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

The large size of many novel therapeutics impairs their transport through t he tumor extracellular matrix and thus limits their therapeutic effectivene ss. We propose that extracellular matrix composition, structure, and distri bution determine the transport properties in tumors. Furthermore, because t he 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 m acromolecules and liposomes in tumors growing in cranial windows (CWs) and dorsal chambers (DCs) were measured by fluorescence recovery after photoble aching. For the same tumor types, diffusion of large molecules was signific antly 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 orga nization 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 tum ors. The slower diffusion in DC tumors was associated with a higher density of host stromal cells that synthesize and organize collagen type I. Our re sults point to the necessity of developing site-specific drug carriers to i mprove the delivery of molecular medicine to solid tumors.