Enhanced macromolecule diffusion deep in tumors after enzymatic digestion of extracellular matrix collagen and its associated proteoglycan decorin

Mazin Magzoub, Songwan Jin, A. S. Verkman

    Research output: Contribution to journalArticle

    Abstract

    Drug access to tumors is limited by diffusion through the tumor interstitium. We used a microfiberoptic epifluorescence photobleaching method to determine the role of extracellular matrix (ECM) components in macromolecule diffusion deep in tumor tissue. In subcutaneous B16 tumors in living mice, translational diffusion of 10 kDa FITC-dextran was slowed 2- to 3-fold (compared with its diffusion in water) within a depth of 0.2 mm from the tumor surface, but >10-fold beyond a depth of 1 mm. Diffusion of larger macromolecules, FITC-albumin and 500 kDa FITC-dextran, was slowed by up to 40-fold at 0.5 mm and 300-fold at 2 mm. Intratumoral collagenase (to digest collagen) or cathespin C (to digest decorin) each increased diffusion of 10 kDa FITCdextran by ∼2-fold. However, these treatments dramatically increased diffusion (>10-fold) of larger macromolecules, such as 500 kDa dextran, in deep tumor (2 mm depth). Intratumoral hyaluronidase, in contrast, slowed diffusion throughout the tumor. In vitro measurements in defined gel-like mixtures of collagen, hyaluronan, and decorin closely recapitulated results in tumors in vivo. Mathematical modeling quantified the roles of extracellular space volume fraction and dimensions, and indicated a substantial effect of cell density on diffusion in deep tumor. Our data define the determinants of diffusion in deep tumor and suggest collagen and decorin digestion to greatly facilitate macromolecule delivery.

    Original languageEnglish (US)
    Pages (from-to)276-284
    Number of pages9
    JournalFASEB Journal
    Volume22
    Issue number1
    DOIs
    StatePublished - Jan 1 2008

    Fingerprint

    Decorin
    proteoglycans
    Proteoglycans
    Macromolecules
    extracellular matrix
    Extracellular Matrix
    collagen
    Tumors
    Digestion
    Collagen
    digestion
    neoplasms
    Neoplasms
    dextran
    Photobleaching
    hyaluronoglucosaminidase
    hyaluronic acid
    photobleaching
    Hyaluronoglucosaminidase
    collagenase

    Keywords

    • ECS
    • FRAP
    • Hyluronan

    ASJC Scopus subject areas

    • Agricultural and Biological Sciences (miscellaneous)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Biochemistry
    • Cell Biology
    • Medicine(all)

    Cite this

    Enhanced macromolecule diffusion deep in tumors after enzymatic digestion of extracellular matrix collagen and its associated proteoglycan decorin. / Magzoub, Mazin; Jin, Songwan; Verkman, A. S.

    In: FASEB Journal, Vol. 22, No. 1, 01.01.2008, p. 276-284.

    Research output: Contribution to journalArticle

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