Nanomaterial Therapeutics & Toxicology

Overview

Technological innovations have led to the emergence of nanotechnology as a new field that will revolutionize industrial development. In fact, manufacture of nanomaterials of various shapes and compositions has increased in the last few years, with a vast potential of use ranging from diagnostic imaging to molecular construction. More than 1000 nanotech based consumer products are already in the market worldwide. Nanodevices are also being used as sensors in diagnosis of human disease. Nanotechnology is associated with unprecedented dimensions related to nanomaterial safety that may affect the consumers, occupational workers and the environment as a whole.

At present, more than 20 countries worldwide are manufacturing and marketing different varieties of nanotech-based consumer products of which cosmetics form the largest category. Due to the large scale use of nanomaterials globally, the dimension of exposure to flora and fauna will be unrestricted as the nanomaterials have the ability to cross the cellular barriers. The biological interaction of the nanomaterials when compared to their bulk counter parts is largely different. This is due to the extremely small size of the nanoparticles (NPs) that may interact directly with macromolecules such as DNA. To assess the safety/toxicity of nanomaterials, it is imperative that proper characterisation is done especially before in vitro/in vivo studies are undertaken.

With the realisation of entirely new dimensions of safety of nanomaterials CSIR-IITR initiated work in the area of safety/toxicity evaluation of nanomaterials. Contribution of CSIR-IITR in the field is evident by the publications in peer reviewed journals.The team of scientists working at CSIR-IITR has the experience both in synthesis as well as safety / toxicity evaluation and impact assessment of engineered nanomaterials (ENMs). Some of the most critical issues that need to be addressed for safety/toxicity assessment of ENMs include: 1) effect of shape & size; 2) dosimetry; 3) route of delivery and tracking; 4) development and validation of test models; 5) in vitro vs. in vivo extrapolation; 6) ecotoxicity; 7) environmental monitoring and 8) life cycle analysis. Therefore, the aim of the group working at CSIR-IITR is to devise new methods and validate existing techniques that can be applied for safety/toxicity assessment of ENMs and nanodevices.

Mission and goals
To investigate health and environmental effects of nanomaterials to delineate their toxicity and assure safe usage in consumer products and therapeutics.

Competencies
Synthesis and detailed characterization of nanoparticles. Infra-structure facilities and expertise to investigate interactions of different types of nanomaterials with biological systems (from whole organism to molecular level) to evaluate their toxicity. Battery of in vitro and in vivo toxicity assays addressing issues of cytotoxicity, genotoxicity, immunotoxicity, dermal toxicity, neurotoxicity, reproductive toxicity, biodistribution, metabolism, elimination and ecotoxicological impact.

Glimpses of current research
Nano-products are creating new domains and potential unknown hazards associated with their usage are not well understood. A variety of nanoparticles including ZnO, CeO2, Cr2O3 and TiO2 nanoparticles are among the most commonly utilized nanomaterials, with wide applications in industrial and consumer products. Studies were conducted to show the impact of ZnO nanoparticles on murine peritoneal macrophages. Cerium oxide and chromium oxide nanoparticles were shown to exert toxicity in exposed human lung cells by inducing oxidative stress mediated DNA damage and apoptosis. Wistar rats along with bead based multiplex protein analysis using antibodies specific for known and proven early nephrotoxicity markers were used to develop an in vivo model of nephrotoxicity assessment. Mutagenic effect of TiO2 NPs was shown in Chinese hamster lungs fibroblast (V79) cells by employing forward mutation assay. Photoprotective mechanism of curcumin nanoparticles under ambient UV-R exposure was studied. Further, as a part of NanoSHE network programme, reference TiO2 nanoparticles have been synthesized by NPL, Delhi and their toxicity assessment have been initiated in this institute at different tiers. A GLP compliant acute toxicity study on rats using TiO2 nanoparticles was successfully completed during this period.

Studies were conducted to demonstrate the efficiency of synthesized nanoparticles (polyethylenimines based) as vectors for gene delivery in vitro and in vivo. In similar context, linear polyethylenimine (LPEI, 25 kDa) based nanoparticle (LPN) was shown to enhance the efficiency of transformation (transgenesis) by using Drosophila based germ-line transformation technology.

Towards nanoparticle based drug delivery in different disease models, it was demonstrated that curcumin-loaded nanoparticles can induce adult neurogenesis and reverse cognitive deficits in Alzheimer's disease model via canonical Wnt/b-catenin pathway. In another study, nicotine-encapsulated poly (lactic-co-glycolic) acid nanoparticles was shown to improve neuroprotective efficacy against MPTP-induced Parkinsonism. Further, O-Hexadecyl-dextran entrapped berberine nanoparticles were found to abrogate high glucose stress induced apoptosis in primary rat hepatocytes. Studies were conducted to show enhanced anticancer activity of Se-curcumin nanoparticles in colon cancer cells.

Towards application of nanoparticles, bio-catalytic and anti-microbial activities of gold nanoparticles synthesized by Trichoderma sp. were demonstrated. In another study, nano-sized multi-template imprinted polymer was synthesized and efficiently employed for the simultaneous extraction of polycyclic aromatic hydrocarbon metabolites in urine samples and detection. In similar context, imprinted nano-spheres based on precipitation polymerization were synthesized for the simultaneous extraction of six urinary benzene metabolites from urine samples followed by injector port silylation and gas chromatography-tandem mass spectrometric analysis. Chemo-preventive effects exerted by Bromelain encapsulated in poly (lactic co-glycolic acid) nanoparticles were demonstrated against chemically induced two-stage skin tumorigenesis model in mice. Bio-composite cryogels as tissue-engineered biomaterials were synthesized and their efficiency was demonstrated for the regeneration of critical-sized cranial bone defects. Nano encapsulated ascorbic acid was shown to inhibit tert-butyl hydroperoxide induced oxidative stress and apoptosis in HepG2 cells.

Studies were conducted to show that exposure of Caenorhabditis elegans to ZnO-NPs disrupts various physiological processes and causes apoptosis in the germ-line even at very low concentration in a size-dependent manner. The findings suggest the inclusion of size as an additional measure for the cautious monitoring of ZnO-NPs disposal into the environment. In another study, altered metabolic response of Caenorhabditis elegans that were exposed to nano-sized titanium dioxide was shown using gas chromatography-mass spectrometry combined with pattern recognition methods. For assessing ecotoxic potential of nanomaterials, a protozoan model, Tetrahymena was established.

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