title: Hyaluronan-Lysine Cisplatin Drug Carrier for Treatment of Localized Cancers: Pharmacokinetics, Tolerability, and Efficacy in Rodents and Canines.
abstract: The purpose of this study was to develop a safe and efficacious drug delivery platform for sustained release of cisplatin after locoregional administration. We successfully synthesized hyaluronan-cisplatin nanoconjugates (HA-Lys-Pt) using an N-Ac-lysine linker, which formed a thermodynamically stable five-membered ring with the platinum. The conjugate was characterized for release kinetics, in vitro anti-proliferative activity, degradability, impurity content, formation of Pt-DNA adducts, pharmacokinetics, tolerability in rodents and canines, and for efficacy in rodents. The 75 kD HA-Lys-Pt (75HA-Lys-Pt) sustained release of platinum with a 69 h half-life in phosphate buffered saline without substantial burst release. Compared to intravenous cisplatin, subcutaneously injected 75HA-Lys-Pt formed 3.2-fold more Pt-DNA adducts in rat peripheral blood mononuclear cells compared to intravenous cisplatin over 96 h. Subcutaneous 75HA-Lys-Pt was tolerable in rats at 40 mg/kg (4 × LD50 of conventional cisplatin) and resulted in 62.5% partial response and 37.5% stable disease in murine xenografts of head and neck squamous cell cancer (20 mg/kg/wk × 3 weeks). 75HA-Lys-Pt demonstrated extended tmax and improved area-under-the-curve compared to cisplatin in rats and canines. Canine safety was demonstrated by liver enzyme and electrolyte levels, complete blood count, and urinalysis.
authors.affiliation: HylaPharm, Lawrence, Kansas 66047; Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas 66047.
authors.forename: Ti
authors.initials: T
authors.lastname: Zhang
authors.affiliation: HylaPharm, Lawrence, Kansas 66047; Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas 66047.
authors.forename: Shuang
authors.initials: S
authors.lastname: Cai
authors.affiliation: HylaPharm, Lawrence, Kansas 66047.
authors.forename: Chad
authors.initials: C
authors.lastname: Groer
authors.affiliation: HylaPharm, Lawrence, Kansas 66047.
authors.forename: Wai Chee
authors.initials: WC
authors.lastname: Forrest
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas 66047.
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Yang
authors.affiliation: HylaPharm, Lawrence, Kansas 66047; Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas 66047.
authors.forename: Eva
authors.initials: E
authors.lastname: Mohr
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas 66047.
authors.forename: Justin
authors.initials: J
authors.lastname: Douglas
authors.affiliation: HylaPharm, Lawrence, Kansas 66047; Division of Dermatology, Department of Internal Medicine, School of Medicine, The University of Kansas Medical Center, Kansas City, Kansas 66160.
authors.forename: Daniel
authors.initials: D
authors.lastname: Aires
authors.affiliation: Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, Missouri 65211.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Axiak-Bechtel
authors.affiliation: Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, Missouri 65211.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Selting
authors.affiliation: Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, Missouri 65211.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Swarz
authors.affiliation: Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, Missouri 65211.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Tate
authors.affiliation: Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, Missouri 65211.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bryan
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas 66047. Electronic address: lforrest@ku.edu.
authors.forename: M Laird
authors.initials: ML
authors.lastname: Forrest
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008239:Lysine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010865:Pilot Projects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D006820:Hyaluronic Acid; D008239:Lysine; D002945:Cisplatin
keywords: biodegradable polymers; cancer chemotherapy; controlled release; pharmacokinetics; polymeric drug delivery systems; synthesis