Intratumoural administration of cisplatin in slow-release devices

Abstract

In this study we investigated the effect of the incorporation of cisplatin in slow-release systems on tumour response and animal toxicity after intratumoural (i.t.) administration. Solid slow-release rods with incorporated cisplatin were prepared either from starch or from three different polyether-hydrogel formulations. In vitro release rates from these rods were widely different. With the starch system, approximately 100% release was obtained in 2 h. For the hydrogel formulations, release was approximately 100% in 1 day for a formulation with 40% water uptake (T3), 45% within 4 days for a formulation with 14% water uptake (T2) and 8% within 4 days for a formulation with 4% water uptake (T1). The slow-release rods containing graded amounts of cisplatin were implanted i.t. in s.c. RIF1 murine tumours. The i.t. administration of cisplatin in starch rods did not reduce animal toxicity or increase tumour response relative to i.t. injections of cisplatin in solution. For the hydrogel rods, the tumour response and animal toxicity for a given dose of cisplatin decreased with decreasing release rate. Higher doses of cisplatin could therefore be delivered with the slower-releasing hydrogel formulations. The slowest-release hydrogel rods (T1) had very little effect on either tumour (growth delay) or host (animal weight loss), even at cisplatin doses 8 times that tolerated as an i.p. injection. The fast (T3)- and intermediate (T2)-release hydrogel rods resulted in dose dependent tumour growth delays that were longer than those obtained with i.p. or i.t. administration of cisplatin. The highest response, a tumour growth delay of 55 days, was obtained with the intermediate-release hydrogel rods (T2) at a cisplatin dose of 40 mg/kg. Analysis of tumour growth delay for a given level of toxicity indicated that the intermediate-release formulation (T2) was slightly better than the fast-release formulation (T3) and confirmed the therapeutic advantage of i.t. implants over systemic therapy.