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  1. A Research Proposal on “Mitocondrial Targeted Lonidamine Loaded Liposomes for the Treatment of Breast Cancer” 1 Submitted by: Hemendra Kumar RET Reg.No: 21000490 Email id:
  3. INTRODUCTION:- • Breast cancer is a systemic disease. It has become the most frequently diagnosed cancer and the leading cause of cancer-related death among females worldwide, with an stimated 2.1 million cases and 627,000 deaths in 2018. Signs and symptoms of breast cancer may include- • A breast lump or thickening that feels different from the surrounding tissue. • Change in the size, shape or appearance of a breast. • Changes to the skin over the breast, such as dimpling. • Peeling, scaling, crusting or flaking of the pigmented area of skin surrounding the nipple or breast skin. • Redness or pitting of the skin over your breast, like the skin of an orange 3
  4.  A liposome is an artificial vesicle composed of one or more concentric phospholipid bilayers and used especially to deliver microscopic substances (such as drugs or DNA) to body cells. The liposome is designed for the following optimized properties: • Drug loading and control of drug release rate • Overcoming the rapid clearance of drug • Intracellular delivery of drugs • Receptor-mediated endocytosis of ligand-targeted liposomes • Reduce the toxicity • Delivery of nucleic acids and DNA 4 Contd..
  5. • Lonidamine is a derivative of indazole-3- carboxylic acid and is known to inhibit aerobic glycolysis and energy metabolism selectively in tumor cells. • Lonidamine (LND), first introduced in 1979 as an antispermatogenic agent, has limited antineoplastic activity. Current evidence indicates that LND inhibits glycolysis by the inactivation of hexokinase. Hexokinase is an enzyme that catalyzes glucose, the first step in glycolysis. • Lonidamibe also inhibits lactate export by the proton-linked monocarboxylate transporter(s) (MCT) and pyruvate uptake into mitochondria via the mitochondrial pyruvate carrier (MPC), whereas inhibition of respiration involves both diminished mitochondrial uptake of pyruvate. 5 Contd..
  6. DRUG PROFILE • Chemical Name- Lonidamine • Synonyms- AF 1890, DICA, Diclondazolic Acid • Chemical Formula- - C15H10Cl2N2O2 • Molecular Weight- 321.2 g/mol • Chemical Structure- 6
  7. • Color- white • Taste- Sour • Solubility- Freely soluble in water, almost chloroform & methanol, insoluble in oil. • Storage temperature – cold • Stability- ≥2 Years • Mechanisms of Action- LND inhibits glycolysis by the inactivation of hexokinase. Hexokinase is an enzyme that catalyzes glucose, the first step in glycolysis. 7
  8. EXCIPIENT PROFILE 8 Cholesterol Synonym – Cholesterin, Cholesteryl alcohol, Cholest-5-en-3beta-ol. Molecular weight – 386.7 g/mol Structural formula –
  9. • Description- In its pure state it is a white, crystalline substance that is odourless and tasteless • Solubility: insoluble in water, slightly soluble in alcohol, freely soluble in acetone, chloroform, benzene • Applications- • A major component of the cell membrane • Precursor in hormone biosynthesis. 9
  10. Soya lecithin • Lecithin is a group of yellow-brownish fatty substance occurring in animal and plant tissues, and in egg yolk, composed of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides, and phospholipids . • Structural formula – 10
  11. Description: • Colour: Yellowish brown • Molecular Formula: C36H72NO8P • Molecular Weight: 677.93gm • Iodine value: 85-95 • Solubility: Lecithin is soluble in both aqueous and organic phase. Hence it can be used as emulsifier in food industry and it is also capable of forming vesicles thereby it is used in pharmaceutical industry. It gives clear or slightly opalescent solutions with both phases. 11
  12. PLAN OF WORK 1.Preformulation studies- Identification of drug-  Physical appearance  Melting point  Solubility Analysis  HPLC assay  Fourier Transform infrared radiation Measurement (FT-IR) 2. Screening & Optimization of Suitable Method to Form Liposomes  Solvent Evaporation Method  Thin Film Hydration Method 12
  13. 3. Formulation of Pharmaceutical Liposmes by Best Selected Method. 4. Characterization- • Percentage yield (% yield) • Drug content estimation • Drug entrapment Study • Determination of size distribution of Liposmes • In-vitro drug release • Scanning electron microscopy • In-vivo study 5. Stability Studies (as per ICH Guidelines) 6. Computation & Compilation of Work 13
  14. Method for preparation of Liposomes- 14 Accurately weighed Cholestrol and Soya Lecithin was transferred in solvent Solvent was evaporated by using Rotatory Evaporator and a thin film formed Liposomal dispersion is formed Liposome of reduced size is obtained Stirring till dissolve Phosphate Buffer + DRUG added for the hydration of film Sonication for size reduction Vortex untill the formation of milky solution
  15. Formulation and Development :- S.No. Formulation code Soya Lecithin (mg) Cholesterol (mg) Sonication Time (Min) 1 F1 200 10 15 2 F2 200 10 10 3 F3 200 20 15 4 F4 100 10 10 5 F5 200 20 10 6 F6 100 10 15 7 F7 100 20 15 8 F8 100 20 10 9 F9 150 15 12.5  By using DesignExpert-12 15 DoE of the formulation
  16. Expected Outcome: • Enhance the Bioavailability of lonidamide. • Enhance Solubility • Increase Stability • Reduce the toxicity 16
  17. REFERENCES • Rangarajan Bharath, Shet tanuja, Wadasadawala tabassum, Nair S. Nita “Breast Cancer: An overview of published indian data” South Asian Journal of Cancer; sept 2016; vol 5: issue 3. • Sharma N. Ganesh, Dave Rahul, Sanadya Jyotsana, Sharma Piyush “Various types and Management of Breast Cancer: An overview” Journal of Advanced Pharmaceutical Technology & research; 2010 Apr-Jun; 1(2): 109-126. • Sharma Amarnath, Sharma S. Uma, ”Liposome in drug delivery: progress and limitation”, International journal of Pharmaceutics 154 (1997) 123-140 • Dua J.S.,Prof. Rana A.C.,Dr.Bhandari A.K. “LIPOSOME:Methods of prepration and Applications” International journal of Pharmaceutical studies and research Vol. III/Issue II/April-June,2012/14- 20 17
  18. • Eugenia, Cruz M, Manuela, Gaaspar M, Lusia Corovo M, Manuela Carvalheiro. Applications of lposomes in drug delivery. Novas Formas de Agents Bioactivos 1996; 22: 1649-1652. • Nath Kavindra, Guo Lili, Nancolas Bethany et al. ”Mechanism of antineoplastic activity of lonidamine”, Elsevier’s Biochimica et Biophysica Acta 2016; 152-156 • Cheng Gang, Zhang Qi, Pan Jing, Lee Yongik, Ouari Olivier et al, ”Targetting lonidaminen to mitochondria mitigates lung tumorigenesis and brain metastasis” Nature Communications (2019) 10:2205. • www.Wikipedia. Org/wiki/lecithin 18
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