Anti Cancer Drug and Molecular Docking Studies of Drug Conjugated Silver Nanoparticles from Hyaluronic Acid
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Hyaluronan (HA) as an anticancer drug carrier, nano-polymer is of interest because it has considerable affinity to the CD44 receptors, which are ubiquitously present glycoprotein on the surface of mammalian cells that play a significant role in a number of biological functions. Since the discovery that the receptor is over-expressed in a variety of solid tumours, HA has become the focus as an ‘Active Targeting’ drug delivery molecule for the treatment of cancer, discriminating between healthy and malignant tissues. Camptothecin and methotrexate anticancer drugs have for this reason being conjugated at the C-6 position of the N-acetyl-2-deoxy-D-glucopyranosyl unit of the HA molecule (Ref., 1 & 2).
Researchers have explored the use of silver nanoparticles as carriers for delivering various small molecule drugs. It is of interest to note that the introduction of silver nano particles has shown to have synergistic activity with common antibiotics against E. coli and S. aureus. (Ref., 3 & 4).
The novelty of the ongoing research activity is the use of combination of an anticancer drug conjugated to a natural nano-biopolymer and silver nanoparticles to develop an ‘Active Targeting’ system to provide high payload concentrations at specific target sites and minimize side effects. Such system hitherto has not been studied.
Norbedo S., Dinon, F., Bergamin M., Bosi S., Aroulmoji V., Khan, R., Murano, E., Synthesis of 6-amino-6-deoxyhyaluronan as an intermediate for conjugation with carboxylate-containing compounds: application to hyaluronan–camptothecin conjugates. Carbohydr. Res.344: 98-104 (2009).
R. Khan, B. Mahendhiran & V. Aroulmoji. Chemistry of Hyaluronic Acid and its significance in drug delivery strategies- Review. International Journal of Pharmaceutical Sciences & Research, 4 (10), 3699-3710 (2013).
Pickup, J.C.; Zhi, Z.L.; Khan, F.; Saxl, T.; Birch, D.J. (2008). Birch nanomedicine and its potential in diabetes research and practice. Diabetes Metab Res Rev. 24 (8): 604–610 (2008).
Shahverdi, Ahmad R.; Fakhimi, Ali; Shahverdi, Hamid Q.; Minaian, Sara Synthesis and effect of silver nanoparticles on the antibacterial activity of different antibiotics against Staphylococcus aureus and Escherichia coli, Nanomedicine. 3 (2): 168–171 (2007).
Developing a novel and effective targeted drug delivery system
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An effective drug delivery system which can be targeted to the part of the body organ where it is needed is still lacking. The drug delivery system has to overcome problems such as poor solubility, limited chemical stability of the drug in vitro and in vivo following the administration, poor bioavailability, and most importantly for the drug to be effective, and to avoid wastage and unwanted side effects, it has to be delivered directly to the site.
Hyaluronic acid (HA) is an important naturally occurring polysaccharide present in extracellular matrices and are important to many biochemical functions of living tissues; it consists of a linear repeating disaccharide unit of β-(1→4)-linked D-glucopyranuronic acid and β-(1→3)-linked 2-acetamido-2-deoxy-D-glucopyranose, and is present in extracellular matrices, the synovial fluid of joints, and scaffolding that comprises cartilage. HA is rapidly metabolised in vivo by enzymes such as hyaluranidase and by free radical oxidations, which limits its use in native form as a biomaterial; in addition, HA is highly soluble in water; in order to overcome these limitations, the physicochemical properties of hyaluronic acid have to be modified1-3.
HA has two most important receptors, the cell-surface glycoprotein CD44 and the receptor for HA-mediated motility (RHAMM), which are involved in various tumors, for example, epithelial, ovarian, colon, stomach, and acute leukemia; hence, we investigated the chemistry of hyaluronic acid and explored HA’s potentially important role as a vehicle for targeted delivery of anticancer drugs such as Camptothecin and Methotrexate 4,5.
The Proposed Approach to Drug Delivery:
Cross-linked hyaluronic acids with special properties and structure, such as different degradation rate, different surface characteristics, different porosities, have applications as tissue engineering scaffolds for the delivery of cells, gene transfer, wound healing, post-surgical adhesion prevention, and implantation of bioactive compounds in vivo repair sites.
Engineered HA cross-linked polymer scaffolds with drugs co-ordinately immobilised and or entrapped for targeted delivery of the drug in vivo or in vitro. Chemical cross-linking and photo cross-linking methodologies will be used to generate interpenetrating polymer net work with appropriate pore structures and pore size to entrap drugs within the scaffold. The research programme will relate to various chemical and biochemical processes for the production of the biopolymer scaffolds comprising the following steps: (i) producing a stable biopolymer scaffold of appropriate pore size, by using HA and polyethylene glycol (PEG) dimethacrylate; (ii) different molecular weights of HA will be employed to modulate the functionality of the scaffold containing the drug; (iii) the structural integrity of the HA-PEG-Drug scaffolds and their physico-chemical characteristics will be measured to ascertain its solubility, the chemical stability of the drug, the porosity of the scaffold to retain the drug, and the delivery of the drug at the appropriate target; and finally, (iv) their therapeutic efficacy will be evaluated.
Khan, I. B. Mahendhiran, V. Aroulmoji, chemistry of hyaluronic acid and its significance in drug delivery strategies: A review. IJPSR, 2013; Vol. 4(10): 3699-3710.
Murano, E., Perin, D., Khan R., Bergamin, M. Hyaluronan: from biomimetic to industrial business strategy. Natural Products Communications. 2011; 6: 555-572.
Schanté, C. E., Zuber, G., Herlin, C., Vandamme, T. F. Chemical modifications of hyaluronic acid for the synthesis of derivatives for a broad range of biomedical applications. Carbohydrate Polymers. 2011; 85: 469–489.
Sorbi C., Bergamin M., Bosi S., Dinon F., Aroulmoji V., Khan R., Murano E., Norbedo S. Synthesis of 6-O-methotrexylhyaluronan as a drug delivery system. Carbohydr. Res. 2009; 344 : 91-97.
Norbedo S., Dinon, F., Bergamin M., Bosi S., Aroulmoji V., Khan, R., Murano, E., Synthesis of 6-amino-6-deoxyhyaluronan as an intermediate for conjugation with carboxylate-containing compounds: application to hyaluronan–camptothecin conjugates. Carbohydr. Res. 2009; 344: 98-104.
Fire Retardant for Textile Applications
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Our approach to R & D in this area resulted in a novel cost-effective and foolproof formula of significant importance in the textile technology; to be precise; we have developed a new and efficient fire retardant to be used in textiles.
Following the breakthrough, we have been developing novel methods in textile engineering mainly on the synthesis of impurity-free Multi Walled Carbon Nano Tubes (MWCNT) based on nano composites to be coated on the fabrics for fire retardation. We know that the bio-based plant carbon nano tube-based flame-retardant composites are a promising technology applied to fabrics to inhibit or suppress the combustion process. Carbon nanotubes are now being incorporated in various materials as an agent providing non-flammability to products and coating layers. As flame-retardant additives, Multi walled carbon nanotubes (MWCNT) result in stronger and more fatigue-resistant materials.
Moreover, we are developing efficient rapid silver nanoparticles using Neem leaf as a reducing agent and Zinc nanoparticles using Coffee beans as reducing agent. The bio-synthesized silver nanoparticles is combined with the Zinc nanoparticles, then formulated and coated on cotton fabrics using acacia as binder. The structural morphology, thermal and optical properties of these nanomaterials will be studied and nanoparticles size and shape will be evaluated. The optical property of nanoparticle is characterized by UV-vis spectroscopy; Fourier transform infrared spectroscopy (FT-IR) shows nanoparticles with different functional groups. The X-ray diffraction (XRD) study reveals grain size of the nano particles and their crystalline nature. AFM study shows surface roughness and 3D dimension of the synthesized nanoparticles, which is correlated with XRD. The zeta potential of AgNPs gives the stability of the synthesized NPs. DLS provides the average size distribution of particles. TEM reveals the core size of the nanoparticles. The synthesized nanoparticles will be used for microbial textile coatings. This novel technology is cost effective, eco-friendly and easily scaled up with large scale production. The fabric with antimicrobial resistance has raised its concern as a health issue. These fabrics with consistency and durability with long lasting metal nanoparticles even after several washing will attract the textile manufacturers. This technology is economical and user-friendly.
In addition to the above, we have been working on novel hybrid metal oxides nanomaterials for antibacterial and fire retardant textile materials for defence application. The aim of this work is to develop high efficient new type of hybrid structures of metal oxides (MyN1-yOx) using microwave irradiation technique and spray pyrolysis method. The synthesized products will be characterized by using powder X-ray diffractometer, Optical absorption instruments (UV – VIS spectrophotometer & PL), Microscopic analysis (FE - SEM & TEM), antibacterial activity and coatings on textile products in order to know the suitability for above said applications.
Improved Version of Dye Sensitized Solar Cells (DSSC) Using Perovskite Derivatives
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Globally, the steady yearly increase of 5% energy has urged the need for alternative sources of renewable energy and this has become a challenge. The PV technology has become the most promising technology in harvesting solar‐energy. Owing to toxicity limitation and cost‐effective solutions of single silicon crystal solar panels, the usage of Dye Sensitized Solar Cells gained attention for solar energy harvesting.
In this project activity, we are developing a new design of DSSC device with improved reproducibility, long-term stability that can address the large scale production with low cost fabrication in ambient conditions, high lifetime, economical in mass production and environmental sustainability.
In line with this, to achieve thermal robustness, we propose to replace titania with a novel electron accepting nanoporous semiconductor with a band gap suitable for optimized solar harnessing and a very high absorption coefficient to allow total absorption within 2 µm across its absorption spectrum. This multidisciplinary challenge can be achieved with a group of experts and industrial leaders in PV solar cells production. The successful completion of the project will lead to an improved version of DSSC using Perovskite derivatives.
The usage of engineered Perovskites and nano based electrodes as light absorbing, electron transporting, hole transporting and panchromatic sensitizers for the design of DSSCs would result in the new breakthrough materials for harvesting solar energy with long-term stability and low cost fabrication to address the large scale production in ambient conditions. We introduce new types of novel perovskites and their derivatives which include graphene, a new technology and synthesis method to achieve high efficient, eco friendly and cost effective Perovskites based DSSC solar cells. The present findings will be helpful to generate useful data for future development and implementation of such projects in the field of solar cells and also in the field of energy based devices. The fabricating modules in this project will be used for research and as test platforms for large and small scale solar energy technologies. The outcome of this project will initiate new and augment the existing programs for long term research & development in solar power generation, storage, distribution, management and policy making in the institute as well as for research. The outcome of the results will initiate practical knowledge about DSSCs for young researchers and increase the awareness amongst the public about green technologies.
A comprehensive bioinformatics pipeline for HIV and HCV quasispecies identification through NGS data analysis
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The major pathogenic viruses responsible for most human death worldwide include the hepatitis B and C viruses (HBV and HCV) and the human immunodeficiency virus (HIV). Despite enormous ongoing research efforts, they remain extremely difficult to diagnose, treat and prevent due to their high mutation rates and this inherent to replication of RNA viruses create a wide variety of mutants in the virus populations as quasispecies. Thus Deep sequencing by NGS techniques allows to detect low abundance drug resistant HIV/HCV variants and the development of computational methods for estimation of the quality of sequences and for error correction, algorithms for sequence alignment and haplotype reconstruction, statistical models to infer the frequencies of the haplotypes in the population, for comparative analysis and their visualization will be an promising tool to analyze the HIV/HCV quasispecies population and provides new insights into the dynamics of resistance acquisition by HIV/HCV. The pipeline is proposed to analyse the virus quasispecies while reporting the high genetic diversity within and among viruses, mutation information for Monitoring Antiviral Drug Resistance Error assessment of the generated data during the course of data analysis and mutation analysis, specialized computational tools to track, analyse and predict known and emerging mutations, estimate diversity, predict mutational processes underlying variation signatures, and map them to protein structure data and personalized clinical application as more HCV drugs are approved that have unique mechanisms of action, this can aid physicians in selecting therapy regimens on an individual, patient by patient basis. Finally, pipeline will be a comprehensive platform with combined attributes with simple and user friendly interface for an efficient diagnostic commercial platform for HIV/HCV discovery.
Surfactant Assisted, Doped Novel Metal Oxide Based Hybrid Nano Structures for Electrochromic Applications
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We have been synthesizing oxide-based pure and doped hybrid nano-dimensional materials by microwave irradiation method, spray pyrolysis and spin coating techniques without employing hydrothermal process. In addition to the above said method, hybrid nanostructures will be made into thin films by spin coating method and compared with the existing other methods. Subsequently we have aimed to study the role of surfactants and dopants in hybrid nano structures with special focus for smart window applications. Moreover, we believe that surface modulators play an important role in controlling the particle size and morphology which are crucial factors in application point of view. The low temperature resistivity and magnetic susceptibility will be analyzed in order to find their suitability for smart windows applications. Also, attempts will be made to understand the growth mechanism of hybrid nano structures in microwave atmosphere.