This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krol, A. Articles by Yuan, F. Search for Related Content PubMed PubMed Citation Articles by Krol, A. Articles by Yuan, F.

Available Volume Fraction of Macromolecules in the Extravascular Space of a Fibrosarcoma: Implications for Drug Delivery¹

Departments of Biomedical Engineering [A. K., J. M., F. Y.] and Radiation Oncology [M. W. D.], Duke University, Durham, North Carolina 27708

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 M_r 10,000–2,000,000 in polymer gels and fibrosarcoma tissues. The measurement involved: (a) sectioning of gels or tumor tissues into thin slices (600 µm) 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 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 range 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 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.

This article has been cited by other articles:

				M. M. Schmidt and K. D. Wittrup A modeling analysis of the effects of molecular size and binding affinity on tumor targeting Mol. Cancer Ther., October 1, 2009; 8(10): 2861 - 2871. [Abstract] [Full Text] [PDF]

				W. Mok, T. Stylianopoulos, Y. Boucher, and R. K. Jain Mathematical Modeling of Herpes Simplex Virus Distribution in Solid Tumors: Implications for Cancer Gene Therapy Clin. Cancer Res., April 1, 2009; 15(7): 2352 - 2360. [Abstract] [Full Text] [PDF]

				M. Magzoub, S. Jin, and A. S. Verkman Enhanced macromolecule diffusion deep in tumors after enzymatic digestion of extracellular matrix collagen and its associated proteoglycan decorin FASEB J, January 1, 2008; 22(1): 276 - 284. [Abstract] [Full Text] [PDF]

				M. S. Dennis, H. Jin, D. Dugger, R. Yang, L. McFarland, A. Ogasawara, S. Williams, M. J. Cole, S. Ross, and R. Schwall Imaging Tumors with an Albumin-Binding Fab, a Novel Tumor-Targeting Agent Cancer Res., January 1, 2007; 67(1): 254 - 261. [Abstract] [Full Text] [PDF]

				M. R. Dreher, W. Liu, C. R. Michelich, M. W. Dewhirst, F. Yuan, and A. Chilkoti Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J Natl Cancer Inst, March 1, 2006; 98(5): 335 - 344. [Abstract] [Full Text] [PDF]

				D. W. Bartlett and M. E. Davis Insights into the kinetics of siRNA-mediated gene silencing from live-cell and live-animal bioluminescent imaging Nucleic Acids Res., January 12, 2006; 34(1): 322 - 333. [Abstract] [Full Text] [PDF]

				H. Wiig, O. Tenstad, and t. l. J. L. Bert Effect of hydration on interstitial distribution of charged albumin in rat dermis in vitro J. Physiol., December 1, 2005; 569(2): 631 - 641. [Abstract] [Full Text] [PDF]

				H. Wiig, C. C. Gyenge, and O. Tenstad The interstitial distribution of macromolecules in rat tumours is influenced by the negatively charged matrix components J. Physiol., September 1, 2005; 567(2): 557 - 567. [Abstract] [Full Text] [PDF]

				M. F. Flessner, J. Choi, K. Credit, R. Deverkadra, and K. Henderson Resistance of Tumor Interstitial Pressure to the Penetration of Intraperitoneally Delivered Antibodies into Metastatic Ovarian Tumors Clin. Cancer Res., April 15, 2005; 11(8): 3117 - 3125. [Abstract] [Full Text] [PDF]

				L. Eikenes, O. S. Bruland, C. Brekken, and C. d. L. Davies Collagenase Increases the Transcapillary Pressure Gradient and Improves the Uptake and Distribution of Monoclonal Antibodies in Human Osteosarcoma Xenografts Cancer Res., July 15, 2004; 64(14): 4768 - 4773. [Abstract] [Full Text] [PDF]

				Y. Wang, J. K. Hu, A. Krol, Y.-P. Li, C.-Y. Li, and F. Yuan Systemic dissemination of viral vectors during intratumoral injection Mol. Cancer Ther., November 1, 2003; 2(11): 1233 - 1242. [Abstract] [Full Text] [PDF]

				H. Wiig, O. Kolmannskog, O. Tenstad, and J. L Bert Effect of charge on interstitial distribution of albumin in rat dermis in vitro J. Physiol., July 15, 2003; 550(2): 505 - 514. [Abstract] [Full Text] [PDF]

				C. P. Graff and K. D. Wittrup Theoretical Analysis of Antibody Targeting of Tumor Spheroids: Importance of Dosage for Penetration, and Affinity for Retention Cancer Res., March 15, 2003; 63(6): 1288 - 1296. [Abstract] [Full Text] [PDF]

				Y. van Hensbergen, H. J. Broxterman, R. Hanemaaijer, A. S. Jorna, N. A. van Lent, H. M. W. Verheul, H. M. Pinedo, and K. Hoekman Soluble Aminopeptidase N/CD13 in Malignant and Nonmalignant Effusions and Intratumoral Fluid Clin. Cancer Res., December 1, 2002; 8(12): 3747 - 3754. [Abstract] [Full Text] [PDF]

				S. McGuire and F. Yuan Quantitative analysis of intratumoral infusion of color molecules Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H715 - H721. [Abstract] [Full Text] [PDF]

				X.-Y. Zhang, J. Luck, M. W. Dewhirst, and F. Yuan Interstitial hydraulic conductivity in a fibrosarcoma Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2726 - H2734. [Abstract] [Full Text] [PDF]