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WIREs Nanomed Nanobiotechnol
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Nanomaterial standards for efficacy and toxicity assessment

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Abstract Decreased toxicity via selective delivery of cancer therapeutics to tumors has become a hallmark achievement of nanotechnology. In order to be optimally efficacious, a systemically administered nanomedicine must reach cancer cells in sufficient quantities to elicit a response and assume its active form within the tumor microenvironment (e.g., be taken up by cancer cells and release a toxic component once within the cytosol or nuclei). Most nanomedicines achieve selective tumor accumulation via the enhanced permeability and retention (EPR) effect or a combination of the EPR effect and active targeting to cellular receptors. Here, we review how the fundamental physicochemical properties of a nanomedicine (its size, charge, hydrophobicity, etc.) can dramatically affect its distribution to cancerous tissue, transport across vascular walls, and retention in tumors. We also discuss how nanoparticle characteristics such as stability in the blood and tumor, cleavability of covalently bound components, cancer cell uptake, and cytotoxicity contribute to efficacy once the nanoparticle has reached the tumor's interstitial space. We elaborate on how tumor vascularization and receptor expression vary depending on cancer type, stage of disease, site of implantation, and host species, and review studies which have demonstrated that these variations affect tumor response to nanomedicines. Finally, we show how knowledge of these properties (both of the nanoparticle and the cancer/tumor under study) can be used to design meaningful in vivo tests to evaluate nanoparticle efficacy. WIREs Nanomed Nanobiotechnol 2010 2 99–112 This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials

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Nanoparticle active and passive targeting (schematic, not drawn to scale). The fact that nanoparticles passively accumulate in tumors via the EPR effect is a result of differences between tumors and healthy tissue. Cancer cell proliferation requires a constant supply of nutrients and oxygen, which is why tumors form a rich vascular network. Tumor vessels are structurally irregular, heterogeneous, and leaky (i.e., they have more and larger endothelial pores/fenestrations) compared to normal vessels. Tumor vessel endothelial cells do not form a normal monolayer, may overlap, may form projections, and are irregularly spaced. In the EPR effect, nanoparticles enter a tumor through gaps (fenestrations/pores) in the tumor vasculature endothelium. These gaps are much larger (100 nm to 2 µm)6 in tumor endothelium than in healthy tissue (2–6 nm), and provide a route for nanoparticle extravasation. Furthermore, tumors lack functional lymphatic drainage. This means that nanoscale particles that have permeated the tumor vasculature are likely to be retained, whereas small molecules can diffuse freely back into the bloodstream.7 Finally, tumor vessels have been shown to exhibit receptors (e.g., VEGF, αvβ3 integrins) that can serve as potential targets for actively targeted nanoparticles.

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MicroPET images showing that VEGF expression is inversely correlated to tumor size. The animal model used here is U87MG tumor‐bearing mice, shown 16 h after injection of [64Cu]DOTA‐VEGF121. The small tumor has high VEGFR‐2 expression, whereas the large tumor has low VEGFR‐2 expression. %ID/g, percent injected dose per gram of tissue (Reproduced with permission from Ref 56. Copyright 2006 the Society of Nuclear Medicine).

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Minimal drug release in vitro correlates with minimal efficacy in vivo. (a) The results of a high pressure liquid chromatography assay for paclitaxel (PTX) release from a dendrimer–PTX conjugate in mouse plasma is shown. The PTX must be released from the dendrimer platform to be toxic. Less than 8% of the PTX was released after 48 h, and the rate of release decreased with time (evidenced by the plateau in the release graph in (a)). (b) The figure shows the measured tumor volumes from an in vivo efficacy study in LS 174T colon cancer xenograft‐bearing mice. Treatment with the PTX–dendrimer did not significantly affect tumor growth in comparison to treatment with a control (phosphate buffered saline, PBS).

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Receptor spacing, not amount of ligand on the nanoparticle surface, may limit avidity of nanoparticle–cell binding for actively targeted nanoparticles. Increasing the density of ligand on the nanoparticle surface does not necessarily increase avidity, as steric considerations may prevent the formation of multiple, simultaneous ligand–receptor bonds. (a) A schematic (not to scale) of a hypothetical nanoparticle with a high density of active targeting ligands on its surface. Because of the spacing between the cellular receptors the particle is intended to target, only one bond is formed with the cell (receptor spacing varies depending on the receptor and cell type). This is in contrast with (b), where a nanoparticle with lower ligand surface density also forms one bond with the cell.

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Variations in the density of the polymer coating on a nanomedicine can influence biodistribution. This figure contains the results of several experiments on two different batches (batch 1 and 2) of PEGylated (PEG‐5000) gold/silica nanoparticles. Batch 1 was synthesized almost a year earlier than batch 2, but the two batches were otherwise identically prepared. As can be seen in (a), from the gels of centrifuged samples of both batches, batch 2 has more PEG in the nanoparticle pellet and less free PEG in the sample supernatant than batch 1, suggesting that the nanoparticles in batch 2 have more PEG bound to their surfaces than those in batch 1. This could be because of a slow dissociation of PEG from the particle surface over time. (b) The figure shows that batch 1 also adsorbed greater amounts of plasma protein than batch 2. Finally, (c) shows a representative histology image from a 14‐day acute toxicology study in which equal doses of batch 1 and batch 2 nanoparticles were administered to Sprague Dawley rats. Batch 1 caused pronounced pulmonary toxicity (lung inflammations as shown in the figure) whereas batch 2 did not. These results illustrate the degree to which variations in the density of a nanomedicine's polymer coating can influence in vivo outcomes.

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