Intratumoral infusion of fluid: estimation of hydraulic conductivity and implications for the delivery of therapeutic agents

• Published in: British journal of cancer Vol. 78; no. 11; pp. 1442 - 1448
• Main Authors: BOUCHER, Y, BREKKEN, C, NETTI, P. A, BAXTER, L. T, JAIN, R. K
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.12.1998; Nature Publishing Group|1
• Subjects: Absorption; Animal tumors. Experimental tumors; Animals; Biological and medical sciences; Coloring Agents - administration & dosage; Coloring Agents - pharmacokinetics; Evans Blue - administration & dosage; Evans Blue - pharmacokinetics; Experimental tumors, general aspects; Extracellular Space; General pharmacology; Humans; Injections, Intralesional; Medical sciences; Mice; Mice, Nude; Miscellaneous; Neoplasm Transplantation; Neoplasms - metabolism; Pharmacokinetics; Pharmacology. Drug treatments; Tumor Cells, Cultured; Tumors; Adenocarcinoma; Human; Animal model; Sarcoma; Rodentia; Intratumoral administration; Hydraulic conductivity; Malignant tumor; Route of administration; Pressure; Colonic disease; Infusion; Liquid; Vertebrata; Mammalia; Mouse; Interstitial fluid; Animal; Established cell line; Digestive diseases; Intestinal disease; Colon
• DOI: 10.1038/bjc.1998.705
• ISSN: 0007-0920

We have developed a new technique to measure in vivo tumour tissue fluid transport parameters (hydraulic conductivity and compliance) that influence the systemic and intratumoral delivery of therapeutic agents. An infusion needle approximating a point source was constructed to produce a radially symmetrical fluid source in the centre of human tumours in immunodeficient mice. At constant flow, the pressure gradient generated in the tumour by the infusion of fluid (Evans blue-albumin in saline) was measured as a function of the radial position with micropipettes connected to a servo-null system. To evaluate whether the fluid infused was reabsorbed by blood vessels, infusions were also performed after circulatory arrest. In the colon adenocarcinoma LS174T with a spherically symmetrical distribution of Evans blue-albumin, the median hydraulic conductivity in vivo and after circulatory arrest at a flow rate of 0.1 microl min(-1) was, respectively, 1.7x10(-7) and 2.3x10(-7) cm2 mmHg(-1) s. Compliance estimates were 35 microl mmHg(-1) in vivo, and 100 microl mmHg(-1) after circulatory arrest. In the sarcoma HSTS 26T, hydraulic conductivity and compliance were not calculated because of the asymmetric distribution of the fluid infused. The technique will be helpful in identifying strategies to improve the intratumoral and systemic delivery of gene targeting vectors and other therapeutic agents.