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. 2001 Apr 10;98(8):4628-33.
doi: 10.1073/pnas.081626898. Epub 2001 Mar 27.

Role of tumor-host interactions in interstitial diffusion of macromolecules: cranial vs. subcutaneous tumors

A Pluen  1 , Y Boucher, S Ramanujan, T D McKee, T Gohongi, E di Tomaso, E B Brown, Y Izumi, R B Campbell, D A Berk, R K Jain
Affiliations

Role of tumor-host interactions in interstitial diffusion of macromolecules: cranial vs. subcutaneous tumors

A Pluen et al. Proc Natl Acad Sci U S A. .

Abstract

The large size of many novel therapeutics impairs their transport through the tumor extracellular matrix and thus limits their therapeutic effectiveness. We propose that extracellular matrix composition, structure, and distribution determine the transport properties in tumors. Furthermore, because the characteristics of the extracellular matrix largely depend on the tumor-host interactions, we postulate that diffusion of macromolecules will vary with tumor type as well as anatomical location. Diffusion coefficients of macromolecules and liposomes in tumors growing in cranial windows (CWs) and dorsal chambers (DCs) were measured by fluorescence recovery after photobleaching. For the same tumor types, diffusion of large molecules was significantly faster in CW than in DC tumors. The greater diffusional hindrance in DC tumors was correlated with higher levels of collagen type I and its organization into fibrils. For molecules with diameters comparable to the interfibrillar space the diffusion was 5- to 10-fold slower in DC than in CW tumors. The slower diffusion in DC tumors was associated with a higher density of host stromal cells that synthesize and organize collagen type I. Our results point to the necessity of developing site-specific drug carriers to improve the delivery of molecular medicine to solid tumors.

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Figures

Figure 1
Figure 1
(a) Effective diffusion coefficients, Deff, as a function of their experimental hydrodynamic radius, RH. Diffusion coefficients in PBS solution were measured at T = 26°C and scaled to 37°C according to the Stokes–Einstein equation. Diffusion coefficients were measured in DC (filled symbols and dotted lines) and CW (open symbols and continuous line) tumors. (b) Interstitial diffusion coefficients in tumors (Dint = τformula imageDeff) as a function of hydrodynamic radius, RH, using the experimentally obtained value τg = 1.19. The diffusion coefficients in solution (D0) are pictured (▴) to illustrate the ECM influence on retardation.
Figure 2
Figure 2
Light microscopy (LR White sections) of the peripheral region of DC and CW tumors. The capsule of U87 (a) and Mu89 (b) DC tumors is composed of several layers of fibroblast-like cells separated by ECM. Note the large intercellular spaces in U87 and the narrow space that separates two cellular nodules in Mu89. The connective tissue at the edge of U87 (c) and Mu89 (d) in the CW is composed of one fibroblast cell layer; the tumor cells are separated by narrow intercellular spaces. C, capsule; T, tumor; black arrows, ECM; white arrows, fibroblast-like cells. (Bar = 10 μm.)
Figure 3
Figure 3
Immunostaining for collagen type I (a and b) and decorin (c and d), and labeling for HA (e and f) in DC (a, c, and e) and CW (b, d, and f) tumors. Collagen type I occupies a greater area of the periphery in DC than in CW tumors. In both DC and CW tumors the decorin staining is restricted to the periphery of the tumor. HA staining is intense in the center of Mu89 in the DC, whereas in the periphery the staining is weak. (Bar = 100 μm.)
Figure 4
Figure 4
Electron microscopy of the organization of collagen fibrils in the capsule of U87 tumors in the DC. (a) The longitudinally oriented fibrils are parallel to one another with an interfibrillar spacing that varies from 20 to 42 nm. (b) The fibrils are poorly organized. The interfibrillar spacing varies between 75 and 130 nm. (Bar = 200 nm.)
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