¹Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, MA 02110, USA

Correspondence: R K Jain, E-mail: jain@steele.mgh.harvard.edu

²Current address: Department of Physics, The Norwegian University of Science and Technology, Trondheim, Norway

³School of Pharmacy and Pharmaceutical Science, University of Manchester, Manchester, UK

Received 3 September 2001; Revised 28 February 2002; Accepted 28 February 2002.

Abstract

The tumour extracellular matrix acts as a barrier to the delivery of therapeutic agents. To test the hypothesis that extracellular matrix composition governs the penetration rate of macromolecules in tumour tissue, we measured the diffusion coefficient of nonspecific IgG in three rhabdomyosarcoma subclones growing as multicellular spheroids in vitro or as subcutaneous tumours in dorsal windows in vivo. In subcutaneous tumours, the diffusion coefficient decreased with increasing content of collagen and sulphated glycosaminoglycans. When grown as multicellular spheroids, no differences in either extracellular matrix composition or diffusion coefficient were found. Comparison of in vitro vs in vivo results suggests an over-riding role of host stromal cells in extracellular matrix production subjected to modulation by tumour cells. Penetration of therapeutic macromolecules through tumour extracellular matrix might thus be largely determined by the host organ. Hence, caution must be exercised in extrapolating drug penetrability from spheroids and multilayer cellular sandwiches consisting of only tumour cells to tumours in vivo.