Vascular permeability in a human tumour xenograft: molecular charge dependence

Molecular charge is one of the main determinants of transvascular transport . There are, however, no data available on the effect of molecular charge o n microvascular permeability of macromolecules in solid tumours. To this en d, we measured tumour microvascular permeability to different proteins havi ng similar size but different charge. Measurements were performed in the hu man colon adenocarcinoma LS174T transplanted in transparent dorsal skinfold chambers in severe combined immunodeficient (SCID) mice. Bovine serum albu min (BSA) and IgG were fluorescently labelled and were either cationized by conjugation with hexamethylenediamine or anionized by succinylation. The m olecules were injected i.v, and the fluorescence in tumour tissue was quant ified by intravital fluorescence microscopy. The fluorescence intensity and pharmacokinetic data were used to calculate the microvascular permeability . We found that tumour vascular permeability of cationized BSA (pl-range: 8 .6-9.1) and IgG (pl: 8.6-9.3) was more than two-fold higher (4.25 and 4.65 x 10(-7) cm s(-1)) than that of the anionized BSA (pl approximate to 2.0) a nd IgG (pl: 3.0-3.9; 1.11 and 1.93 x 10(-7) cm s(-1), respectively). Our re sults indicate that positively charged molecules extravasate faster in soli d tumours compared to the similar-sized compounds with neutral or negative charges. However, the plasma clearance of cationic molecules was similar to 2 x faster than that of anionic ones, indicating that the modification of proteins enhances drug delivery to normal organs as well. Therefore, cautio n should be exercised when such a strategy is used to improve drug and gene delivery to solid tumours. (C) 2000 Cancer Research Campaign.