In vitro and in vivo responses of doxorubicin ion exchange microspheres to hyperthermia

Abstract

The utility of microspheres as targeted drug delivery agents is addressed with reference to using heat during formulation and to administration in combination with hyperthermia. It was demonstrated that rate of loading of the drug doxorubicin onto resin microspheres is enhanced under conditions of elevated temperature but this was shown to increase the incidence of microsphere aggregation. Total amount of drug loaded was related to time rather than temperature such that low temperature loading for up to 24 h produced optimum quality injectates. However, release of doxorubicin from microspheres was significantly increased during elevations of temperature to 43°C. Thus, during hyperthermia doxorubicin release can be increased to provide periods of high drug availability targeted to tumour tissue for concomitant thermochemotherapy with microspheres. The therapeutic benefit derived from this combined therapy was assessed in 20 rabbits with VX2 carcinoma implanted in the liver. Hyperthermia was delivered by 2450 MHz microwave applicator to the exteriorized liver at 43°C for 30 min, while chemotherapy was administered by intratumoural injection of doxorubicin microspheres (2·3 mg) into each tumour. Both hyperthermia and chemotherapy alone significantly reduced the size of tumours 10 days following treatment (p<0·01). However, in animals treated with both modalities, the size of tumours was significantly less than either treatment alone (p<0·05). These results provide a strong rationale for combining hyperthermia with targeted chemotherapy using microspheres.

Key Words:

• Microsphere
• doxorubicin
• hyperthermia
• liver