Effects of cell damage and glycosaminoglycan degradation on available extravascular space of different dextrans in a rat fibrosarcoma.
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 approximately 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 degrees 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 degrees 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 degrees C for 3 h caused similar cell damage to that at 37 degrees 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 degrees 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.
Krol, A; Dewhirst, MW; Yuan, F
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