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

Abstract

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.

Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx™) in human osteosarcoma xenografts

“…A positive correlation between the diffusion coefficient of IgG and the amount of hyaluronan has also been reported (Davies et al, 2002). All together, this may reflect that the structure of the ECM is more important for the penetration of macromolecules than the amount of hyaluronan and other ECM constituents (Pluen et al, 2001;Brown et al, 2003).…”

Electromobility of plasmid DNA in tumor tissues during electric field-mediated gene delivery

“…13 Dextran (2 000 000 MW), which has a hydrodynamic radius of approximately 20 nm, has the interstitial diffusion coefficients on the orders of 10 Ϫ7 to 10 Ϫ8 . 13,14 Furthermore, the diffusion coefficient of linear DNA in 2% agarose gels has been measured. 15 A linear DNA fragment (4.4 kb), similar in length to the plasmid (5.1 kb) used in our study, has a diffusion coefficient of~5 × 10 Ϫ9 cm 2 /s.…”

“…Collagen matrix is a major barrier for transport of large molecules. 13,14 The diffusion coefficient of a large molecule may differ by more than one order of magnitude in tissues containing different amounts of collagen. 13 Collagen interfibrillar distances in tissues with wellaligned and poorly aligned bundles are 20-40 nm and 75-140 nm, respectively.…”

“…13 Collagen interfibrillar distances in tissues with wellaligned and poorly aligned bundles are 20-40 nm and 75-140 nm, respectively. 14 The radius of gyration of a 5.4 kb plasmid was on the order of 100 nm. 31 Thus, the diffusion of molecules with hydrodynamic radii approaching interfibrillar distances will be extremely difficult, due to frictional and steric interactions, as well as path tortuosity.…”

Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11

“…The uniformly elevated interstitial fluid pressure in solid tumours leads to negligible convection in the tumour interstitium (Boucher et al, 1990), and drug delivery through the extracellular matrix (ECM) relies on passive diffusive transport (Netti et al, 1999). This transport is influenced by the constituents and characteristics of the ECM (Pluen et al, 2001). Interstitial pressure decreases by 74% in the LS174T colorectal cancer tumour model after pretreatment with A4.6.1 (Lee et al, 2000).…”