Molecular-weight-dependent pharmacokinetics and cytotoxic properties of cisplatin complexes prepared with chondroitin sulfate A and C.

In order to screen out an optimum complex for reducing the nephrotoxicity of cisplatin (CDDP), we investigated and compared CDDP-chondroitin sulfate complexes to CDDP in terms of in vivo pharmacokinetics and in vitro cytotoxicity. The polymeric carriers used in the study were chondroitin sulfate A (CSA, 4-sulfate) with mean molecular weights of 10 kDa (CSA-1) and 23 kDa (CSA-2), and chondroitin sulfate C (CSC, 6-sulfate) with mean molecular weights of 8 kDa (CSC-1) and 25 kDa (CSC-2). The resultant complexes (CDDP-CSA-1, CDDP-CSA-2, CDDP-CSC-1 and CDDP-CSC-2) were administered intravenously to rats. The obtained plasma concentration-time curves during the 3 h period studied for all complexes are biphasic. The plasma dispositions of complexes were dependent on the molecular sizes with urinary excretion as main elimination pathway. CDDP-CSA-1 and CDDP-CSC-1 were unable to effectively increase the plasma retention of platinum due to rapid renal excretion. Furthermore, CDDP-CSA-1 disappeared from plasma more quickly than CDDP-CSC-1. CDDP-CSA-2 and CDDP-CSC-2, with similar urinary excretion as CDDP, gave rise to approximately five and four-fold increase in AUC(0-3 h) values, respectively, than that was achieved with native CDDP treatment. Biodistribution was compared between CDDP-CSA-2 and CDDP-CSC-2. Both complexes effectively suppressed the extensive distribution of CDDP into most tissues, especially kidney. However, CDDP-CSC-2 showed less reduction effect than CDDP-CSA-2. In addition, a significantly higher accumulation in tumor tissue was found with the administration of CDDP-CSA-2 than CDDP. Moreover, CSA complexes displayed an IC(50) of 6 microM Pt-equivalents against SW4800 human colon cancer cells, similar to that of CDDP, whereas CSC complexes were less active than CDDP. These studies indicate that the complex prepared with CSA, which is greater than 20 kDa of molecular size, is superior to that of CSC, exhibiting improved pharmacokinetics and similar pharmacological activity to the native drug.