4.8 Article

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

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NATL ACAD SCIENCES
DOI: 10.1073/pnas.081626898

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  1. NCI NIH HHS [R35-CA56591, P01 CA080124, F32 CA083248, P01-CA-80124, T32 CA073479, T32-CA73479, F32-CA83248] Funding Source: Medline
  2. NIGMS NIH HHS [T32 GM008334, 5 T32 GM08334] Funding Source: Medline

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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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