title: Pharmacokinetics and disposition of a localized lymphatic polymeric hyaluronan conjugate of cisplatin in rodents.
abstract: Cisplatin (CDDP) is an effective anticancer agent for many solid tumors but has significant systemic toxicity limiting its use in many patients. We have designed a loco-regional delivery system to increase platinum levels in the lymphatics, where early metastasis is most likely to occur, while reducing systemic toxicities. CDDP was conjugated to a biocompatible polymer hyaluronan (HA), with a conjugation degree of approximately 20% (w/w). Conjugates were delivered via subcutaneous injection into the mammary fat pad of rats. Intravenous hyaluronan-cisplatin (HA-Pt) exhibited an increased plasma area under the curve (AUC) 2.7-fold compared to conventional CDDP but with a reduced peak plasma level (C(max)), and HA-Pt increased the ipsilateral lymph node AUC by 3.8-fold compared to CDDP. Urine creatinine was unchanged over 30 days following dosing of HA-Pt. This study demonstrates that intralymphatic drug delivery with polymer-conjugated platinum may provide greater tissue and systemic plasma concentrations of platinum than intravenous CDDP. In addition, localized particle delivery augmented distribution in the loco-regional tissue basin where tumor burden predominates, while renal toxicity compared to standard intravenous CDDP was significantly reduced.
authors: Department of Pharmaceutical Chemistry, University of Kansas, 2095 Constant Ave., Lawrence, Kansas 66047, USA.
authors: Shuang
authors: S
authors: Cai
authors: Yumei
authors: Y
authors: Xie
authors: Neal M
authors: NM
authors: Davies
authors: Mark S
authors: MS
authors: Cohen
authors: M Laird
authors: ML
authors: Forrest
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D005260:Female; D006820:Hyaluronic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use; D007272:Injections, Intralymphatic; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy; D008198:Lymph Nodes; D008208:Lymphatic System; D010984:Platinum / Q000493:pharmacokinetics / Q000627:therapeutic use; D011108:Polymers / Q000493:pharmacokinetics / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012377:Rodentia
chemical_list: D000970:Antineoplastic Agents; D011108:Polymers; D010984:Platinum; D006820:Hyaluronic Acid; D002945:Cisplatin