Research J. Engineering and Tech. 4(4): Oct.-Dec.

, 2013

ISSN 0976-2973

www.anvpublication.org

rjet

RESEARCH ARTICLE

A Computational Analysis to Study the Application of Lipid Nanotechnology in the Field of Drug Delivery to Treat Liver Diseases
Karthick J.1, Praveen Kumar P.K.2
2

Final Year, Department of Biotechnology, Sri Venkateswara College of Engineering, Sriperumbudur Assistant Professor, Department of Biotechnology, Sri Venkateswara College of Engineering, Sriperumbudur *Corresponding Author Email: karthick840@gmail.com

ABSTRACT:
The Present Study is to analyse the targeted delivery of Ursodiol, a drug used in the treatment of Primary Sclerosing Cholangitis (PSC) using Lipid Bilayer Nano-Particles or Solid Lipid Nano Particles(SLNPs) which is taken for insilico binding studies with various 4 different liver receptors. 3 Solid Lipid Nano Particles are chosen and Binding Efficiency of the Drug with Solid Lipid Nano Particles are Studied Using DFT Analysis and FEM Analysis. It was seen that the complete drug binding is seen in Small Unilamellar Vessicle (SUV). Chosen Liver Receptors with Ursodiol of the SUV are checked for binding studies using AutoDock 4. The Study revealed that Liver X Receptor has a greater efficiency in binding with the Solid Lipid Nano Particles.

KEYWORDS: Ursodiol, Solid Lipid Nano Particles, Small Unilamellar Vessicle, Liver Receptors. INTRODUCTION:
Nano-Biotechnology is a combination of Nanotechnology or Nano sciences and Biotechnology and it is the recently emerged field that deals with the Nano scale Biological compounds, their structures and their predominant involvement in the living system. The important objectives are applying nano tools to relevant medical/biological problems and refining these applications and developing new tools for the medical and biological fields. Nano Imaging of biomolecules and biological membranes, cantilever array sensors usage in nanophotonics for manipulating molecular processes in living cells dominate the field. Using microorganisms in synthesizing functional nanoparticles has been of great interest. As with nanotechnology and biotechnology, it too has many potential ethical issues associated with it. Primary Sclerosing Cholangities is a disease of bile ducts causing inflammation and subsequent obstruction of bile ducts both at intrahepatic and extrahepatic level and the cause may be due to autoimmunity. More than 80% of those with PSC have ulcerative colitis. Commonly diagnosed by endoscopic retrograde cholangiopancreatography, early detection and proper medication can cure the disease. The definitive treatment is liver transplantation but an alternative treatment is by chemotherapy, but only under certain circumstances. Ursodiol, also called as Ursodeoxycholic acid and abbreviated as UDCA, is a Primary Bile Acid, stored in gall bladder and are metabolized to Secondary Bile Acid by Intestinal Bacteria. The Structure of Ursodiol is as shown in the Figure 1. Ursodiol, a drug is used for the treatment of Primary Sclerosing Cholangities. They are currently synthesized commercially and are available as Actigall, Ursosan, Ursofalk, BILIVER, Egyurso, Urso, Urso Forte, Deursil and Coric, Udiliv, Ursocol etc. They function by inhibiting apoptosis and reduce cholesterol levels and dissolves Gall stones. They are predominately used in treating common Liver Disorders and it is the common drug for almost all Primary Liver Cirrhosis.

Received on 24.08.2013 Accepted on 01.09.2013 A&V Publications all right reserved

Research J. Engineering and Tech. 4(4): Oct.-Dec., 2013 page 284-287

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Research J. Engineering and Tech. 4(4): Oct.-Dec., 2013

Solid Lipid Nano Particles (SLNPs) are spherical in shape with size 10-1000 1000 nm and they are new Pharmaceutical Formulations or Pharmaceutical Drug Delivery Systems. As shown in Table 1, direct administration of Ursodiol might have serious symptoms ms in Humans, hence using SLNPs as delivery vehicles might be a correct alternative. The advantages in using SLNPs are much more than in Table 2, it t is evident that future holds a good hand in SLNP research, which is evident from Figure 2.

MATERIALS AND METHODS:

Databases Used are NCBI National Centre for Biotechnological Information RCSB Research Collaboratory for Structural Bioinformatics. EMBL European Molecular Biology Laboratory Laboratory. Softwares used are QUANTUM ESPRESSO: is a software suite for ab initio electronic-structure structure calculations and materials modeling distributed for free (under the GNU General Public License), based on Density Functional Theory for Research in Electronic Structure, Simulation, and Optimization. CMISS: is a Continuum Mechanics, Image analysis, Signal processing and System Identification which is a mathematical modelling environment and 3D visualization tool that allows the application of finite element analysis, boundary element and collocation techniques to a variety o of complex bioengineering problems AutoDock: is a suite of automated docking tools. It is designed to predict how small molecules, such as substrates or drug candidates, bind to a receptor of known 3D structure.

c. Selection of Liver Receptors: As there are chances for the liposomes to bind to various receptors of the liver, it was formulated to consider many liver receptors for the study. Hence around 10 different liver receptors are chosen and their significance are studied (Table 4). d. Docking Studies of Liver Receptor and SLNPs: SLNPs Then Docking studies were performed using AutoDock (Figure10) and the Binding Energy Scores in terms of Kcal/mol and Inhibition Constant value as Ki2 were tabulated (Table 5). Then the results are summarized.

RESULTS:
Initial Drug-SLNP SLNP Binding study using CMISS and QUANTUM ESPRESSO show that Small Sm Unilamellar Vessicle icle (SUV) have the higher Binding Capability (79.36%) and Multiple Lamellar Vessicle Ves (MLV) has the least Binding Efficiency (32.43%). Secondly, the Docking studies using AutoDock show that Docking of SUV with receptor in terms of Binding Energy scores is that Liver X Receptor (LXR ) and Liver X Receptor (LXR ) binding values are High and they are comparable and the Lyso Phosphatidic hosphatidic Acid Receptors (LPAr) has low binding scores.

Methodology Adopted: In order to analyse the efficiency in Targeted delivery of drugs, the following methodology is followed. a. Drug-Structural Analysis: The Structure of Synthetic Ursodiol varies a lot which depends on the synthesis method and raw materials used. Figure 1: Structure of Ursodiol or UDSA. For this study, the structure is obtained ined from ChemSpider with the ID No. 29131 (Figure 1). This is the basic structure without any R-groups added. b. Binding of Drug and SLNPs: In order to deliver the drug efficiently, the drug should be properly bind to SLNPs and it t should be inside the ball of Liposome (SLNP). About 6 different Liposomes namely Small Unilamellar Vesicle (SUV), Large Unliamellar Vesicle (LUV), Cochleate Vesicle(CV), Reverse Micelles, Micelles, Multi Lamellar Vesicle (MLV) (MLV). The 3D visualization of the Drug-SLNP binding for all the 6 SLNPs are done using CMISS (as shown in Figure 3 3, 4, 5, 6, 7, 8 and 9) and the results are re summarized using QUANTUM ESPRESSO (Table 3). Figure 2: Increase in Number of Papers in Solid Lipid
Nanoparticles Research. (S.Mukherjee et al.)

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Figure 3: Binding of Drug to a SLNP. Greater the Drug size exposed, Lower the binding

Figure 6 and 7 :( RMcs and CV)

Figure 4: MLV

Figure 8:(LUV)

Figure 5: Mcs

Figure 9:(SUV) D74 and E202 Terminal Ends of the Liposomes called as Lipid Chains made of Phosphotidylcholine.

Table 1: Side Effects of Ursodiol Usage S.No Side Effects of Ursodiol Usage 1. Loss of Appetite and prolonged weight Loss. 2. Promotes Colon Carcinogenesis, when come in contact with other bile acids like chenodeoxycholic and lithocholic acids, producing Pro-Carcinogenic Bile Acids. 3. At inert conditions, Intestinal Bacteria degrades Ursodiol to Azoxymethane, a carcinogenic and Neurotoxic compound. 4. Unclear Specificity of the drug, thereby leading to multiple organ Binding, thereby leaving the disease, untreated. 5. LD50 dosage is 7.5g/kg rats and 5g/kg in mice for 7-10 days. Table 2: Advantages of Solid Lipid Nano Particles (SLNPs) S.No Advantages of Lipid Bilayers or Liposomes or SLNPs 1. Dissolves all Stability Issues with Pharmaceuticals 2. Sterlizable, Improved Stability and easy to Scale-Up 3. Avoids Organic Solvents as they are Water Based 4. Targeted and Controlled Release of the Drug 5. Feasible, Biodegradable and Biocompatable 6. More Affordable than polymeric or surfactant carriers.

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Research J. Engineering and Tech. 4(4): Oct.-Dec., 2013 Table 3: Results of Compatibility Analysis of Drug and Liposome using QUANTUM ESPRESSO. S.No Name of the Liposome or SLNPs % Compatibility 1. Small Unilamellar Vesicle(SUV) 79.36 2. Large Unliamellar Vesicle(LUV) 69.17 3. Cochleate Vesicle(CV) 51.43 4. R. Micelles 50.44 5. Micelles 43.42 6. Multi Lamellar Vesicle(MLV) 32.43 S.No 1. 2. 3. 4 5. 6. 7. 8. 9. 10. Name of the Receptor Liver X Receptors Liver X Receptors . Low Density Lipoprotein receptor. Sterol Regulatory Element-Binding Protein SREBP Cleavage Binding Protein. Thyroid Hormone Receptor-Like Receptors Lyso Phosphatidic Acid Receptors Hepatocyte Specific CB1 (CannoBinoid) Receptors Toll-Like Receptors Asialo Glyco Protein Binding Receptor Abbreviation LXR LXR LDLr SREBP SREBP-2/SCAP THRLr EDG or LPA HSCBr TLRs ASGPr Significance Important in Metabolism of Cholesterol Metabolic homeostasis of Glucose and Fatty Acids A mosaic Protein involved in endocytosis of Cholesterol-Rich LDL Trancription factors binding to the Sterol Sterol Regulatory Binding Protein of Cholesterol Depleted Cells. Key role in Innate immunity System Act Like GPCRs, Involved in cell growth and Proliferation Maintenance of Lipid and fatty acid Profile Important in Thyroid hormone Binding. Involved in maintaining Blood Flow Significant Glycoprotein Binding Receptors

S.NO

Name of Receptor

the

1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

LXR LXR LDLr SREBP SREBP-2/SCAP THRLr EDG or LPA HSCBr TLRs ASGPr

Binding Energy (Kcal/Mol)) -6.65 -6.6 -6.0 -6.0 -5.5 -4.3 -3.9 -2.1 -1.4 -0.8

Inhibition Constant Ki2 18 21 38 59 66 74 89 93 103 174

7.

8.

9.

CONCLUSIONS:

Hence this study gave us In-Depth Knowledge about the Binding of the drug for Liver cirrhosis, Ursodiol with various Liposomes and further the docking studies of SUV 11. with that of Various Liver Receptors.

10.

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