q 2006 by Taylor & Francis Group, LLC - Developers

Active Targeting Strategies in Cancer with a Focus on Potential Nanotechnology Applications 29
ligand–nanoparticle complexes could lead to receptor internalization that might not occur by the
presence of the targeting ligand alone. The basis for this difference might come from the potential
for nanoparticles to contain a coordinated ligand matrix to sequester of cell-surface receptors in a
manner that facilitates internalization.
Antibody-based targeting of nanoparticles to solid tumors has been a highly promising strategy
that is augmented by the enhanced vascular permeability (EPR effect) of solid tumors. For example,
an antibody-directed (anti-p185HER2) liposome loaded with an anti-neoplastic can be an effective
cancer therapeutic approach. 73 Blood cell-based cancers (e.g., leukemias and lymphomas) can also
be targeted by nanoparticles as a way to reduce unwanted systemic side effects. Nanoparticles could
be targeted to T-cell leukemia cells using an antibody to a surface cluster of differentiation (CD)
antigen, CD3, on the surface of lymphocytes. 74 B-cell lymphomas can be targeted by anti-idiotypic
antibodies specific for the unique monoclonal antibody expressed by each individual cancer. 75 In
both of these cases, the potential for these B- and T-cell-derived cancer cells to actively take up
particles on their surfaces as part of their normal function in antigen surveillance and presentation
might facilitate and even augment the desired outcome using a targeted nanoparticle.
Efficient, targeted delivery of gene therapy elements and/or antigens to antigen presentation
cells (APC) has long been a goal for the induction of anti-cancer cell immune responses. Nanoparticles
provide an exciting possibility to achieve this goal. Coating nanoparticles with mannan
facilitates their uptake by APCs such as macrophages and dendritic cells that acts to target these
materials to local-draining lymph nodes following their administration. 76 Such an approach is likely
to provide additional synergy in APC activation because polymer nanoparticles are efficiently
phagocytosed by dendritic cells. 77 Many APCs express LDL-type receptors, and molecules that
interact with this class of receptors could be a means of targeting as well. 78 Interestingly, LDL
receptors can be an attractive targeting strategy for cancers because many tumors of different
origins express elevated levels of this receptor. 79 Therefore, LDL-based nanoparticles could be
useful in targeting cancer. 31
It might also be possible to intentionally alter the surfaces of cancer cells to improve nanoparticle
targeting. Cells could be transfected with a protein that expresses the appropriate acceptor
peptide recognized by a surface-applied bacterial biotin ligase. 80 Although there would be multiple
issues to overcome prior to clinical application, this approach outlines one strategy where cancer
cells might be altered to express a unique surface structure such as biotin that could be very
selectively targeted. Reversed-response targeting might also be performed using discriminating
cell-surface properties. Hepatocytes can be targeted using nanocapsules decorated with the surface
antigen of hepatitis B virus (SAgHBV). 81 Because liver cells may lose their capacity to bind
SAgHBV following oncogenic conversion, this targeting strategy could be used to deliver cytoprotective
materials to normal hepatocytes and enhance the efficacy of chemotherapeutics aimed
at liver cancers. Similarly, hepatocytes exclusively express high affinity cell-surface receptors for
asialoglycoproteins, and this ligand–receptor system has been used to target albumin nanoparticles
to non-cancer cells of the liver. 8 Nanoparticles coated with galactose might also be used to target
the liver. 82
3.4.2 METABOLIC PROPERTIES
One of the most detrimental aspects of cancer cells, their high rate of proliferation, can also be
considered their Achilles’ heel. As proliferation rate increases, metabolic requirements follow
accordingly. This places cancer cells in a precarious position where a blockade of critical metabolic
steps can lead to cytotoxic outcomes; this is the basis from a number of currently approved anticancer
agents that function as metabolic poisons. 83 There are two obvious approaches that could be
used for targeting using this characteristic of cancer cells: ligands that emulate the nutrient, vitamins
or co-factors, and antibodies that recognize these surface transport elements. Nanoparticles
coated with a ligand for one of these receptors such as folate can be used to target to cancer cells. 84
q 2006 by Taylor & Francis Group, LLC