Cytotoxicity issues

Cui, H.F. et al. (2010) Interfacing carbon nanotubes with living mammalian cells and cytotoxicity issues. Chemical Research in Toxicology, 23 (7), 1131-1147. 

Cytotoxicity Issues. In-vivo hemolysis has been observed with parenteral administration of all of the parent CDs. In-vitro studies with human erythrocytes have demonstrated that the damaging effect of the CDs is in the order p-CD > ot-CD > y-CD. This cellular destruction has also been observed in studies with human skin fibroblasts and intestinal cells, P388 murine leukaemic cells, E. coli bacterial cells, and immortalized human corneal epithelial cells.f " Mechanistic studies suggest that CDs extract either cholesterol (p-CD and y-CD) or phospholipids (a-CD) from the cell membrane causing small pores which allow leakage and eventually lead to cell lysis. 

Cytotoxicity Issues. As with renal toxicity, the various derivatives show dramatically different hemolytic behaviors. The dimethyl derivative shows substantial hemolysis more than even the parent p-CD. This is well illustrated in Fig. 10 where the percentage of cells imdergoing hemolysis is shown as a function of CD concentration. Hemolysis started at concentrations below 0.1% for the DM-p-CD. Four to five times higher concentrations of p-CD are required to give the same hemolysis. This behavior is in agreement with the demonstration of DM-p-CD as a penetration enhancer in skin " and nasal tissue. ... 

The application of MPS in biosensor has received more and more attention in the past few years. It was reported that functionalized mesoporous silica nanomaterials have good biocompatibility to be internalized by animal and plant cells without posing any cytotoxicity issue in vitro [27-29], These findings may generate new types of drug/gene delivery and biosensor, particularly in the development of electrochemical biosensors. We will mainly discuss the advancements in morphology control and surface functionalization of MPS for proteins immobilization and the recent developments of proteins encapsulated MPS biosensors. 

Because the use of QDs as reporters in living cells may soon become conventional, the possibility of QD cytotoxicity is of interest and concern. Almost aU of the reports of QDs in living cells have revealed little or no obvious cytotoxicity or changes in ceUular differentiation [8,13]. Although QDs contain toxic elements, most importantly divalent cadmium, cytotoxicity issues may only become relevant for truly long-term (months to years) visualization of QDs in cells, a time period in which QD degradation could become significant. 

Two main apoptotic pathways have been identified in mammalian cells the extrinsic pathway that is activated by the binding of ligands to cell-surface death receptors, and the intrinsic pathway that involves the mitochondrial release of cytochrome cP The activation of extrinsic and intrinsic apoptotic pathways promotes the cleavage into the active form of the pro-caspase-8 and pro-caspase-9, respectively, that mainly determine the activation of effector caspase-3. ° The intrinsic pathway is the main apoptotic pathway activated by chemotherapeutic drugs, while the cytotoxic drug-induced activation of the extrinsic pathway is a more controversial issue. ... 

Shvedova, A.A., Castranova, V., Kisin, E.R., Schwegler-Berry, D., Murray, A.R., Gandelsman, V.Z., Maynard, A., and Baron, P. (2003) Exposure to carbon nanotube material assessment of nanotube cytotoxicity using human keratinocyte cells. Journal of Toxicology and Environmental Health, Part A Current Issues, 66 (20), 1909-1926. 

Vaccination to induce an adaptive immune response is expected for a broad range of infectious diseases and cancers. Traditional vaccines are mainly composed of live attenuated viruses, whole inactivated pathogens, or inactivated bacterial toxins. In general, these approaches have been successful for developing vaccines that can induce an immune response based on antigen-specific antibody and cytotoxic T lymphocyte (CTL) responses, which kill host cells infected with intracellular organisms (Fig. 1) [1,2], One of the most important current issues in vaccinology is the need for new adjuvants (immunostimulants) and delivery systems. Many of the vaccines currently in development are based on purified subunits, recombinant... 

Reasons for chopping clinical candidates at any stage of the drug approval process included (1) stability, formulation, or other pharmaceutical development issues, (2) renal toxicity or neurotoxicity, and (3) insufficient advantage over current chugs. Since 1997, the NCI has also operated a screen for compounds active against the cytotoxic effects of HIV in CEM cells. Of 80,000 compounds tested, 4050 (or about 5%) were active. Of the compounds tested, 2291 have included metals. Of those, 136 (about 6%) were active, and two became clinical candidates. Both were chopped due to toxicity problems. One clinical candidate was a polyoxometallate, and therefore about 80 other similar molecules were tested. These were found to be strongly active in vitro, but too toxic in animal models in vivo. If a way around the toxicity problem can be found, interest in these... 

Toxicity of nanoparticles is a much more complicated issue as compared with organic fluorophores Nanoparticles may be nanotoxic, they may contain cytotoxic elements or compounds, or their surface ligands/coating may contain toxic species. Nanotoxicity refers to the ability of a substance to be intrinsically cytotoxic due to its size (and independent of its constituent materials). The most prominent example of nanotoxicity is asbestos. Even though there are no systematic studies on the nanotoxicity of different nanocrystals available the results from several cytotoxicity studies suggest that nanotoxicity is not dominating for nanoparticular reporters [85, 86]. 

The pseudodipeptide amides represented a major advance in the substrate-based design of FTIs. They removed the metabolic liability of the prodrug, were cell active, and were considerably simpler chemically. However, the majority of pseudodipeptide amides were not potent enough and too cytotoxic to demonstrate activity in cell culture. Although the potency issue was perceived as solvable, the dark cloud of nonspecific cytotoxicity hovered over this particular class of compounds like an unwelcome visitor. Changes to the molecule which virtually destroyed FTase activity had no effect on the level of cytotoxicity, indicating that the observed toxicity was unlikely to be mechanism related. 

Benzyl-substituted titanocenes do not have stereo centres and therefore stereoisomers do not exist, unlike their ansa analogues. In terms of in vivo and in vitro cell testing, this is advantageous. Previously, the presence of unseparated stereoisomers means that the issue of whether the compounds cytotoxicities are related to specific isomers was not addressed. This is not of concern in the achiral benzyl-substituted titanocenes presented here. 

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