Enhancement of fluid filtration across tumor vessels: Implication for delivery of macromolecules

Cancer therapies using genes and other macromolecules might realize their f ull clinical potential if they could be delivered to tumor tissue in optima l quantities. Unfortunately, the compromised circulation within tumors pose s a formidable resistance to adequate and uniform penetration of these agen ts. Previously, we have proposed elevated interstitial fluid pressure (IFP) as a major physiological barrier to delivery of macromolecules. Here we po stulate that modulation of tumor microvascular pressure (MVP) and associate d 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 c hanges in IFP and uptake of macromolecules. We used the nicotinyl hydrazine derivative of human polyclonal IgG (HYNIC-IgG) as a nonspecific macromolec ule and CC49 antibody as a specific macromolecule. We found that both chron ic and periodic modulation of tumor MVP enhances transvascular fluid filtra tion, leading to a 40% increase in total uptake of the specific antibody wi thin 4 hr of its administration. Conversely, neither continuous nor periodi c infusion of, AII induced any increase in uptake of nonspecific antibodies . Strategies to improve delivery of macromolecules and limitations of this approach are identified.