title: Deposition of doxorubicin in rats following administration of three newly synthesized doxorubicin conjugates.
abstract: We previously reported the synthesis of three DOX conjugates that represented different targeting vehicles and showed them to have antitumor activity both in vitro and in vivo. However, the relationships between the pharmacokinetics of these DOX conjugates and their chemical structures were not characterized. In the current study, free DOX derived from each of the conjugates was found at low levels in the rat circulatory system, with conjugated DOX being the major form. The two polyethylene glycol (PEG) conjugates slowly released DOX, and t₁/₂β for total DOX from DOX-LNA, PEG-ami-DOX, and PEG-hyd-DOX was 5.79, 10.22, and 15.18 h, respectively. All three conjugates also deposited less DOX into normal organs than did an equivalent dose of free DOX, and the C(max) value of free DOX released by DOX-LNA, PEG-ami-DOX, and PEG-hyd-DOX was 32.5, 9.5, and 4.7 μg/g, respectively. Among the conjugates, the compound with an acid-labile bond between PEG and DOX exhibited the lowest free DOX deposition in healthy tissues, which should decrease the systemic toxicity of free DOX while allowing for tumor targeting by PEG.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaan'xi 710032, China.
authors.forename: Menglei
authors.initials: M
authors.lastname: Huan
authors.affiliation: Department of Obstetrics & Gynecology, PLA General Hospital, Beijing 100853, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Tian
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaan'xi 710032, China.
authors.forename: Han
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaan'xi 710032, China.
authors.forename: Bangle
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Clinic Pharmacology, Wuhan General Hospital of Guangzhou Military Area Command, Wuhan, Hubei 430070, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Su
authors.affiliation: Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaan'xi 710038, China.
authors.forename: Jieping
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Radiation Medicine, School of Public Health, Fourth Military Medical University, Xi'an, Shaan'xi 710032, China.
authors.forename: Kangchu
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaan'xi 710032, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Cao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D051381:Rats; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; D004317:Doxorubicin