Premium
The interstitial distribution of macromolecules in rat tumours is influenced by the negatively charged matrix components
Author(s) -
Wiig Helge,
Gyenge Christina C.,
Tenstad Olav
Publication year - 2005
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2005.089615
Subject(s) - interstitial fluid , extracellular fluid , chemistry , albumin , distribution volume , interstitial space , serum albumin , distribution (mathematics) , volume of distribution , extracellular , centrifugation , extracellular matrix , biophysics , pathology , biochemistry , medicine , pharmacokinetics , biology , mathematical analysis , mathematics
Knowledge of macromolecular distribution volumes is essential in understanding fluid transport within normal and pathological tissues. In this study in vivo we determined the distribution volumes of several macromolecules, including one monoclonal antibody, in tumours and tested whether charges associated with the tumour extracellular matrix influence their available volumes. Steady state levels of the monoclonal antibody trastuzumab (Herceptin) (pI = 9.2), IgG (pI = 7.6) as well as native (pI = 5.0) and cationized albumin (pI = 7.6) were established in rats bearing dimethylbenzanthracene (DMBA)‐induced mammary tumours by continuous infusion using osmotic minipumps. After a 5–7 day infusion period, the rats were nephrectomized and the extracellular volume was determined with 51 Cr‐labelled EDTA. Plasma volumes were measured with 125 I‐labelled human serum albumin or rat IgM in a separate series. Steady state concentrations of probes were determined in the interstitial fluid that was isolated by centrifugation from tumours or by post mortem wick implantation in the back skin. Calculations were made for interstitial fluid volume ( V i ), along with the available ( V a / V i ) and excluded ( V e / V i ) relative interstitial volume fractions. The V e / V i for the positively charged trastuzumab in tumours averaged 0.29 ± 0.03 ( n = 16), a value which was significantly lower than the corresponding one for IgG of 0.36 ± 0.02 ( n = 16). Native albumin was excluded from 38% of the tumour interstitial fluid, whereas cationization of albumin reduced the excluded volume by ∼50%. Our experiments suggest that the tumour interstitium acts as a negatively charged matrix and is an important factor in determining the macromolecular distribution volume.