Hyaluronan-Lysine Cisplatin Drug Carrier for Treatment of Localized Cancers: Pharmacokinetics, Tolerability, and Efficacy in Rodents and Canines

作者：Zhang Ti; Cai Shuang; Groer Chad; Forrest Wai Chee; Yang Qiuhong; Mohr Eva; Douglas Justin; Aires Daniel; Axiak Bechtel Sandra M; Selting Kimberly A; Swarz Jeffrey A; Tate Deborah J; Bryan Jeffrey N; Forrest M Laird^*

来源：Journal of Pharmaceutical Sciences, 2016, 105(6): 1891-1900.

DOI：10.1016/j.xphs.2016.03.018

• cancer chemotherapy
• polymeric drug delivery systems
• controlled release
• pharmacokinetics
• synthesis
• biodegradable polymers

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 x 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 x 3 weeks). 75HA-Lys-Pt demonstrated extended t(max) 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.

• 出版日期2016-6