q 2006 by Taylor & Francis Group, LLC - Developers

Active Targeting Strategies in Cancer with a Focus on Potential Nanotechnology Applications 25
recognized by RES cells in a non-selective fashion, typically before achievement of effective
targeting. 13,42 In some instances, this inherent targeting can provide a means to selectively delivery
materials. 43 In most cases, it is possible to modify the physical and chemical characteristics of
nanoparticles to reduce their default uptake by the RES. 44 Methods to avoid the RES will be
addressed in depth in other chapters in this text. In general, these measures follow principles
initially outlined in the development of stealth liposomes that provided a means of extending the
circulating half-life of a nanoparticle. Although PEG molecules of various lengths coupled using
various chemistries 45 are frequently used in this approach, heparan sulfate glycosaminoglycans
(HSGs) have also been shown to provide a protective coating that reduces immune detection. 46
Interestingly, HSGs might be shed at tumors by tumor-associated heparanase activity.
Another inherent targeting aspect of nanoparticles relates to the nature of tumor-associated
vasculature. In general, nanoparticles smaller than 20 nm have the ability to transit out of blood
vessels. Solid tumors grow rapidly; tumor-associated endothelial cells are continually bathed by a
plethora of cancer cell-secreted growth factors. In turn, endothelial cells sprout new vessels to
provide needed nutrients for the continued growth of the tumor. This cancer cell-endothelial cell
relationship, however, leads to the establishment of a poorly organized vasculature that, under the
constant drive of growth factor stimulation, fails to organize into a mature vascular bed. Therefore,
tumor-associated vascular beds are poorly organized and more leaky that normal vasculature.
Nanoparticles will inherently target to tumors as exudates through leaky vasculature. This phenomenon,
referred to as the enhanced permeability and retention (EPR) effect, 47 will be covered
extensively in other chapters in this text.
Finally, peculiar surface properties of certain nanomaterials might affect their inherent
interactions that could act to detract from a targeted delivery strategy. For example, some polyanionic
dendrimers can be taken up by cells and act within those cells to interfere with replication of
human immunodeficiency virus (HIV) that is considered to be the causative agent of AIDS. 48
Although, from such studies, it is unclear if these dendrimers interact with the host cell or the
pathogen to block their interaction; such a finding points to the potential for nanoparticles to
interact with structures that might affect their cellular properties or cell function. In some cases,
a nanoparticle with inherent capacity to interact with a cell or tissue might provide an added
advantage of using that material for a specific indication. In other cases, such an inherent capacity
to bind to or recognize cell or tissue components might highlight potential distractive aspects of that
material for certain indications.
3.3.2 COMPLICATING ASPECTS
By their eponymous descriptor, nanoparticles have physical dimensions in the nanometer size scale
similar to viruses and other materials that are either recognized by the body as pathogens or are
elements associated with an infective event. Toll-like receptors (TLR) present on monocytes,
leukocytes, and dendritic cells play a critical role in innate immunity with the capacity to recognize
organized patterns present on viruses and bacteria. 49 TLR proteins are present on the surface of
cells in the lung, spleen, prostate, liver, and kidney. Because the patterned surfaces of nanoparticles
can look like pathogen components recognized by TLR proteins such as DNA, RNA, and repeating
proteins like flagellin, it is possible that a number of cell types might non-selectively interact with
some nanoparticles. If such an interaction occurs, there are several potential outcomes that might
produce complicating aspects for nanoparticle targeting to cancers. Nanoparticle materials might be
immediately recognized and cleared by cells of the innate immune system, limiting the usefulness
of even their initial application. Alternately, only a fraction of the applied nanoparticles might
engage TLR that would not significantly affect the effectiveness of the administration. Recognition
of even a small fraction of the administered nanoparticles, however, might lead to immune events
that diminish the effectiveness of subsequent administrations. Nanoparticles that the naïve body
initially tolerates may become a focus of immune responses upon repeated exposure.
q 2006 by Taylor & Francis Group, LLC