Effects of cell damage and glycosaminoglycan degradation on available extravascular space of different dextrans in a rat fibrosarcoma

Abstract

Drug delivery to solid tumors may be enhanced through increasing the available volume fraction ( K AV ) of drugs. Therefore, two approaches were investigated that may increase K AV of dextrans in a rat fibrosarcoma: (a) damaging cells in tumours via ex vivo incubation of tumour tissues, and (b) degrading tumour glycosaminoglycans (GAGs) with exogenous hyaluronidase. The molecular weights of dextrans used in this study were ~ 10 000 (D10), 70 000 (D70) and 2 000 000 (D2000), respectively. It was found that GAG degradation had minimal effects on K AV of dextrans. Ex vivo incubation at 37°C for up to 3 h caused only minor cell damage and had minimal effects on K AV of D10 and D70. However, the ex vivo incubation reduced K AV of D2000 ( p < 0.05). When the incubation at 37°C was maintained for 20 h, the amount of viable cells in tumours was reduced by 56% and K AV of all dextrans were significantly increased ( p < 0.05). Ex vivo incubation at 41°C for 3 h caused similar cell damage to that at 37°C for 20 h, but only K AV of D10 and D70 were increased significantly ( p < 0.05). There was no significant change in K AV of D2000, although it was higher than that in tumours incubated at 37°C for 3 h ( p < 0.05). These data suggest that cell damage is a more effective approach than GAG degradation for increasing K AV of macromolecules and that the amount of increase depends on the degree of cell damage and the size of molecules.