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

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Folate has been used to target dendrimers , and iron oxide nanoparticles. Folate receptor-targeted lipid nanoparticles for the delivery of a lipophilic paclitaxel prodrug have shown promising pre-clinical outcomes.88 Cancer cells can also overexpress transferrin receptors (REF), and trans-ferrin-conjugated gold nanoparticle uptake by cells has been demonstrated.89 A transferrin-modified cyclodextrin polymeric nanoparticle has been described that could be used to deliver genetic material to cancer cells.90

Increased nutrient uptake associated with increased requirements for amino acids and nucleic acids may also provide a targeting strategy for nanoparticles. That many classical anti-cancer agents function by interfering with amino acid or nucleic acid incorporation into polymer structures should provide an important template for strategies to use nanoparticle technologies to effectively target cancer cells. For example, pancreatic cancer cell lines appear to overexpress the peptide transporter system PepT1,91 possibly providing a growth advantage by its ability to provide additional amino acid uptake. Nanoparticles decorated with (or composed of) ligands recognized by this uptake pathway may provide an important targeting opportunity. Such an approach can be used for similar target-specific delivery of other molecules. It is important to remember that materials such as amino acids and nucleic acids, unlike co-factors discussed above that are used more as part of catalytic cellular events, are required in stoiciometric amounts for cell growth. Targeting strategies using uptake processes against vitamins and co-factors will have the added benefit of potentially depriving cancer cells of these critical materials whereas targeting strategies using amino acids and nucleic acids will probably not affect the overall influx of these materials and their incorporation into nascent polymers required for continued cell growth.

A growing bank of experimental and clinical data has provided strong evidence that chronic inflammation can drive epithelial cell populations into an oncogenic phenotype.92 It is this pre-neoplastic character that may act to alter the metabolic character of cells that might be useful for targeting nanoparticles. Such a targeting strategy would make use of transitions in cellular function in response to pro-inflammatory signals (Figure 3.4). In this regard, one could envisage ligand-directed targeting to inflammatory sites as well as activation of nanoparticles (or their components) for localized delivery at these sites by the presence of unique enzymatic activities. Additionally, one could contemplate nanoparticles that deliver cancer prevention agents that work through suppression of inflammatory events. A ligand peptide that binds endothelial vascular adhesion molecule-1 (VCAM-1) on the surfaces of inflamed vessels has been used to target nanoparticles.93 One major concern with using such metabolic processes for targeting nanoparticles is that inflammatory events are a common and essential function of the body, and they are not necessarily associated with pre-cancerous or cancerous states. Some nanoparticles can induce an inflammatory response. Therefore, the method selected for such a nanoparticle-targeting strategy most keep this in mind. It might be possible to utilize additional cancer-targeting mechanisms (e.g., the EPR effect) to augment inflammation-based strategies.

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