Disposition characteristics of macromolecules in the perfused tissue-isolated tumor preparation.
Disposition characteristics of model macromolecules with different physicochemical characteristics and macromolecular prodrugs of mitomycin C, namely mitomycin C-dextran conjugates, were studied in tissue-isolated tumor preparations of Walker 256 carcinoma with the use of a single-pass vascular perfusion technique. In constant infusion experiments, all radiolabeled macromolecules accumulated in the tumor tissue, but the degree and pattern of distribution greatly varied, depending on their electric charges. Positively charged macromolecules were markedly accumulated compared with those that were neutral or negatively charged. In addition, their concentrations were significantly higher in viable than in necrotic regions, while neutral and negative compounds were distributed in necrotic rather than in viable regions. Pharmacokinetic analysis of tissue concentration-time courses of positively charged diethylaminoethyl and neutral dextrans showed that their movement occurred by convective fluid flow, and that high tissue accumulation of positively charged macromolecules could be explained by strong binding due to electrostatic interaction. For neutral and anionic macromolecules with negligible affinity to the tissue, it was suggested that the final concentration gradient between the viable and necrotic regions was decided by their tissue fluid content. Thus, the present study revealed the basic disposition characteristics of macromolecules in tumor tissue relative to their physicochemical properties.
Imoto
H
H
Department of Basic Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Sakamura
Y
Y
Ohkouchi
K
K
Atsumi
R
R
Takakura
Y
Y
Sezaki
H
H
Hashida
M
M
D000818:Animals; D002199:Capillary Permeability; D002279:Carcinoma 256, Walker / Q000098:blood supply / Q000378:metabolism*; D003911:Dextrans / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D005110:Extracellular Space / Q000378:metabolism*; D005260:Female; D016685:Mitomycin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D010477:Perfusion; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
D003911:Dextrans; D011355:Prodrugs; C042790:mitomycin C-dextran; D016685:Mitomycin