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Active Targeting Strategies in Cancer with a Focus on Potential Nanotechnology Applications 31
(a)
(b)
(c)
Macropage
Macropage
Cell division
Macropage
FIGURE 3.4 Effect of chronic pro-inflammatory stimulus on epithelial barrier patency. (a) A variety of stimuli
( ) can incite the release of pro-inflammatory cytokine (e.g., TNFa and IFNg) from macrophages and other
cells. Genetic predisposition can enhance these responses. (b) Released pro-inflammatory cytokines act to open
tight junction (TJ) structures ( ), allowing entry of additional activating stimuli that, in turn, attract more cells
associated with inflammation. (c) Chronic inflammation leads to breakdown of basement membrane, loss of TJ
function, and disorganization of the epithelia characteristic with a pre-neoplastic state.
remove by-products is required for cell survival. Cancer cells secrete a variety of growth factors
that stimulate the formation of nascent blood and lymph vessels. Tumor-associated vascular beds
have unique surface properties that are associated with their rapid growth characteristics, resulting
in aberrant vascular beds that have been used to design a combined vascular imaging and therapy
approach using nanoparticles. 94 Non-specific targeting of nanoparticles (10–500 nm in diameter) to
solid tumors through this EPR capacity of solid tumors 47 can provide a means to enrich the
localization of an anti-neoplastic agent to a tumor when it is coupled to a nanoparticle compared
to its free form. 95 The EPR effect has also been used to increase localization through inherent
targeting 96 of long-circulating liposomes. 97
PAMAM dendrimers useful for boron neutron capture therapy (BNCT) of cancers have been
targeted to tumor vasculature by attachment of vascular endothelial growth factor (VEGF) that acts
to target VEGF receptors that are frequently overexpressed on tumor neovasculature. 98 Targeting
VEGF receptors Flk or Flt on tumor-associated endothelial cells could also be effective; this has
been done with a complex material composed of anti-Flk-1 antibody-coated 90 Y-labeled nanoparticles
99 . PECAM (or CD31) is highly expressed on the surface of endothelial cells present in
immature vasculature. Platelet endothelial cell adhesion molecule (PECAM) up-regulation
occurs following VEGF stimulation of endothelial cells. The presence of such endothelial
surface markers also provides the opportunity to target nanoparticles that contain DNA for gene
therapy applications, 100 release anti-angiogenesis agents as well as chemotherapeutics, 101 and
q 2006 by Taylor & Francis Group, LLC