The study of the potential risks associated with the manufacture, use, and disposal of nanoscale materials, and their mechanisms of toxicity, is important for the continued advancement of nanotechnology. Currently, the most widely accepted paradigms of nanomaterial toxicity are oxidative stress and inflammation, but the underlying mechanisms are poorly defined. This review will highlight the significance of autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity. Most endocytic routes of nanomaterial cell uptake converge upon the lysosome, making the lysosomal compartment the most common intracellular site of nanoparticle sequestration and degradation. In addition to the endo-lysosomal pathway, recent evidence suggests that some nanomaterials can also induce autophagy. Among the many physiological functions, the lysosome, by way of the autophagy (macroautophagy) pathway, degrades intracellular pathogens, and damaged organelles and proteins. Thus, autophagy induction by nanoparticles may be an attempt to degrade what is perceived by the cell as foreign or aberrant. While the autophagy and endo-lysosomal pathways have the potential to influence the disposition of nanomaterials, there is also a growing body of literature suggesting that biopersistent nanomaterials can, in turn, negatively impact these pathways. Indeed, there is ample evidence that biopersistent nanomaterials can cause autophagy and lysosomal dysfunctions resulting in toxicological consequences.

Nanotechnology is an emerging science involving manipulation of matter at the nanometer scale. Due to concerns over nanomaterial risks, there has been a dramatic increase in focused safety research. The present review provides a summary of these published findings, identifying areas of agreement and discordance with regard to: (1) the potential for nanomaterial exposure, (2) the relative hazard nanomaterials pose to humans and the environment, and (3) the present deficits in our understanding of risk. Special attention is paid to study design and methodologies, offering valuable insight into the complexities encountered with nanomaterial safety assessment. Recent data highlight the impact of surface characteristics on nanomaterial biocompatibility and point to the inadequacy of the current size-dependent mechanistic paradigms, with nanoscale materials lacking unique or characteristic toxicity profiles. The available data support the ability of the lung, gastrointestinal tract, and skin to act as a significant barrier to the systemic exposure of many nanomaterials. Furthermore, the acute systemic toxicity of many nanomaterials appear to be low. By contrast, the potential pulmonary toxicity of certain nanomaterials, such as carbon nanotubes, is significant, requiring a better understanding of exposure to further evaluate their risk. While these findings arrive at an overall picture of material-specific rather than nanogeneralized risk, any conclusions should clearly be tempered by the fact that nanomaterial safety data are limited. Until such time as the exposures, hazards, and environmental life cycle of nanomaterials have been more clearly defined, cautious development and implementation of nanotechnology is the most prudent course.

Quantum dots (QDs) are being investigated as novel in vivo imaging agents. The leaching of toxic metals from these QDs in biological systems is of great concern. This study compared the cytotoxic mechanisms of two QD species made of different core materials (cadmium selenide [CdSe] vs. indium gallium phosphide [InGaP]) but similar core sizes (5.1 vs. 3.7 nm) and surface compositions (both ZnS capped, lipid-coated and pegylated). The CdSe QD was found to be 10-fold more toxic to porcine renal proximal tubule cells (LLC-PK1) than the InGaP QD on a molar basis, as determined by MTT assay (48 h IC₅₀ 10nM for CdSe vs. 100nM for InGaP). Neither of the QD species induced appreciable oxidative stress, as determined by lipid peroxide and reduced glutathione content, suggesting that toxicity was not metal associated. In agreement, treatment of cells with CdSe QDs was not associated with changes in metallothionein-IA (MT-IA) gene expression or Cd-associated caspase 3 enzyme activation. By contrast, incubation of the LLC-PK1 cells with the InGaP QD resulted in a dramatic increase in MT-IA expression by 21- and 43-fold, at 8 and 24 h, respectively. The most remarkable finding was evidence of extensive autophagy in QD-treated cells, as determined by Lysotracker Red dye uptake, TEM, and LC3 immunobloting. Autophagy induction has also been described for other nanomaterials and may represent a common cellular response. These data suggest that QD cytotoxicity is dependent upon properties of the particle as a whole, and not exclusively the metal core materials.

Nanoparticle (NP) delivery to solid tumors has recently been questioned. To better understand the magnitude of NP tumor delivery, we reanalyzed published murine NP tumor pharmacokinetic (PK) data used in the Wilhelm et al. study. Studies included in their analysis reporting matched tumor and blood concentration versus time data were evaluated using classical PK endpoints and compared to the unestablished percent injected dose (%ID) in tumor metric from the Wilhelm et al. study. The %ID in tumor was poorly correlated with standard PK metrics that describe NP tumor delivery (AUC_tumor/AUC_blood ratio) and only moderately associated with maximal tumor concentration. The relative tumor delivery of NPs was ~100-fold greater as assessed by the standard AUC_tumor/AUC_blood ratio than by %ID in tumor. These results strongly suggest that PK metrics and calculations can influence the interpretation of NP tumor delivery and stress the need to properly validate novel PK metrics against traditional approaches.