Polymeric Micelles for siRNA Delivery - RNA Interference from Biology to Therapeutics - page 162

8.3 Passive and Active Targeting in Cancer

8.3.1 Passive Targeting

Rapidly dividing cancerous cells require a continuous supply of nutrients to main-
tain 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 pas-
sive 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, avoid-
ing 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 par-
ticles 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 ] .

8.3.2 PEGylated Micelles

A common strategy to improve the blood circulation and the pharmacokinetic prop-
erties of a nanocarrier to successfully passive target solid tumors by EPR is
PEGylation. PEGylation is the addition of a poly(ethylene glycol) (PEG) shell to
the nanoparticles to utilize its protective properties and produce stealth particles.
PEG has a general structure of HO-(CH 2 CH 2 O) n -CH 2 CH 2 -OH, encompassing a
flexible polyether backbone, with ether oxygen molecules forming hydrogen bonds
with water molecules in solution. The protective effect of PEG is due to the forma-
tion of a dense, hydrated layer of long flexible chains on the surface of the colloidal
particle that reduces nonspecific interactions with plasma proteins [ 26 ] . Importantly,
an increase of PEG molecular weight >2,000 Da improves the blood circulation
half-life of the PEGylated particles, probably due to the increased chain flexibility
of higher MW PEG polymers [ 27 ]. Thus, PEGylation provides nanocarriers with