Available volume fraction of macromolecules in the extravascular space of a fibrosarcoma: implications for drug delivery.

Steric exclusion of molecules in the extravascular space of tissues can be quantified by the available volume fraction (K(AV)). Despite its clinical importance, however, there is a paucity of data in the literature regarding the available volume fraction of macromolecules in the extravascular space of tumor tissues. In this study, we quantified K(AV) of inulin, BSA, and dextran molecules of Mr 10,000-2,000,000 in polymer gels and fibrosarcoma tissues. The measurement involved: (a) sectioning of gels or tumor tissues into thin slices (approximately 600 microm) using a Vibratome, (b) ex vivo incubation of the slices in solutions containing fluorescently labeled tracers, and (c) quantification of the equilibrium tracer concentrations in both slices and solutions. We found that K(AV) in gels decreased monotonically when the Mr of dextran was increased from Mr 10,000 to 2,000,000. However, K(AV) in tumor tissues was insensitive to the molecular weight of dextran in the range between Mr 10,000 and 40,000. There was a sharp decrease in K(AV) from 0.28 +/- 0.14 to 0.10 +/- 0.06 when the molecular weight was increased from Mr 40,000 to 70,000. In addition to the molecular weight dependence, K(AV) was heterogeneous in tumors, with intertumoral difference being greater than intratumoral variation. The interstitial fluid space, which was quantified by K(AV) of inulin, was 50% of the total tissue volume. These data indicate that the fraction of the extravascular volume in tumors that is accessible to large therapeutic agents is heterogeneous and depends on the size of agents.