Pharmacokinetics and Disposition of a Localized Lymphatic Polymeric Hyaluronan Conjugate of Cisplatin in Rodents

• DOI: 10.1002/jps.22016
• Publication Date: 2009-12-03T19:32:43Z
• Authors: Shuang Cai; Yumei Xie; Neal M. Davies; Mark S. Cohen; M. Laird Forrest
• Keywords: Polymers; 610; Antineoplastic Agents; Rodentia; Biodegradable polymers; Lymphatic System; Rats, Sprague-Dawley; Cancer Chemotherapy; Random Allocation; 03 medical and health sciences; Lymphatic transport; Drug Delivery Systems; 0302 clinical medicine; Controlled release; Animals; Pharmacokinetics; Polymeric drug carrier; Hyaluronic Acid; Platinum; Polymeric drug delivery systems; Injections, Intralymphatic; 540; Rats; 3. Good health; Female; Kidney Diseases; Lymph Nodes; Cisplatin

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.