Nanomaterials are engineered structures with at least one dimension of 100 nanometers or less. These materials are increasingly being used for commercial purposes such as fillers, opacifiers, catalysts, semiconductors, cosmetics, microelectronics, and drug carriers. Materials in this size range may approach the length scale at which some specific physical or chemical interactions with their environment can occur. As a result, their properties differ substantially from those bulk materials of the same composition, allowing them to perform exceptional feats of conductivity, reactivity, and optical sensitivity. Possible undesirable results of these capabilities are harmful interactions with biological systems and the environment, with the potential to generate toxicity. The establishment of principles and test procedures to ensure safe manufacture and use of nanomaterials in the marketplace is urgently required and achievable.

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Toxic Potential of Materials at the Nanolevel

With the increased presence of nanomaterials in commercial products, a growing public debate is emerging on whether the environmental and social costs of nanotechnology outweigh its many benefits. To date, few studies have investigated the toxicological and environmental effects of direct and indirect exposure to nanomaterials and no clear guidelines exist to quantify these effects.

The potential environmental impact of engineered nanomaterials

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.

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Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity

Fullerenes have attracted considerable attention in different fields of science since their discovery in 1985. Investigations of physical, chemical and biological properties of fullerenes have yielded promising information. It is inferred that size, hydrophobicity, three-dimensionality and electronic configurations make them an appealing subject in medicinal chemistry. Their unique carbon cage structure coupled with immense scope for derivatization make them a potential therapeutic agent. The study of biological applications has attracted increasing attention despite the low solubility of carbon spheres in physiological media. The fullerene family, and especially C60, has appealing photo, electrochemical and physical properties, which can be exploited in various medical fields. Fullerene is able to fit inside the hydrophobic cavity of HIV proteases, inhibiting the access of substrates to the catalytic site of enzyme. It can be used as radical scavenger and antioxidant. At the same time, if exposed to light, fullerene can produce singlet oxygen in high quantum yields. This action, together with direct electron transfer from excited state of fullerene and DNA bases, can be used to cleave DNA. In addition, fullerenes have been used as a carrier for gene and drug delivery systems. Also they are used for serum protein profiling as MELDI material for biomarker discovery. In this review we report the aspects of medicinal applications of fullerenes.

Medicinal applications of fullerenes.

Cerium oxide nanoparticles (nanoceria) have shown great potential as antioxidant and radioprotective agents for applications in cancer therapy. Recently, various polymer-coated nanoceria preparations have been developed to improve their aqueous solubility and allow for surface functionalization of these nanoparticles. However, the interaction of polymer-coated nanoceria with cells, their uptake mechanism and subcellular localization are poorly understood. Herein, we engineered polymer-coated cerium oxide nanoparticles with different surface charge (positive, negative and neutral) and studied their internalization and toxicity in normal and cancer cell lines. Results showed that nanoceria with a positive or neutral charge enters most of the cell lines studied, while nanoceria with a negative charge internalizes mostly in the cancer cell lines. Moreover, upon entry into the cells, nanoceria is localized to different cell compartments (e.g. cytoplasm and lysosomes) depending on the nanoparticle's surface charge. The internalization and subcellular localization of nanoceria plays a key role in the nanoparticles’ cytotoxicity profile, exhibiting significant toxicity when they localize in the lysosomes of the cancer cells. In contrast, minimal toxicity is observed when they localize into the cytoplasm or do not enter the cells. Taken together, these results indicate that the differential surface-charge-dependent localization of nanoceria in normal and cancer cells plays a critical role in the nanoparticles’ toxicity profile.

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Surface-charge-dependent cell localization and cytotoxicity of cerium oxide nanoparticles.

Polyalkylsulfonated C60, or FC4S, a highly water-soluble caged fullerene derivative, is believed to be a free radical remover or an antioxidant in biological systems. A 50 mg/ml aqueous solution was prepared as a master solution and administered to female Sprague-Dawley CD(Crl:CDR (SD)BR) rats in a single-dose acute toxicity study or a 12-day subacute toxicity study where rats were given the solution daily. In a study of the median lethal dose (LD50), no rats died after oral administration, and thus FC4S was considered to nontoxic if administered orally. In an LD50 intraperitoneal injection study, rats died within 30 hr after injection; the LD50 was determined to be approximately 600 mg per kilogram of body weight. Rats injected with the compound intraperitoneally or intravenously immediately eliminated the compound through the kidney; the kidney appeared to be the primary target organ. The compound induced a distinct lysosome-overload nephrosis, a phagolysosomal nephropathy characterized by a tinctorial ...

https://journals.sagepub.com/doi/pdf/10.1177/019262339802600117

Acute and Subacute Toxicity Study of Water-Soluble Polyalkylsulfonated C60 in Rats

The hydrophilic molecular micellar hexa(sulfo-n-butyl)[60]fullerene (FC₄S), first synthesized in 1998 as a photosensitizer (PS) has been reported to exhibit high efficacy for singlet oxygen generation and antimicrobial photodynamic inactivation. The purpose of this study was to investigate the effects of photoactivated FC₄S for free radical generation and to mediate photodynamic therapy (PDT) of cancer in vitro and in vivo. The results demonstrated that following light irradiation, FC4S produced singlet oxygen, but after addition of electron donors such as ferrocytochrome c or NADH, FC4S also produced superoxide. The combination of FC4S with light irradiation was able to induce cytotoxicity to human fibrosarcoma cells and murine sarcoma 180 cells in vitro. Cell-killing was proportional to fluence as well as FC4S concentration. Photoirradiation by argon-ion laser after intraperitoneal injection of FC4S also resulted in inhibition of S180 tumor growth in vivo (up to 80% reduction of tumor volume). Hematological and blood biochemistry parameters of the cancer-bearing mice were improved by PDT. Based on these findings, we conclude that FC₄S has a great potential as a nanomedicine in PDT for cancer.

Bao J. Chen

Papers

Acute and Subacute Toxicity Study of Water-Soluble Polyalkylsulfonated C60 in Rats

Photodynamic Therapy with Hexa(sulfo-n-butyl)[60]Fullerene Against Sarcoma In Vitro and In Vivo.