A. Krol et al., Available volume fraction of macromolecules in the extravascular space of a fibrosarcoma: Implications for drug delivery, CANCER RES, 59(16), 1999, pp. 4136-4141
Steric exclusion of molecules in the extravascular space of tissues can be
quantified by the available volume fraction (K-AV). Despite its clinical im
portance, however, there is a paucity of data in the literature regarding t
he available volume fraction of macromolecules in the extravascular space o
f tumor tissues, In this study, we quantified K-AV of inulin, BSA, and dext
ran molecules of M-r 10,000-2,000,000 in polymer gels and fibrosarcoma tiss
ues. The measurement involved: (a) sectioning of gels or tumor tissues into
thin slices (similar to 600 mu m) using a Vibratome, (b) en vivo incubatio
n 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
M-r of dextran was increased from M-r 10,000 to 2,000,000. However, K-AV in
tumor tissues was insensitive to the molecular weight of dextran in the ra
nge between M-r 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
M-r 40,000 to 70,000, In addition to the molecular weight dependence, K-AV
was heterogeneous in tumors, with intertumoral difference being greater th
an intratumoral variation. The interstitial fluid space, which was quantifi
ed by K-AV of inulin, was 50% of the total tissue volume, These data indica
te that the fraction of the extravascular volume in tumors that is accessib
le to large therapeutic agents is heterogeneous and depends on the size of
agents.