Pharmacokinetics and disposition of a localized lymphatic polymeric hyaluronan conjugate of cisplatin in rodents.
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.
Cai
Shuang
S
Department of Pharmaceutical Chemistry, University of Kansas, 2095 Constant Ave., Lawrence, Kansas 66047, USA.
Xie
Yumei
Y
Davies
Neal M
NM
Cohen
Mark S
MS
Forrest
M Laird
ML
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
D000970:Antineoplastic Agents; D011108:Polymers; D010984:Platinum; D006820:Hyaluronic Acid; D002945:Cisplatin