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 (Cmax), 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.

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

“…We have replicated this result in the present study, as well as previous studies [53]. In contrast, 75HA-Lys-Pt showed very different pharmacokinetics.…”

“…When cisplatin is directly conjugated to the carboxylate groups of hyaluronan, it forms a HA-Pt ionic and covalent complex that has been evaluated in our previous studies [19, 22–29]. HA-Pt exhibited a similar anti-proliferative activity as cisplatin against the human head and neck squamous cell carcinoma (HNSCC) cell line, MDA-1986.…”

Polymeric films loaded with cisplatin for malignant pleural mesothelioma: a pharmacokinetic study in an ovine model

“…It is evident that the cisplatin concentration measured at 21 days is still close to 1 μg/mL and comparable to those obtained during the intravenous and intrapleural treatment with cisplatin solution after 9 days. This could be explained by the formation of a complex between hyaluronate and cisplatin that could be responsible for a reduction of the elimination rate of the drug (17).…”

Uniform polymer–protein conjugate by aqueous AGET ATRP using protein as a macroinitiator

“…In biotechnology and biochemical engineering practice, the application of enzyme catalysis has been constantly pursued, in which great efforts have been directed to enhance enzyme stability and performance under adverse conditions, such as high temperature and the presence of organic solvent, which denature the native enzymes. Recent years have witnessed immense efforts in the fabrication of enzyme-polymer conjugates for the use of enzymatic catalysis in applications such as biosensors [1], drug delivery [2,3] and biomedical devices. In addition to the almost unlimited availability of their different structures, various properties of polymers, including responses to stimuli [4], biocompatibility [5] and surface characteristics, provide options to enhance or operate enzymatic catalysis under given conditions.…”