TOPIC TITTLE INVESTIGATE OF ALBUMIN COATED POROUS

THAI NGUYEN UNIVERSITY UNIVERSITY OF AGRICULTURE AND FORESTRY TRAN THI THUY HA TOPIC TITTLE: INVESTIGATE OF ALBUMIN COATED POROUS HOLLOW Fe3O4 NANOPARTICLES FOR DUAL DRUGS DELIVERY BACHELOR THESIS Study Mode: Full-time Major: Environmental Science and Management Faculty: International Training and Development Center Batch: 2010-2015 Thai Nguyen, 15/01/2015 THAI NGUYEN UNIVERSITY UNIVERSITY OF AGRICULTURE AND FORESTRY TRAN THI THUY HA TOPIC TITTLE: INVESTIGATE OF ALBUMIN COATED POROUS HOLLOW Fe3O4 NANOPARTICLES FOR DUAL DRUGS DELIVERY BACHELOR THESIS Study Mode: Full-time Major: Environmental Science and Management Faculty: International Training and Development Center Batch: 2010-2015 Thai Nguyen, 15/01/2015 Thai Nguyen University of Agriculture and Forestry Degree Program Bachelor of Environmental Science and Management Student name Tran Thi Thuy Ha Student ID DTN1053110065 Thesis Title Investigate of Albumin-Porous Holow Fe3O4 Nanoparticles for Dual Drug Delivery Supervisor(s) Prof Huang Yu-Fen & Dr Do Thi Ngoc Oanh Abstract: Dual-functional drug carrier has been a modern strategy in cancer treatment Photodynamic therapy (PDT) is a non-invasive treatment modality for selective destruction of cancer malignant cells, which involves light irradiation, and a photosensitizer for free radicals generation; hence archiving photocytotoxicity On the other hand, the use of a chemotherapeutic agent is most effective at killing cells that are rapidly dividing However, most of the photosensitizers and chemotherapeutical agents lack of efficient bio-distribution and cellular uptake; for instance the use of nanoparticles provides an ideal carrier of a photodynamic drug In the present work, a photosensitizer drug protoporphyrin IX (PpIX), and a chemotherapeutic drug Doxorubicin (DOX), are encapsulated onto porous hollow iron nanoparticles (PHNPs) via oil in water emulsion procedure using BSA as a stabilizer, with the aim of a synergistic effect through a combination therapy Carriers were successfully characterized; sizes and charges were monitored via DLS and Zeta Potential respectively The intracellular uptake and localization of ii polymeric particle was investigated by fluorescence microscope The photodynamic effect was evaluated by MTT cytotoxicity assay Together, the dual drug carrier nanoparticle combined chemo-photodynamic therapy strategy in one delivery system, which is a potential dual-functional carrier for the synergistic combination for the treatment of cancer Keywords Porous holow Fe3O4 nanoparticles, drug delivery, albumin Number of pages Date of submission 15th January, 2015 iii ACKNOWLEAGEMENT Firstly, I would like to say thanks to the cooperation between Thai Nguyen University of Agriculture and Forestry and National Tsing Hua University for providing me an amazing opportunity to internship in Taiwan It brings me great pleasure to work and submit my thesis report for graduation I would like to express my deeply gratitude to Prof Huang Yu-Fen whose guidance, encouragement, suggestion and very constructive criticism have contributed immensely to the evolution of my ideas during the project Without her guidance, I may not have this report I sincerely thank to Dr Do Thi Ngoc Oanh for her advices, assistance, sharing experiences before and after I went to Taiwan, helping me to understand and complete proposal and report I am also thankful to Andrea del Valle for teaching me the synthesis of nanoparticles and various other techniques and methods used in biomedical field She was very helpful in providing me constructive feedback and suggestions on my project and helping me to successful complete several of my experiments and report Without her help and devotion, I would not be able to reach this stage I am really fortunate to be in Prof Huang’s lab Thanks to all the members in Professor Huang’s laboratory who hearty help me a lot when I work in there iv I also thank to my family for providing me emotional, unceasing encouragement and physical and financial support At last, I would like to thank all those other persons who helped me in completing this report Because of my lack knowledge, the mistake is inevitable, I am very grateful if I receive the comments and opinions from teachers and others to contribute my report Thank you v TABLE OF CONTENT LIST OF FIGURES LIST OF ABBREVIATIONS PART I INTRODUCTION 1.1 Research rationale 1.2 Research’s objectives 1.3 Research questions 1.4 Limitations 1.5 Definitions PART II LITERATURE REVIEW 2.1 Cancer Problem 2.2 Photodynamic Therapy 2.3 Nanoparticles in biomedical application 2.4 Protein coated nanoparticles 2.5 Albumin coated nanoparticles 2.6 Bovine Serum Albumin (BSA) 10 2.7 Porous hollow Fe3O4 nanoparticles 10 2.8 Cancer treatment Drugs 12 2.8.1 DOXorubicin 12 vi 2.8.2 Protoporphyrin IX 13 PART III MATERIALS AND METHODS 15 3.1 Materials 15 3.2 Treatments 17 3.3 Procedure 18 3.4 Experiment 1: Characterization of nanocarrier 18 3.4.1 Particle Size and Surface charge Measurement 18 3.4.2 Encapsulation Efficiency Measurements 19 3.5 Experiment 2: Cytotoxic assay 20 3.5.1 Dark toxicity 20 3.5.2 Light-induced toxicity 20 PART IV RESULTS 22 4.1 Particle size and Surface charge 22 4.2 Efficiency of Drugs Loading 22 4.3 Cytotoxic assay 23 4.3.1 Dark toxicity 23 4.3.2 Light-induced Toxicity i PART V DISCUSSION AND CONCLUSION 24 5.1 Discussion 24 vii 5.1.1 Particle Size and Surface charge 24 5.1.2 Efficiency Drugs loading 24 5.1.3 Cytotoxic Assay 25 5.1.3.1 Dark Toxicity 25 5.1.3.2 Light-induced Toxicity 26 5.2 Conclusion 26 REFERENCES 28 viii LIST OF FIGURES Figure 1: Schematic illustration of simultaneous surfactant exchange and cisplatin loading into a PHNP and functionalization of this PHNP with Herceptin 12 Figure 2: Chemical structure of DOX 13 Figure 3: Chemical Structure of PpIX 13 Figure 4: Photodynamic therapy of PpIX 14 Figure 5: Photo of Sonicator 16 Figure 6: Photo of Refrigerated Centrifuge 16 Figure 7: Photo of Plate reader 16 Figure 8: Photograph of four treatments was prepared successfully 17 Figure 9: Schematic diagram of the PHNPs:BSA:DOX:PpIX nanocarrier 21 Figure 10: The average size of PHNPs: BSA: DOX/ PpIX 22 Figure 11: The average zeta potential of PHNPs:BSA:DOX:PpPIX 22 Figure 12: Drug loading efficiency in PHNPs 22 Figure 13: MTT dark cytotoxicity results 23 Figure 14: MTT cytotoxicity results 23  Sodium chloride was purchased from J.T.Baker (Center Valley, PA, USA)  Dulbecco's phosphate-buffered saline (DPBS) was purchased from Biological Industries (Camarillo, CA, USA)  Equipment  Fluorescence spectrometer, Fluoromax-4 (Horiba Jobin Yvon, Edison, NJ, USA)  Refrigerated centrifuge, Sigma 3-30K (Sigma, Germany)  Plate reader, Tecan Infinite 200 (Tecan Group AG, Basel, Switzerland)  Dynamic light scattering, DLS Zetasizer Nano (Malvern Instruments, United Kingdom)  Ultrasonic cleaner, DELTA DC200H (DELTA , Taiwan) Figure Figure Refrigerated centrifuge Sonicator Figure Plate reader 16 3.2 Treatments Nano: DOX Nano: PpIX Nano: DOX/PpIX Nano Figure 8: Photograph of four treatments was prepared successfully Four treatments were prepared: Albumin coated nanoparticles only (PHNPs:BSA only): symbol: Nano Albumin coated nanoparticles loading DOX ( PHNPs:BSA:DOX): symbol: Nano:DOX Albumin coated nanoparticles loading PpIX (PHNPs:BSA:PpIX), symbol: Nano:PpIX Albumin coated nanoparticles loading DOX & PpIX (PHNPs:BSA:DOX:PpIX) symbol: Nano:D/P 17 Each treatment was repeated three times (three replications) 3.3 Procedure Prepare samples Prepare PHNPs (concentration: 0.125M) From PHNPs with concentration 3.8 M, PHNPs samples (0.125 M) were prepared by diluting a stock solution of 500 µL PHNPs (0.5M) with 1.5 mL Hexane Ethanol was added with prepared samples (ratio 1:1) Final total volume in each tube was mL The prepared samples were further centrifugated with speed 10,000g during minutes under 20oC temperature Particles were re-suspended in mL of chloroform (CHCl3) Coated PHNPs into emulsion BSA: Drugs Emulsion (BSA: Drugs) was coated in PHNPs by under frequency 80 during minutes with 10s pulse off and 10s pulse on Samples were further vortex continuously per 24 hours The finished samples were stored for further characterization of nanoparticles 3.4 Experiment 1: Characterization of nanocarrier 3.4.1 Particle Size and Surface charge Measurement Dynamic Light Scattering (DLS) sample was prepared by washing twice the nanoparticle Then samples was diluted with distilled water The particle size and 18 surface charge determinations were performed by Zetasizer Nano-ZS, (Malvern, UK) 3.4.2 Encapsulation Efficiency Measurements The concentration of unbounded DOX molecules to the nanoconjugates was calculated from the fluorescence emission intensity of DOX at 590 nm (excitation at 480 nm) in the supernatants (Tecan Sfire Plate Reader, Tecan Group AG, Basel, Switzerland) The fluorescence maxima measured from each different supernatant was converted to molar concentration from a standard linear calibration curve; which was prepared with known DOX concentrations, same buffer pH and equal salt concentrations Drug loading capacity and efficiency on the nanoconjugates were calculated by the following formula: Efficiency = Amount of DOX release/ Amount of initial concentration x100 release The concentration of unbounded PpIX molecules to the nanoconjugates was calculated from the fluorescence emission intensity of PpIX at 696 nm (excitation at 480 nm) in the supernatants (Tecan Sfire Plate Reader, Tecan Group AG, Basel, Switzerland) The fluorescence maxima measured from each different supernatant was converted to molar concentration from a standard linear calibration curve; which was prepared with known PpIX concentrations, same buffer pH and equal salt concentrations Drug loading capacity and efficiency on the nanoconjugates were calculated by the following formula: Efficiency = Amount of PpIX release/ Amount of initial concentration x100 release 19 3.5 Experiment 2: Cytotoxic assay 3.5.1 Dark toxicity 3,000 Tramp C1 cells per well were incubated per 12 hours in a 96 well cell culture plate Furthermore, cells were washed twice with DPBS and particles were added in different dilution ratios (0.5X and 1X) to the cells 20 minutes of magnetofection was applied to the cells for increasing cellular uptake of particles Afterwards, cells were washed twice with DPBS Fresh DMEM medium was further added to the cells and left for 48 hours of recovery Cell survival was assessed using the MTT Alamar Blue Assay 3.5.2 Light-induced toxicity 3,000 Tramp C1 cells per well were incubated per 12 hours in a 96 well cell culture plate Furthermore, cells were washed twice with DPBS and particles were added in different dilution ratios (0.5X and 1X) to the cells 20 minutes of magnetofection was applied to the cells for increasing cellular uptake of particles Afterwards, cells were washed twice with DPBS and light treatment was applied to them per 20 Fresh DMEM medium was further added to the cells and left for 48 hours of recovery Cell survival was assessed using the MTT Alamar Blue Assay 20 Figure 9: Schematic diagram of the PHNPs:BSA:DOX:PpIX nanocarrier causing cell damage under the 632 irradiation exposure 21 PART IV RESULTS 4.1 Particle size and Surface charge Figure 10 Figure 11 Figure 10: The average size of PHNPs: BSA: DOX/ PpIX (mean ± SD) (n=3) Figure 11: The average zeta potential of PHNPs:BSA:DOX:PpPIX (mean±SD) (n=3) 4.2 Efficiency of Drugs Loading Figure 12: Drug loading efficiency in PHNPs (n=3) 22 4.3 Cytotoxic assay 4.3.1 Dark toxicity Figure 13: MTT dark cytotoxicity results from cells incubated with PHNPs per hours and 20 minutes of magnetofection 4.3.2 Light-induced Toxicity Figure 14: MTT cytotoxicity results from cells incubated with PHNPs per hours and 20 mins of magnetofection, particles were irradiated with 632 nm light per 20 minutes 23 PART V DISCUSSION AND CONCLUSION 5.1 Discussion 5.1.1 Particle Size and Surface charge The particle size influences the cellular uptake and drug release of nanoparticles and their bio-distribution properties The ideal size for nanocarriers is between 100 to 200 nm in diameter The figure 10 shows that all the experimented samples have size less than 200 nm, which is ideal size for nanocarriers Among of those samples, Nano: DOX has the smallest size while Nano: PpIX has biggest size Cationic DOX helps nanocarriers size smaller, while Anionic PpIX is reason made nanocarriers size bigger The surface charges of particle were calculated by Zeta-potential data The zeta-potential is a measure of the effective electric charge on the nanoparticle surface The magnitude of the zeta potential provides information about particle stability, with particles with higher magnitude zeta potentials exhibiting increased stability due to a larger electrostatic repulsion between particles The figure 11 presents the range of magnitude of all the experimented samples is between -21 to 22 mV that indicate particles were moderately stable in aqueous suspension 5.1.2 Efficiency Drugs loading The figure 12 shows the percentage efficiency of DOX and PpIX entrapped onto the protein nanoparticles The percentage of DOX loading in dual drugs carrier 24 is higher approximately 10 percent than in single DOX nanocarrier Efficiency of PpIX loading in dual drugs carrier lower than its in single PpIX drug carrier 5.1.3 Cytotoxic Assay The cytotoxic assay is to measure the toxicity of drug nanocarriers to the cell The drug nanoparticles should be not harmful to the targeted cell until the light exposure Cell viability was studied in order to monitor PpIX and Doxorubicin’s synergistic therapy 5.1.3.1 Dark Toxicity The figure 14 presents MTT dark cytotoxicity results from cells incubated with PHNPs per hours and 20 minutes of magnetofection from cells incubated left 48 hours to recover in different dilution ratio 0X: control cells (free drugs, 0.5X: drug nanocarriers with half concentration of 1X Data represent (mean ± SD) (n = 3)) The dark toxicity of nanocarriers was shown in figure 14 Control cells show the toxicity of free DOX that caused more than a 50 percent reduction in cell viability The drug nanocarriers show the low dark toxicity in both 0.5X and 1X concentration In the double concentration (1X), nanocarriers exhibited higher toxicity Among of experimented samples, single DOX nanocarriers sample shows the lowest dark toxicity, followed by single PpIX nanocarriers in different dilution 25 The dual drug carriers exhibited the highest toxicity; however, the cell viability was still high around 80 percent 5.1.3.2 Light-induced Toxicity Figure 13 shows MTT cytotoxicity results from cells incubated with PHNPs per hours and 20 mins of magnetofection, particles were irradiated with 632 nm light per 20 minutes and left over 48 hours to recover 0X: control cells (free drugs), 0.5X and 1X: drug with nanocarriers with double concentration Data represents mean ± SD (n = 3) From the figure 13, it can be seen that the cell viability decreased in all drug carriers samples upon to different dilution ratio In 1X dilution ratio, the efficiency of all the samples is highest Single Ppix nanocarrier shows higher efficiency than free drug PpIX 5.2 Conclusion Combing photosensiter PpIX and chemotherapeutic DOX onto PHNPs created ideal size of nanocarrier (less than 200 nm), which was stable in its aqueous suspensions Combining PpIX and DOX onto PHNPs had high drugs loading efficiency which 70% for DOX and 80% for PpIX 26 Dark toxicity of dual-drugs carrier at 0.5X and 1X exhibited lower than control At 0.5X concentration, dual drugs carrier exhibited lower than its at 1X concentration Light-induced toxicity, dual drugs carrier at 0.5X and 1X concentration exhibited higher than control At 0.5X concentration, dual drugs carrier exhibited worse than its at 1X concentration In summary, we were able to successfully load both drugs, the hydrophobic PpIX molecules and the chemotherapeutic agent DOX into BSA capped PHNPs, with a high loading efficiency under a simple ultrasonication condition MTT Assays proved the synergistic effect of dual drug delivery when particles were irradiated with 632 nm light PHNPs:BSA:DOX:PpIX exhibit high biocompatibility and low dark toxicity, all these features greatly reduce side effects for further applications at in vivo systems 27 REFERENCES Agnieszka, Z W., Wilczewska, Katarzyna Niemirowicz, Karolina, H., Markiewicz, Halina Car (2012) Nanoparticles as drug delivery systems Pharmacological Reports, 64(5), pp 1020 Calvo, E (2014) Cancer Management Retrieved from: Cancer Network: http://www.cancernetwork.com/cancer-management/chemotherapeuticagents-and-their-uses-dosages-and-toxicities (accessed on 04/11/2015) Dolmans, D.E., Fukumura, D., Jain, R.K (2003) Photodynamic therapy for cancer Nature Reviews Cance, 3(5), pp 380–387 Elzoghby, A.O., Samy, W.M., Elgindy, N.A (2012) Albumin-based 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Nano: PpIX Nano: DOX/PpIX Nano Figure 8: Photograph of four treatments was prepared successfully Four treatments were prepared: Albumin coated nanoparticles only (PHNPs:BSA only): symbol: Nano Albumin coated nanoparticles loading DOX ( PHNPs:BSA:DOX): symbol: Nano:DOX Albumin coated nanoparticles loading PpIX (PHNPs:BSA:PpIX), symbol: Nano:PpIX Albumin coated nanoparticles loading DOX & PpIX (PHNPs:BSA:DOX:PpIX)... oral delivery Nowadays active research is focused on the preparation of nanoparticles using proteins like albumin, gelatin, gliadin and legumin (Jahanshahi M B., 2008) The most promising areas of the application of protein nanoparticles seem to be their use as parenteral carriers for different drugs 2.5 Albumin coated nanoparticles Albumin is an attractive macromolecular carrier and widely used to prepare... modifications and also albumin nanoparticles offer the advantage that ligands can easily be attached by covalent linkage Drugs entrapped in albumin nanoparticles can be digested by proteases and drug loading can be quantified A number of studies have shown that albumin accumulates in solid tumors (Takakura et al., 1990) making it a potential macromolecular carrier for the site-directed delivery of antitumor... 2008) 9 2.6 Bovine Serum Albumin (BSA) BSA is a single polypeptide chain consisting of about 583 amino acid residues and no carbohydrates Albumins are readily soluble in water and can only be precipitated by high concentrations of neutral salts such as ammonium sulfate The solution stability of BSA is very good, (especially if the solutions are stored as frozen aliquots) In fact, albumins are frequently... PHNP and functionalization of this PHNP with Herceptin 2.8 Cancer treatment Drugs 2.8.1 DOXorubicin Among the antitumor antibiotics, doxorubicin is commonly used in the treatment of a wide range of cancers such as hematological malignancies, carcinomas, and soft tissue sarcomas DOXorubicin is a type of chemotherapy drug called an anthracycline It slows or stops the growth of cancer cells One-way that... system, the size of particle is very important in distribution of drug in human body Generally, the large particle is easily removed by liver and spleen Moreover, the stability of a small particle is higher than the large particle in drug delivery devices reducing the size of colloidal particle carriers in the range of 50 to 100 nm enhances carrier’s stability and creates the chance of escaping from... body (Jahanshahi et al., 2005) 2.7 Porous hollow Fe3O4 nanoparticles Recently, studies on magnetically and optically active NPs with hollow interiors and porous shells have gained (Lou et al., 2008) Compared with their solid 10 counterparts of the same sizes, porous hollow NPs (PHNPs) provide larger specific surface to encapsulate small molecules Once inside the porous structures, small drug molecules... process Previous results showed that porous hollow nanoparticles with opening pores (~2–4 nm) nanoparticles facilitated the cisplatin diffusion into the cavity of the hollow structure The results clearly the potential applications of porous magnetic hollow nanoparticles as nanocarriers for anticancer drug (Kai Cheng et al., 2009) 11 Figure 1: Schematic illustration of simultaneous surfactant exchange... designed to improve the pharmacological and therapeutic properties of conventional drugs The incorporation of drug molecules into nanocarrier can protect a drug against degradation as well as offers possibilities of targeting and controlled release 2.4 Protein coated nanoparticles Proteins are a class of natural molecules that have unique functionalities and potential applications in both biological as... drug using in photodynamic therapy) onto porous hollow Fe 3O4 3 nanoparticles via oil in water emulsion procedure using Bovine Serum Albumin (BSA) as a stabilizer to facilitate combine chemotherapy and photodynamic in one system This study aim to assessment of the effectiveness of combining a photosensitizer drug and a chemotherapeutic drug encapsulated onto porous hollow Fe3O4 nanoparticles in photodynamic ...THAI NGUYEN UNIVERSITY UNIVERSITY OF AGRICULTURE AND FORESTRY TRAN THI THUY HA TOPIC TITTLE: INVESTIGATE OF ALBUMIN COATED POROUS HOLLOW Fe3O4 NANOPARTICLES FOR DUAL DRUGS DELIVERY... University of Agriculture and Forestry Degree Program Bachelor of Environmental Science and Management Student name Tran Thi Thuy Ha Student ID DTN1053110065 Thesis Title Investigate of Albumin- Porous. .. for the synergistic combination for the treatment of cancer Keywords Porous holow Fe3O4 nanoparticles, drug delivery, albumin Number of pages Date of submission 15th January, 2015 iii ACKNOWLEAGEMENT