Nanomaterials have gained a rapid increase in use in a variety of applications that pertain to many aspects of human life. The majority of these innovations are centered on medical applications and a range of industrial and environmental uses ranging from electronics to environmental remediation. Despite the advantages of NPs, the knowledge of their toxicological behavior and their interactions with the cellular machinery that determines cell fate is extremely limited. This review is an attempt to summarize and increase our understanding of the mechanistic basis of nanomaterial interactions with the cellular machinery that governs cell fate and activity. We review the mechanisms of NP-induced necrosis, apoptosis and autophagy and potential implications of these pathways in nanomaterial-induced outcomes. Abbreviations: Ag, silver; CdTe, cadmium telluride; CNTs, carbon nanotubes; EC, endothelial cell; GFP, green fluorescent protein; GO, graphene oxide; GSH, glutathione; HUVECs, human umbilical vein endothelial cells; NP, nanoparticle; PEI, polyethylenimine; PVP, polyvinylpyrrolidone; QD, quantum dot; ROS, reactive oxygen species; SiO2, silicon dioxide; SPIONs, superparamagnetic iron oxide nanoparticles; SWCNT, single-walled carbon nanotubes; TiO2, titanium dioxide; USPION, ultra-small super paramagnetic iron oxide; ZnO, zinc oxide.

https://www.tandfonline.com/doi/pdf/10.1080/15548627.2018.1509171

Necrotic, apoptotic and autophagic cell fates triggered by nanoparticles

Radiotherapy is one of the major therapeutic strategies for cancer treatment. In the past decade, there has been growing interest in using high Z (atomic number) elements (materials) as radiosensitizers. New strategies in nanomedicine could help to improve cancer diagnosis and therapy at cellular and molecular levels. Metal-based nanoparticles usually exhibit chemical inertness in cellular and subcellular systems and may play a role in radiosensitization and synergistic cell-killing effects for radiation therapy. This review summarizes the efficacy of metal-based NanoEnhancers against cancers in both in vitro and in vivo systems for a range of ionizing radiations including gamma-rays, X-rays, and charged particles. The potential of translating preclinical studies on metal-based nanoparticles-enhanced radiation therapy into clinical practice is also discussed using examples of several metal-based NanoEnhancers (such as CYT-6091, AGuIX, and NBTXR3). Also, a few general examples of theranostic multimetallic nanocomposites are presented, and the related biological mechanisms are discussed.

Metal-based NanoEnhancers for Future Radiotherapy: Radiosensitizing and Synergistic Effects on Tumor Cells.

The development of different kinds of nanoparticles, showing different physico-chemical properties, has fostered their large use in many fields, including medicine. As a consequence, inorganic nanoparticles (e.g., metals or semiconductors), have raised issues about their potential toxicity. The scientific community is investigating the toxicity mechanisms of these materials, in vitro and in vivo, in order to provide accurate references concerning their use. This review will give the readers a thorough exploration on the entry mechanisms of inorganic nanoparticles in the human body, such as titanium dioxide nanoparticles (TiO2NPs), silicon dioxide nanoparticles (SiO2NPs), zinc oxide nanoparticles (ZnONPs), silver nanoparticles (AgNPs), gold nanoparticles (AuNPs) and quantum dots (QDsNPs). In addition, biodistribution, the current trends and novelties of in vitro and in vivo toxicology studies will be discussed, with a particular focus on immune response.

Exposure to Inorganic Nanoparticles: Routes of Entry, Immune Response, Biodistribution and In Vitro/In Vivo Toxicity Evaluation.

Understanding cell–nanoparticle interactions is critical to developing effective nanosized drug delivery systems. Nanoparticles have already advanced the treatment of several challenging conditions including cancer and human immunodeficiency virus (HIV), yet still hold the potential to improve drug delivery to elusive target sites. Even though most nanoparticles will encounter blood at a certain stage of their transport through the body, the interactions between nanoparticles and blood cells is still poorly understood and the importance of evaluating nanoparticle hemocompatibility is vastly understated. In contrast to most review articles that look at the interference of nanoparticles with the intricate coagulation cascade, this review will explore nanoparticle hemocompatibility from a cellular angle. The most important functions of the three cellular components of blood, namely erythrocytes, platelets and leukocytes, in hemostasis are highlighted. The potential deleterious effects that nanoparticles can have on these cells are discussed and insight is provided into some of the complex mechanisms involved in nanoparticle–blood cell interactions. Throughout the review, emphasis is placed on the importance of undertaking thorough, all-inclusive hemocompatibility studies on newly engineered nanoparticles to facilitate their translation into clinical application.

https://www.mdpi.com/2073-4409/8/10/1209/pdf

The Hemocompatibility of Nanoparticles: A Review of Cell–Nanoparticle Interactions and Hemostasis

Biomedicine represents one of the main study areas for dendrimers, which have proven to be valuable both in diagnostics and therapy, due to their capacity for improving solubility, absorption, bioavailability and targeted distribution. Molecular cytotoxicity constitutes a limiting characteristic, especially for cationic and higher-generation dendrimers. Antineoplastic research of dendrimers has been widely developed, and several types of poly(amidoamine) and poly(propylene imine) dendrimer complexes with doxorubicin, paclitaxel, imatinib, sunitinib, cisplatin, melphalan and methotrexate have shown an improvement in comparison with the drug molecule alone. The anti-inflammatory therapy focused on dendrimer complexes of ibuprofen, indomethacin, piroxicam, ketoprofen and diflunisal. In the context of the development of antibiotic-resistant bacterial strains, dendrimer complexes of fluoroquinolones, macrolides, beta-lactamines and aminoglycosides have shown promising effects. Regarding antiviral therapy, studies have been performed to develop dendrimer conjugates with tenofovir, maraviroc, zidovudine, oseltamivir and acyclovir, among others. Furthermore, cardiovascular therapy has strongly addressed dendrimers. Employed in imaging diagnostics, dendrimers reduce the dosage required to obtain images, thus improving the efficiency of radioisotopes. Dendrimers are macromolecular structures with multiple advantages that can suffer modifications depending on the chemical nature of the drug that has to be transported. The results obtained so far encourage the pursuit of new studies.

https://www.mdpi.com/1420-3049/25/17/3982/pdf

Applications and Limitations of Dendrimers in Biomedicine.

Nowadays, silver nanoparticles (AgNP) are widely used in the medical field mainly for their antibacterial properties. Although some studies report a cytotoxic activity of the particles, the mechanisms involved in AgNP-induced cell death remain to be determined. Herein, we report that AgNP of 2 (AgNP2) and 15 nm (AgNP15) induce apoptosis in human MCF-7 and T-47D breast cancer cells. Treatment with AgNP2 and AgNP15 led to accumulation and aggregation of misfolded proteins causing an endoplasmic reticulum (ER) stress and activating the unfolded protein response (UPR). The three main ER sensors, PERK, IRE-1α and ATF-6, were rapidly activated in response to AgNP2 and AgNP15. Although Grp78 levels remained unchanged, AgNP2 and AgNP15 induced upregulation of the transcription factors ATF-4 and GADD153/CHOP. Moreover, the initiating caspase-9 and the effector caspase-7 were activated in response to these NPs. The expression levels of the pro-apoptotic BIM and BAD proteins remained unchanged. In contrast, a downregulation of Mcl-1 and xIAP protein expression as well as a processing of PARP were observed. Pharmacological inhibition of PERK kinase and IRE-1 endonuclease activities, as well as inhibition of ER-stress, partially protected cells from AgNP2- and AgNP15-induced apoptosis. Of note, the non-cancerous MCF-10A cells were more resistant to both AgNP2 and AgNP15 when compared to MCF-7 and T-47D cell lines. Taken together, our results demonstrate that AgNP induce ER stress and can target the UPR-dependent apoptotic pathway in MCF-7 and T-47D, which highlights new potential strategies for the treatment of breast cancers.

Silver nanoparticles induce irremediable endoplasmic reticulum stress leading to unfolded protein response dependent apoptosis in breast cancer cells.

The aim of this study was to determine whether different generations (G) polyamidoamine (PAMAM) dendrimers possess proinflammatory activities in vivo. Several hundred female CD-1 mice were used to test four different PAMAM dendrimers using the murine air pouch model. Mice received appropriate negative and positive controls or G0-G3 PAMAM nanoparticles at 100 and 500 µg/ml into air pouches. Exudates were harvested after 3, 6, 24 and 48 h. Cell pellets and supernatants were used to determine the number of total leukocytes and neutrophils and to detect the production of several analytes by an antibody array approach, respectively. One-way analysis of variance was used for statistical analysis. PAMAM dendrimers rapidly increased a leukocyte influx after 3 h, the vast majority of cells being neutrophils. This was also observed after 6 and 24 h, and resolution of inflammation was noted after 48 h. In general, the increased production of a greater number of analytes detected in the exudates after 6 h correlated with the number of dendrimer generations (G3 > G2 > G1 > G0). PAMAM dendrimers devoid of any delivering molecules possess proinflammatory activities in vivo by themselves, probably via the production of different chemokines released by air pouch lining cells.

In vivo proinflammatory activity of generations 0-3 (G0-G3) polyamidoamine (PAMAM) nanoparticles.

The aim of this study was to determine potential effects of gold (+) and gold (−) nanoparticles, AuNP(+) and AuNP(−), on neutrophil biology. Freshly isolated human neutrophils were used for the in vitro aspects and CD-1 mice were used in the in vivo murine air pouch model of acute neutrophilic inflammation. Human neutrophils were treated with the indicated concentrations of AuNP(+) or AuNP(−) in vitro and mice received 100 or 500 µg/ml AuNP(+) or AuNP(−) into air pouches. Cellular uptake of AuNP by neutrophils was confirmed by transmission electron microscopy and the ability of the NP to modulate apoptosis, gelatinase activity, and chemokine production and chemotaxis was determined by cytology, zymography, ELISArray, antibody array, and ELISA and by a micro-chemotaxis chamber, respectively. In vivo, exudates were harvested after 6 h to determine the leukocyte infiltration to detect the production of several cytokines by an antibody array approach and ELISA. One-way analysis of variance was used for statistical analysis. AuNP possess proinflammatory activities in vitro and induce mainly a neutrophil influx in vivo, albeit at different degrees. AuNP(+) and AuNP(−) should be added as new candidates into a growing list of NP having proinflammatory activities by themselves.

Evaluation of the in vitro and in vivo proinflammatory activities of gold (+) and gold (-) nanoparticles.

Biological activities of interleukin (IL)-21 in human monocytes and macrophages.

Recently, palladium nanoparticles (Pd-NPs) have been shown to possess pro-inflammatory activities. Herein, we investigated potential in vitro effects of Pd-NPs (primary size of 1–10 nm) on the biology of neutrophils, key player cells in inflammation. Also, the aim of this study was to evaluate the pro-inflammatory activity of Pd-NPs using the murine air pouch model, a model previously proposed to be used as a standard assay for testing in vivo pro-inflammatory effects of NPs. Although the positive controls used in vitro give the expected results in all biological functions tested, Pd-NPs do not affect the production of reactive oxygen species and that of interleukin-1β (IL-1β), IL-6, and IL-8. Pd-NPs moderately increase cellular adhesion of neutrophils onto human endothelial cells and significantly increase the capacity of neutrophils to migrate and to delay apoptosis. We conclude that Pd-NPs possess some pro-inflammatory activity in vitro but do not attract leukocytes in vivo regardless of sex.

Isabelle Durocher

Papers

Silver nanoparticles induce irremediable endoplasmic reticulum stress leading to unfolded protein response dependent apoptosis in breast cancer cells.

In vivo proinflammatory activity of generations 0-3 (G0-G3) polyamidoamine (PAMAM) nanoparticles.

Evaluation of the in vitro and in vivo proinflammatory activities of gold (+) and gold (-) nanoparticles.

Biological activities of interleukin (IL)-21 in human monocytes and macrophages.

Impact of palladium nanoparticles (Pd-NPs) on the biology of neutrophils in vitro and on leukocyte attraction in vivo