Tumors interstitial transport

Interstitial transport of macromolecules implication for nucleic acid delivery in solid tumors... 

Convection is driven by a pressure gradient, whereas diflhsion relies on a concentration gradient. The ratio of convection versus diffusion is defined as the Peclet number. In normal tissues, the Peclet number is, in general, less than unity for small and hydrophilic molecules and larger than unity for macromolecules. Thus, interstitial transport is dominated by diffusion for small molecules and convection for large ones. In solid tumors, the pressure gradient is low due to the uniformly elevated IFP as discussed above. Thus, the Peclet number may also be smaller than unity for macromolecules. In this case, the transport of macromolecules relies on diffusion as well. 

The microenvironment in solid tumors may significantly influence the interstitial transport of drags and genes through various environmental factors. These factors... 

The physical factors include mechanical stresses and temperature. As discussed above, IFP is uniformly elevated in solid tumors. It is likely that solid stresses are also increased due to rapid proliferation of tumor cells (Griffon-Etienne et al., 1999 Helmlinger et al., 1997 Yuan, 1997). The increase in IFP reduces convective transport, which is critical for delivery of macromolecules. The temperature effects on the interstitial transport of therapeutic agents are mediated by the viscosity of interstitial fluid, which directly affects the diffusion coefficient of solutes and the hydraulic conductivity of tumor tissues. The temperature in tumor tissues is stable and close to the body temperature under normal conditions, but it can be manipulated through either hypo- or hyper-thermia treatments, which are routine procedures in the clinic for cancer treatment. 

The chemical environment may affect interstitial transport through various mechanisms. For example, the electric charge of drags depends on local pH, which is low in solid tumors. The acidic environment can be... 

Diffusion coefficients of nucleic acids in solutions and gels have been accurately measured with the development of advanced laboratory techniques, such as pulsed field-gradient NMR and FRAP (Lapham et al., 1997 Pluen et al., 1999 Politz et al., 1998). These data may provide some semi-quantitative information applicable to interstitial transport of nucleic acids in tumor tissues. 

Netti, P.A., Berk, D.A., Swartz, M.A., Grodzinsky, A.J. and Jain, R.K. (2000) Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res., 60, 2497-2503. 

Despite the importance of interstitial transport parameters, it has been difficult to obtain accurate measurements of these values. Accumulation of molecules in tumor or normal tissue can be detected, but it is difficult to distinguish the roles of diffusion, convection, and binding, as well as transvascular transport. One experimental method that has been used successfully to quantitate interstitial diffusion, convection, and binding is fluorescence recovery after photobleaching (FRAP), in conjunction with tumors grown in transparent windows (Chary and Jain, 1987, 1989 Jain et al., 1990 Kaufman and Jain, 1990, 1991, 1992a, b Berk et al., 1993). 

Increased interstitial fluid pressure (IFP) within solid tumors decreases extravasation and inhibits the extravascular transport of larger molecules (e.g., monoclonal antibodies, cytokines) by convection (see Table 15.2). Macromolecules rely more heavily on convection as opposed to simple diffusional transport. Interstitial transport of macromolecules is further impaired by a much denser network of collagen fibers in the extracellular matrix of tumors as compared to normal tissues. CoUagen content in tumors is much higher and collagen fibers are much thicker than in normal tissues, leading to an increased mechanical stiffness of the tissue (Netti et al. 2000 Heldin et al. 2004). 

Transvascular transport involves both convection and diffusion. Under normal physiological conditions, diffusion is the dominant mode of transport for small molecules and convection is more important for transport of macromolecules and nanoparticles. However, interstitial fluid pressure (IFF) at the center of solid tumors is elevated uniformly, and is approximately equal to the microvascular pressure. In addition, the osmotic pressure difference across the microvessel wall is minimal because of the vascular leakiness. Therefore, the driving force for convection is negligible in the middle of sohd tumors. At the periphery, convection can be the dominant mode of transvascular transport of macromolecules due to the rapid decrease in the IFR The convection can make systemically administered macromolecules preferentially accumulate at the edge of tumors (see also the discussion on interstitial transport). ... 

McGuire S, Zaharoff D, Yuan F. Interstitial transport of macromolecules Implication for nucleic acid delivery in soUd tumors. In Mahato RI, Kim SW (eds). Pharmaceutical Perspectives of Nucleic Acid-Based Therapeutics. Taylor 8c Francis Books London, 2002, pp 434-454. 

LT Baxter, RK Jain. Transport of fluid and macromolecules in tumors. I. Role of interstitial pressure and convection. Microvasc Res 37 77-104, 1989. 

Given the complexity in molecular transport in tissues, understanding mechanisms of convection, diffusion, and binding in the interstitial space regardless of administration techniques may provide the means to overcome transport barriers for more uniform and adequate delivery of large therapeutic agents in solid tumors. 

Diffusion in the interstitial space is closely related to the volume fraction of space that is available to fluid and solute transport in tissues. The volume fraction of tumor interstitial fluid space varies from 15% in human gliomas up to 60% in a rat fibrosarcoma 4956 (Jain, 1987). The available volume fraction (KAV) of solutes is a measure of the steady state ratio of drag concentrations between tissues and the plasma (Krol et al., 1999). Thus, drug and gene delivery can be significantly improved through increasing KAV. In ex vivo experiments, KAV determines the ratio of concentrations between tissues and external solutions at the equilibrium state. KAV has been studied extensively in normal tissues but poorly in tumor tissues (Table 20.1) (Krol el al., 1999). KAV depends on the size of solutes and the dependence is determined by both the size and the connectedness of pores (Yuan et al., 2001). 

Pietras K, Ostman A, Sjoquist M, Buchdunger E, Reed RK, Heldin CH, Rubin K, Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors, Cancer Res., 61 2929-2934, 2001. 

Fig. 2 Continued, (c) These macromolecules move toward the center by the slow process of diffusion (=>). In addition, interstitial fluid oozing from tumor carries macromolecules with it by convection (- ) into the normal tissue. Note that the interstitial movement may be further retarded by binding. Products of metabolism may be cleared rapidly by blood. (Reproduced with permission from Jain, 1989.) These transport processes have been mathematically modeled by Jain and Baxter (1988) and Baxter and Jain (1989, 1990, 1991a, b).

Jain, 1989). Since transvascular transport by diffusion is slow for a macromolecule to begin with, macromolecular extravasation would be very small in the high interstitial pressure regions of a tumor. Since high-pressure regions usually coincide with regions of poor perfusion rate and lower vessel surface area, leakage of blood-borne macromolecules from vessels would be further restricted (Baxter and Jain, 1990). 

Now consider a more realistic situation, where the tumor vessels are 200 /urn apart and uniformly perfused, but Pi has increased in the center so that fluid extravasation, and hence convective transport of macromolecules across vessels, has stopped. In such a case the only way macromolecules extravasate in the center is by the slow process of diffusion across vessel walls. Also, they can reach the center from the periphery (where is near zero) by interstitial diffusion. As stated earlier, if the distance between the center and periphery is — 1 mm, it would take days for them to get there, and if it is 1 cm, it would take months (Clauss and Jain, 1990). If, owing to cellular proliferation, the central vessels have collapsed completely, then there is no delivery of macromolecules by blood flow to the necrotic center (Jain, 1988 Baxter and Jain, 1990). In such a case there are no molecules available for extravasation by diffusion across the vessel wall, and consequently the central concentration would be even lower (Baxter and Jain, 1990). However, once the molecules have arrived there, the central region may serve as a reservoir for slow release later when the periphery has been cleared by plasma. 

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