Inherent Targeting

The RES is composed of a series of sentinel cells located in several highly perfused organs, including the liver and spleen.27 Nanoparticles can be rapidly cleared from the blood if they are 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 chemistries45 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 poly-anionic 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.

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