Enhancement of fluid filtration across tumor vessels: implication for delivery of macromolecules.

Abstract:

:Cancer therapies using genes and other macromolecules might realize their full clinical potential if they could be delivered to tumor tissue in optimal quantities. Unfortunately, the compromised circulation within tumors poses a formidable resistance to adequate and uniform penetration of these agents. Previously, we have proposed elevated interstitial fluid pressure (IFP) as a major physiological barrier to delivery of macromolecules. Here we postulate that modulation of tumor microvascular pressure (MVP) and associated changes in IFP would enhance macromolecular delivery into a solid tumor. To test our hypothesis, we altered tumor MVP by either periodic injection or continuous infusion of angiotensin II (AII) and measured the resulting changes in IFP and uptake of macromolecules. We used the nicotinyl hydrazine derivative of human polyclonal IgG (HYNIC-IgG) as a nonspecific macromolecule and CC49 antibody as a specific macromolecule. We found that both chronic and periodic modulation of tumor MVP enhances transvascular fluid filtration, leading to a 40% increase in total uptake of the specific antibody within 4 hr of its administration. Conversely, neither continuous nor periodic infusion of AII induced any increase in uptake of nonspecific antibodies. Strategies to improve delivery of macromolecules and limitations of this approach are identified.

authors

Netti PA,Hamberg LM,Babich JW,Kierstead D,Graham W,Hunter GJ,Wolf GL,Fischman A,Boucher Y,Jain RK

doi

10.1073/pnas.96.6.3137

keywords:

subject

Has Abstract

pub_date

1999-03-16 00:00:00

pages

3137-42

issue

6

eissn

0027-8424

issn

1091-6490

journal_volume

96

pub_type

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