)](n)()NH(2) and n = 1-3. The basic amino group of the prodrug serves three roles. First, at pH ranges of 3-5, the amine enhances aqueous solubility. Second, it enhances responsiveness to a transmembrane ammonium sulfate gradient across the liposomal bilayer, thereby facilitating active loading of the agent into the liposomal aqueous core. Third, at a physiological pH of 7 or above (the pH to be encountered following drug release at the tumor site), the nucleophilicity of the amine manifests itself and cyclization to the C-21 carbonyl carbon occurs. This cyclization triggers a rapid and convenient nonenzymatic decomposition process that releases active camptothecin. Accordingly, this novel liposomal approach offers a potential system for tumor-targeting prodrugs of many water-insoluble camptothecins, including the highly lipophilic and clinically attractive analogues SN-38, 9-nitrocamptothecin and DB-67. The rate of formation of the active agent at the tumor site can be controlled through the selection of n (the length of the alkyl spacer group).
Liu
Xinli
X
Department of Chemistry and Pharmaceutical Sciences, Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA.
Lynn
Bert C
BC
Zhang
Junhong
J
Song
Lin
L
Bom
David
D
Du
Wu
W
Curran
Dennis P
DP
Burke
Thomas G
TG
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry*; D012995:Solubility; D014867:Water / Q000737:chemistry
D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008081:Liposomes; D011355:Prodrugs; D014867:Water; D002166:Camptothecin