Environmental Engineering Reference
In-Depth Information
from the rapid vascularization necessary to provide oxygen and nutrients to
proliferating tumors. These characteristics render tumor blood vessels perme-
able to macromolecules. Furthermore, the tumor lymphatic drainage system
does not operate effectively as a result of immature lymphatic capillaries; thus,
macromolecules are selectively retained for prolonged time periods in the
tumor interstitium [ 40 ]. Thus, numerous studies have shown that the EPR
effect causes passive accumulation of macromolecules and nanoparticulates in
solid tumor, enhancing the therapeutic index while decreasing side effects.
Also, it has been found that in most human tumors the effective pore size in the
vasculature ranges from 200 to 600 nm in diameter, which allows for passive
targeting to tumors [ 41 ]. It has been noted that secretion of various factors
such as nitric oxide, prostaglandins, bradykinin, and basic fibroblast growth
factor in tumor tissues and overexpression of genes such as vascular perme-
ability factor or vascular endothelial growth factor (VEGF) [ 42 , 43 ] cause
hyperpermeability of tumor microvasculature. However, it should be noted
that permeability of vessels in tumor varies during progression, tumor type,
and anatomical location of tumor, whereas the physicochemical properties of
polymer used affect the extravasations of polymeric nanoparticulates [ 44 ]. For
passive targeting, micelles have to circulate in blood for longer periods, and
their size determines their biological fate; thus, PMs smaller than 5 and 5-
10 nm are easily eliminated through the renal glomeruli, whereas the larger
micelles with size range of 50-100 nm are removed by the liver and
spleen [ 45 ].
(b) Active Targeting. In cellular-specific targeting, pilot molecules are installed at
the end of the hydrophilic segment so that they may extend outward from the
micelle corona and readily encounter and interact with membrane receptors.
The main purpose of functionalization of the hydrophilic corona is to modulate
the biodistribution of polymeric micelles and induce specific cellular uptake
by receptor-mediated endocytosis. Certain types of tissues are known to
overexpress specific protein receptors on their surface. The localization of
such site-specific receptors has contributed to several advancements in the
field of targeted drug delivery. The tethering of a ligand to the outer shell of
micelles is most often achieved through the postmodification of a copolymer
with bifunctional spacer molecules [ 46 ] or via the direct synthesis of heterobi-
functional block copolymers [ 47 ]. Targeted micelles generally exhibit greater
cellular uptake and improved in vitro efficacy than their unmodified
counterparts.
Active targeting employs a deliberately modified drug and drug-carrier
molecule capable of recognizing and interacting with a specific cell, tissue,
or organ in the body. Modifications of the carrier systems may include a
change in the molecular size, alterations of the surface properties, incorpora-
tion of antigen-specific antibodies, or attachment of cell receptor specific
ligands [ 48 ].
Here, the carrier can be engineered by means of ligand coupling with
monoclonal antibodies,
folate,
transferrin,
luteinizing hormone-releasing
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