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

Citation
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
Citations number
63
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
00085472 → ACNP
Volume
59
Issue
16
Year of publication
1999
Pages
4136 - 4141
Database
ISI
SICI code
0008-5472(19990815)59:16<4136:AVFOMI>2.0.ZU;2-0
Abstract
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.