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

Alain Pluen, Yves Boucher, Saroja Ramanujan, Trevor D. McKee, Takeshi Gohongi, Emmanuelle Di Tomaso, Edward B. Brown, Yotaro Izumi, Robert B. Campbell, David A. Berk, Rakesh K. Jain

    Research output: Contribution to journalArticlepeer-review


    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 inter-fibrillar 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.
    Original languageEnglish
    Pages (from-to)4628-4633
    Number of pages5
    JournalProceedings of the National Academy of Sciences of the United States of America
    Issue number8
    Publication statusPublished - 10 Apr 2001


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