RNA Interference from Biology to Therapeutics by Kenneth A. Howard

Author:Kenneth A. Howard
Language: eng
Format: epub
Publisher: Springer US, Boston, MA

8.3 Passive and Active Targeting in Cancer

8.3.1 Passive Targeting

Rapidly dividing cancerous cells require a continuous supply of nutrients to maintain proliferation. Cancerous cells, therefore, secrete growth factors that induce angiogenesis and result in a fast and disordered neovascularization around the tumor area. The new blood capillaries present loose interendothelial junctions that allow enhanced permeability to extravascular tissue. Through this leaky vasculature of the tumor, some substances including polymeric micelles are able to extravasate from the blood vessels to the tumor tissue. Moreover, the development of a lymphatic system is insufficient in tumor tissue, resulting in poor drainage of macromolecular substances from the tissue. This preferential macromolecular accumulation in solid tumor tissue is known as enhanced permeability and retention (EPR) effect [22, 23]. The EPR effect found by Matsumura and Maeda has become the guideline for passive targeting in cancer.

For an effective passive accumulation by the EPR effect, the nanocarriers should be small enough to permeate through the gaps in the endothelium from the blood compartment into solid tumors. Secondly, nanocarriers should have long circulation properties. Theoretically, long-circulating nanocarriers have an increased chance to find these gaps between endothelial cells and extravasate to tumor tissue. The long-circulation property is, in fact, a consequence of its stability in the bloodstream, avoiding glomerular excretion by the kidney and nonspecific complement activation and opsonization that could lead to uptake by the MPS in the liver, spleen, and lung. As the renal filtration cutoff is 50 kDa (or 5–6 nm), rapid removal and excretion of particles smaller than this cutoff is expected [24]. On the other hand, larger particles can be recognized and removed by the MPS, resulting in short half-life in the blood [25].

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