Interstitial transport of macromolecules: implication for nucleic acid delivery in solid tumors
Gene delivery in solid tumors has become an important concern to the advances of molecular medicine. One of the major problems in both systemic and local delivery of genes is the interstitial resistance to transport of nucleic acids and their carriers (Jain, 1997). The problem is attributed to several unique characteristics at molecular, cellular, and tissue levels, which include: (a) low convective transport due to uniformly elevated interstitial fluid pressure (IFP) and the lack of functional lymphatics; (b) outward gradient of IFP in tumor periphery, causing convective transport of extravasated genes from interior to surrounding tissues; (c) large diffusion distance in some regions of the interstitium; (d) binding of drugs and genes to both the plasma membrane of cells and the extracellular matrix, and; (e) degradation of nucleic acids in the interstitial space. These factors may significantly hinder the interstitial penetration of genes, limit the accessibility of therapeutic agents to intracellular targets, and thus reduce the efficacy of molecular medicines.