Targeted and Controlled drug delivery of Doxorubicin for cancer

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A new family of folate -decorated and carbon nanotube -mediated drug delivery system: Synthesis and drug delivery response A new family of folate -decorated and carbon nanotube -mediated drug delivery system: Synthesis and drug delivery response Presented by: Sk. Asma Shaheda I/II M.Pharmacy

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Introduction: Cancer is a life threatening disease that was increasing now a days. Causes: Genetic mutations Smoking and U.V exposure Physiological changes that leading to cancer Apoptosis/Necrosis P-53 and P-21 genes Microtubules P-Glycoprotein pump Angiogenesis Immune system Inflammation and Infection Myc Oncogene Exosomes Estrogen receptors( α , β ) Millieu or Environment

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Targeted drug delivery ?????? # Possibility of detection only at advanced stages # Toxicity of chemotherapeutic agents to healthy cells esp. cardiotoxicity of doxorubicin # Combines tumour recognition moiety with loaded vesicle Detections methods: 1. Tissue biopsy 2. Magnetic Resonance Image

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Carbon nanotubes : Comprises of thin sheets of benzene rings rolled up into the shape of seamless cylinders. Single-Walled and Multi-walled nantubes (SWNT,MWNT) Can cross cell membranes barriers and exhibit blood circulation half lives of order of hours. Eg : Amount of Amphotercin was reduced by using as CNT

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Polymers: Biodegradable polymers- chitosan and dextran have been considered because ## Unique integration of drug targeting and visualization. ## Produce quantum spots for imaging the distribution of drug invivo . Chitosan , a natural copolymer of N-acetyl glucosamine and D-Glucosamine, with one amino group and two hydroxyl groups is attractive for encapsulating CNT’s.

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Y Chitosan ?? Presence of reactive amine groups facilitates ligand attachment Chelation and cationic properties Cationic- chitosan based vesicles can effectively adhere to negatively charged phospholipid bilayer of cellular membrane Presence of lysosomes in endocytes of cells degrade chitosan Solubility of chitosan in mild acid ( endosomal pH-5.3) Chitosan structure

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Synthesis of Folate -decorated Chitosan CNT: Various steps involved in synthesis of folate -decorated chitosan Carbon nanotube are: Purification of SWCNT Synthesis of biofunctionalised chitosan Loading of SWCNT’s with DOX Synthesis of DOX-loaded CNT- chitosan - folate carrier Invitro drug release response

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Synthesis of Folate -decorated Chitosan CNT: Purification of SWCNT: 96%H2SO4 + 70%HNO3 single walled carbon nanotubes Sonic irradiation at 4ºC for 24hrs Washed with deionised water , filtered, redispersed in mixture of H2SO4 and H2O2 and stirred for 30mins, centrifuged Wash, centrifuge for 30mins CNT dried at 20ºC for 24hrs

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2.Synthesis of biofunctionalized chitosan : Solution of Dicyclohexyl carbodiimide (DCC) and folic acid in Dimethyl Sulfoxide (DSMO) prepared at room temperature untill folic acid dissolves(1hr). This solution was added to 1%Chitosan in acetate buffer (pH-4.7) Stirred at room temperature in dark for 15hrs Adjust pH to 9 by adding dil.aq.NaoH and dialyse first against Phosphate buffer (pH-7.4) for 3days and against water for 3days Polymer freeze dried *****FTIR for confirmation of Chitosan-folate conjugation.

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3. Loading of SWCNT’s with Doxorubucin : Dox-Hcl (30mg) + Purified CNT’s (10mg) added to 20ml Phosphate buffer solution (pH-7.4) and stirred for 16hrs at room temperature in dark to collect product Centrifuge and wash with PBS untill supernatant becomes color free DOX-CNT was freeze dried

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Cont…. Amount of unbound DOX was measured at 490nm by the following procedure: Centrifuged solution was diluted to 100ml with deionized water. Std DOX solution was prepared for quantitative analysis. Formula for DOX loading efficiency in CNT: DOX loading efficiency (%) = 100( W feed dox - Wfree dox )/ Wfeed dox **The DOX-loading efficiency estimated was ~91%.

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4. Synthesis of DOX-loaded CNT- chitosan - folate carrier 10mg DOX-CNT + 20mg folic acid- chitosan added to 20ml of PBS (pH-7.4) by rapid stirring for 1hr at room temperature in dark DOX-CNT-CHI-FA carriers were collected by repeated centrifugation and washed with PBS untill supernatant becomes color free Chitosan encapsulated DOX-CNT’s were freeze dried **Loading efficiency was determined as ̴ 76%

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5.Invitro drug release response: It was checked by following process 2.8mg of drug carrier was sealed in dialysis membrane tube Submerged in 10ml of Na2HPO4-KH2PO4 buffer solution pH-5.3 pH-7.4 Solutions were withdrawn and measured

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Results and discussions: Invivo drug release mechanism

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Conclusion: SWCNT was synthesised which is used as a targeted and controlled drug delivery for doxorubicin. Controlled release is due to - Degradation of chitosan and diffusion of drug through chitosan s shell - Hydrogen bond between Folic acid and DOX Compared to pH-7.4 higher drug release was observed at pH-5.3 because -Acidic medium promotes higher drug release by promoting chitosan degradation and weakening of H-bonding in acidic medium.

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References: Advanced Drug Delivery reviews 63(2011) 1332-1339 Biochima et Biophysca Acta Reviews on Cancer, Vol-1806, Issue 1, Aug2010 Carbon nanotubes destroying Cancer cell from Youtube uploaded by jjarkman on jan28, 2010. Important factors in cancer cell growth from Youtube uploaded by deeshudream on june9, 2010. Carbon nanotubes GOOGLE images