Tumor interstitium

Jain,R.K. (1987) Transport of molecules in the tumor interstitium areview. Cancer Res., 47, 3039-3051. 

The size of the polyplex is also crucial to its function. The threshold for first-pass elimination by the kidneys is approximately lOnm in diameter defining a rough lower size limit for nanoparticles (21). Upper size limits are more difficult to establish as they depend on a variety of factors that are variable within tumors including penetration of capillary endothelium, diffusion rates in tumor interstitium and intracellular spaces (22). Macromolecular complexes preferentially accumulate in tumors through the enhanced permeability and retention (EPR) effect (23). Ideally, a nanoparticle would be in a size window such that it could take advantage of the EPR effect. The size of the polyplex can be readily modified during complexation by altering the DNA to polymer ratio (24). 

Many substances are concentrated in tumor tissues to some extent after iv injection, by means of nonspecific trapping in tumor interstitium or other more effective mechanisms in special tumor types. Iodine, in particular, achieves high tumormormal tissue concentration ratios by active uptake and is established in routine use as 13 ft for the diagnosis and curative treatment of thyroid carcinoma, with excellent results (1). Metaiodo-benzylguanidine (MIBG), taken up and stored like noradrenaline in neuronal tissue, now has a role in diagnosis and anal palliative treatment of neuroblastoma and pheochromocytoma (2). 

In normal tissues vascular and interstitial oncotic pressures (ttv and 77 ) are approximately 20-25 and 5-15 mm Hg, respectively (Baxter and Jain, 1989). Although there are no direct measurements of in tumors, based on high vascular permeability and high interstitial diffusion coefficient in tumors, one would expect higher concentration of endogenous plasma proteins in the tumor interstitium than in normal interstitium. This hypothesis is supported by the data in the literature (Sylven and Bois, 1960). As a result, in tumors may be higher than that in normal tissues. 

Two major steps in drug delivery are commonly considered first step is the tissue vascular level (organ), accomplished by EPR effect for polymer therapeutics (nanomedicine) which can traverse the vascular wall to the tumor interstitium, where EPR effect plays the single most important role [69]. 

Passive targeting occurs due to extravasation of the nanoparticles at the diseased site where the microvasculature is leaky. Passive delivery refers to nanoparticle s transport through leaky tumor capillary fenestrations into the tumor interstitium and cells by passive diffusion or convection (Haley and Frenkel 2008). What is important to understand, passive targeting proceeds based on natural developed... 

Active targeting can also enhance the distribution of nanomedicine within the tumor interstitium (Drummond et al. 1999). Active targeting has been explored to deliver drugs into resistant cancer cells (Sapra and AUen 2003). 

FIGURE 2.4.5 (a) Illustration of the use of TAT as an example of a CPP to demonstrate the concept of deactivation of a CPP in the blood compartment and its activation in the tumor interstitium or cells for in vivo tumor-targeted drug delivery, (b) Amidization of TAT s primary amines to succinyl amides and their acid-triggered hydrolysis [65]. 

Increased vascular permeability has been demonstrated, with extravasation of blood plasma expanding the interstitial fluid space and— because of the lack of functional lymphatics— drastically increasing the hydrostatic pressure in the tumor interstitium. 

Nanoparticle (size dependant tumor interstitium accumulation)... 

FIGURE 7.4 Light micrographs of Berlin blue-stained osteosarcoma excised 1 h (a) and 2 weeks (b) after IV administration of magnetic doxorubicin liposomes under magnetic force of 0.4 T. Blue spots represent magnetite particles, and they are concentrated and deposited in the endothelium of proliferated tumor vessels and the tumor interstitium in (a) but not (b). (Adapted from Renner, M. W. et al. Anti-Cancer Agents Med. Chem. 2006, 6, 145-157.)... 

Henshaw J W, Zaharoff DA, Mossop BJ, Yuan F. Electric field-mediated transport of plasmid DNA in tumor interstitium in vivo. Bioelectrochemistry 2007 71 233-242. 

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