Risk Assessment of engineered nanoparticles Using Computational Approaches

specifically to area of drug discovery(Pharmacy) by Veera C.S.R, Chittepu

What this presentation is about in brief?

We define what types of risks, types of toxicity , we face from nanomaterial? Some examples on how computional applications has helped nanotechnology scientists to reduce the toxicity of a nanomaterial he synthesized(concentrating mainly on Modeling, simulations and docking and an introduction to QSAR)? Conclusion.

The Questions I would be asking after presentation?

Do we need to mention about the risk of a nanomaterial, which we synthesize in laboratory? Do we need to make use of Computational resources to address Nanotechnology ? Do we need to stop Nanotechnology research, to be on safer side? (better be safe rather than sorry)

Introduction
medicinal, pharmaceutical applications --- biosensing, MRI, optical detection, drug delivery systems, etc., nano market will grow exponentially( $2.6 trillion in 2014) 3 -4 nanotechnology computer projects are introduced into the market.

Risk assessment
nanoparticles can travels anywhere inside our body, can interact with organs, tissues, cellular- sub cellular structures. recently, nanoparticles in direct contact with cells surfaces - 1) results of inflammation, oxidation stress .. leading to diseases. 2) free radicals "steal" electrons from the lipids in membranes. 3) up + down of genes encoding for specific proteins. cytotoxic

toxic ---degree to which a substance can damage an organism.

cytotoxic - quality of being toxic to cells. neurotoxic - to cause damage to nervous tissue genotoxic - Any substance capable of causing damage to cellular DNA and thus producing mutations or cancer. ecotoxic - how chemicals affect the environment and the organisms living in it. examples -- SWCNTs, MWCNTs , fullerenes suspended in water will produce cytotoxicity to human cell line, SiO2 TiO2 , ZnO2 pulumonary inflammation to humans, silver nanoparticles might affect microorganisms in environment.

Commonly accepted and followed risk assessment procedures for ordinary chemicals include

Exposure assessment - exposure assessment defines the sources, pathways, routes, and
the uncertainties in the assessment. bad luck -- we do not have this date on nanomaterial

Hazard assessment -

requires a combination of hazard characterization and hazard identification information for the studied agents. There are few g rou ps of experimental parameters: (1) Nanomaterial Information (2 ) Physical Chemical properties an d Material Characterization ( 3 ) Envir onment al Fate (4) Environmental/Mammalian Toxicology ( 5 ) Material safety Eg: EU Commission Nano Safety C luster

 Major problem with hazard characterization is due to lack of sufficient knowledge about human dose response relationship ?becuase they use short drug response time. and they do on animals. [the data on clinical toxicity in humans associated with long-term exposure to nanoparticles, including different routes of administrationare essential. (which actually they do not provide this information)]

Hazard identification of nanoparticles represents a complex issue. Toxicity of nanoparticle after entering the cell can occur via one, two, three, four, or a combination of all possible four mechanisms described in NATO Advanced Research WorkshopThefirst mechanism is based on the release of chemical constituents from the nanomateria Second possibility is related to the size and shape of the particle, The third mechanism of toxicity is based on the surface properties of the material, The fourth one involves the capacity of nanomaterials to act as vectors for the transport of other toxic chemicals to sensitive tissues.

specific to medicine and Pharmacy(carbon nanoparticles)

metal oxide nanoparticles

When human lung carcinoma A549 cells were exposed to CuO, TiO2, ZnO, CuZnFe2O4, Fe3O4, and Fe2O3 nanoparticles, intracellular ROS level increased in CuO exposed cells, and oxidative stress-related DNA damage was observed in Fe3O4, CuZnFe2O4, ZnO, and CuO nanoparticle exposed cells. Particularly, CuO nanoparticles revealed stronger cytotoxicity than CuO fine-particles. Karlsson et al. suggested that the severe toxicity of CuO nanoparticles was caused by Cu2+ release [140]. Another study showed that CuOand ZnO induced oxidative stress to culture cells, where CuO nanoparticles increased the intracellular ROS level and lipid peroxidation level, and decreased the glutathione level and cell viability [141]. Horie et al. reported the cell response to various metal oxide nanoparticles such as TiO2, ZnO, NiO, CeO2, SiO2, and Fe2O3, by using their disperse system

How modeling and simulations help you ?

(A) A typical structure of HP35 adsorbed on the graphene surface. Here, HP35 is shown as a cartoon with red helix and green loop, the graphene is shown as the cyan lines. (B) The superposition of the adsorbed HP35 structure on graphene (red) with its native structure (green). The aromatic residues that form the stacking interactions are shown in blue.

Fullerene derivatives with HIC-1PR

Fullerene derivatives are promising for inhibition of human immunodeficiency virus type 1 aspartic protease (HIV-1 PR) that is an important target enzyme for antiacquired immunodeficiency syndrome (AIDS) drug design. MD simulations in explicit solvent were performed in complexes of HIV-1 protease with fullerene derivatives

Binding of C60 to the extracellular domains of KcsA (top) and Kv1.2 (middle). The dots represent the position of C60 along theMDtrajectory sampled every 0.1 ns starting at position VSD Voltage sensor domains

Fullerenol lysozyme complex using AutoDock software

How small modifications can help to reduce toxicity

chemical modifications on carbon nanotubes. Structures 1 and 2 correspond to mono-functionalized CNTs; structures 36 correspond to bi-functionalized CNTs; and structure 7 corresponds to trifunctionalized CNTs.

How simulations were utilized to study the interactions of monolayer and up to few-layer graphene (up to 8 layers) with lipid bilayers

Self-insertion of lipid coated monolayer graphene inside the phospholipid membrane The results of MD simulations by Titov et al. revealed that phospholipid molecules could isolate an embedded graphene layer. At room temperature, graphene could self-insert into a lipid bilayer and remained stable in the interior of the membrane when a micelle is formed around it

Quantitative Structure-Activity Relationships for nanomaterials

insufficient toxicity information makes difficult to develop the structuretoxicity relationship of nanoparticles. REACH legislation introduced in Europe allows computational tools in replacing experimental tests in some cases. Some computational tools for example, QSAR. are essential for increasing throughput, reducing the burden of animal testing, providing details of the toxicitymechanisms, and generating novel hypotheses for risk assessment.

How qsar model is developed(in general)

y = f(x) , where y is defined as Molecular structure. And f(x) is defined as a function of Molecular discriptors, or variables.. We need to use statistical analysis to above equation to predict new structure behaviour.
Y = f(x)

How to calculate descriptors?(Nanotechnology)

thousands of descriptors for a single structure can be generated using the commercial programs as DRAGON , CODESSA and CAChe. quite popular and reliable descriptors could be calculated by application of QM and MM methods. Well-known quantum-chemical codes for molecular structure calculations are GAUSSIAN , MOPAC , GAMESS , NWChem ,JAGUAR , and ADF . All these technology has to be used in combination to address the solution in nanotechnology applications.

What kind of descriptors can be developed for nanostructures? new type of descriptor
a QM point of view, nanoparticles (1100 nm, i.e. 101000 ) are very largesystems. Thus, a cube of gold nanoparticle (100 nm dimension) would have millions of atoms, being too large for standard classical MD and remarkably too large for QM calculations. This complicates or even makes it impossible to perform calculations at the proper level of theory. Because of these limitations some additional approximations and approaches are necessary to determine the proper structural and physical descriptors for nano-QSAR

How nanotech can help me ?( specific to get information for QSAR parameters.)
the experimental descriptors of size distribution, agglomeration state, shape, porosity, and surface area can be developed based on images taken from TEM, scanning electron microscopy (SEM), and atomic force microscopy. A series of images taken by these methods for different particles (various size, shape and porosity) of a given nanostructure can be a source of new important structural information.

Conclusion
The problem with Application of QSAR in the field of Nanotechnology is, protocols were not generalised, they vary with experiement to experiment. We get lot of variables. There were few research groups who tired to evaluate the the descriptors, they introduced lot of variables. They could predict lot of models, stating that they found a relation to describe the toxicity. Guidelines has to be clear, interaction between theoritical and experiemental scientists is must , to find a solution to reduce toxicity from materials.

Thank You