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.

Figure 1

Arterial pressure modulation in a s.c. tumor LS174T by a periodic infusion of AII at a rate of 20 μg/min per kg body weight for 3 min followed by a 5-min interval. The IFP measured with a wick-in-needle in the center of the tumor closely follows the arterial pressure changes, indicating a transvascular fluid exchange. The vascular–interstitial fluid exchange occurs mainly during the initial phase of the MVP change; when IFP reaches the plateau, the fluid filtration is minimal. The amount of fluid that extravasates at each cycle is very low because the change of IFP is not higher than 5 mmHg and the time lag between the change of arterial pressure and IFP is approximately 5 sec.

Figure 2

Biodistribution of a nonspecific (A) and a specific (B) mAb in LS174T tumor-bearing mice at 4 hr postinjection. The data, expressed as a percentage of injected dose per g of tissue, are averaged over five animals and represent the sum of interstitial and vascular uptake (bars = SEM). There is no significant effect of MABP modulation on nonspecific mAb uptake (A). A net increase in total tumor uptake of CC49 specific antibody resulted from both continuous (P < 0.03, ANOVA) and cyclic (P < 0.04, ANOVA) infusion of AGII (B). Modulation of MABP also induced significant increases in lung and kidney uptake.

Figure 3

Typical uptake kinetics curve obtained by a gamma camera. The data are reported as a percentage of the ratio between the tumor and the blood counts versus time. The slope is representative of the interstitial uptake of the antibody, and the intercept is representative of the tumor vascular space.