DOCSLIB.ORG

Engineering Polyanhydride Microspheres for the Stabilization and Controlled Release of Proteins Amy Sywassink Determan Iowa State University

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Engineering Polyanhydride Microspheres for the Stabilization and Controlled Release of Proteins Amy Sywassink Determan Iowa State University Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 2006 Engineering polyanhydride microspheres for the stabilization and controlled release of proteins Amy Sywassink Determan Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Biomedical Engineering and Bioengineering Commons, and the Chemical Engineering Commons Recommended Citation Determan, Amy Sywassink, "Engineering polyanhydride microspheres for the stabilization and controlled release of proteins " (2006). Retrospective Theses and Dissertations. 1809. https://lib.dr.iastate.edu/rtd/1809 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Engineering polyanhydride microspheres for the stabilization and controlled release of proteins by Amy Sywassink Determan A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Chemical Engineering Program of Study Committee: Balaji Narasimhan, Co-major Professor Marit Nilsen-Hamilton, Co-major Professor Surya K. Mallapragada Monica H. Lamm Michael J. Wannemuehler F. Chris Minion Iowa State University Ames, Iowa 2006 Copyright © Amy Sywassink Determan, 2006. All rights reserved. UMI Number: 3217264 INFORMATION TO USERS The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleed-through, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. UMI UMI Microform 3217264 Copyright 2006 by ProQuest Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P.O. Box 1346 Ann Arbor, Ml 48106-1346 ii Graduate College Iowa State University This is to certify that the doctoral dissertation of Amy Sywassink Determan has met the dissertation requirements of Iowa State University Signature was redacted for privacy. Co-major Professor Signature was redacted for privacy. Co-major Professor Signature was redacted for privacy. For the Major Program iii TABLE OF CONTENTS ACKNOWLEDGEMENTS vii ABSTRACT ix CHAPTER 1 INTRODUCTION 1 1.1. Introduction 1 1.2. References 5 CHAPTER 2 ENGINEERING SURFACE-ERODIBLE POLYANHYDRIDES WITH TAILORED MICROSTRUCTURE FOR CONTROLLED RELEASE 9 2.1 Introduction 9 2.2 Polymer Synthesis 9 2.2.1 Melt polycondensation 11 2.2.2 Solution polymerization 13 2.2.3 Ring opening reactions 15 2.3 Polymer Characterization 17 2.3.1 Chemical composition 17 2.3.2 Molecular mass 20 2.3.3 Crystallinity and thermal properties 21 2.3.4 Stability 23 2.3.5 Biocompatibility 24 2.4 Structures 25 2.4.1 Aliphatic 26 2.4.2 Aromatic 26 2.4.3 Unsaturated 27 2.4.4 Aliphatic-aromatic homopolymers 28 2.4.5 Amino acid-based 28 2.4.6 Fatty acid-based 30 2.4.7 Poly(ester-anhydrides) and poly(ether-anhydride) 31 2.4.8 Crosslinking 33 2.4.9 Branched 34 2.4.10 Blends 35 2.5 Characterization of Polymer Erosion 36 2.5.1 Polymer degradation 37 2.5.2 Polymer erosion 38 2.6 Mechanisms of Protein Denaturation 41 2.6.1 Disulfide formation & aggregation 42 2.6.2 Deamidation 43 2.6.3 Oxidation 43 2.6.4 Degradation by proteases 44 2.7 Microsphere Fabrication 44 2.7.1 Hot-melt microencapsulation 45 iv 2.7.2 Solvent removal microencapsulation 45 2.7.3 Spray drying microencapsulation 48 2.8 Protein-Loaded Microsphere Characterization 51 2.8.1 Confocal laser scanning microscopy 52 2.8.2 Analysis of secondary structure 52 2.8.3 Analysis of primary structure 53 2.9 In Vitro Release 54 2.9.1 In vitro release kinetics of protein-loaded microspheres 54 2.9.2 In vitro effect of polymer degradation products on protein stability 56 2.10 Summary 56 2.11 References 57 CHAPTER 3 RESEARCH OBJECTIVES & ORGANIZATION 67 3.1. Research Objective 67 3.2. Dissertation Organization 69 CHAPTER 4 ENCAPSULATION, STABILIZATION, AND RELEASE OF BSA-FITC FROM POLY ANHYDRIDE MICROSPHERES 70 4.1 Abstract 70 4.2 Introduction 71 4.3 Materials and Methods 74 4.3.1 Materials 74 4.3.2 Polymer synthesis 75 4.3.3 Polymer characterization 75 4.3.4 Microsphere fabrication 76 4.3.5 Microsphere characterization 77 4.3.6 Protein loading 77 4.3.7 In vitro protein release 78 4.3.8 Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) 78 4.3.9 Fourier transform infrared spectroscopy (FTIR) 79 4.4 Results and Discussion 80 4.4.1 Microsphere characterization 80 4.4.2 Protein loading 84 4.4.3 In vitro release 84 4.4.4 SDS-PAGE analysis 86 4.4.5 FTIR analysis 88 4.5 Conclusions 91 4.6 Acknowledgements 92 4.7 References 93 V CHAPTER 5 PROTEIN STABILITY IN THE PRESENCE OF POLYMER DEGRADATION PRODUCTS: CONSEQUENCES FOR CONTROLLED RELEASE FORMULATIONS 97 5.1. Abstract 97 5.2 Introduction 98 5.3 Materials and Methods 100 5.3.1 Materials 100 5.3.2 In vitro incubation 101 5.3.3 Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) 102 5.3.4 Circular dichroism (CD) 103 5.3.5 Fluorescence spectroscopy 104 5.3.6 TT-specific enzyme-linked-immunosorbent-assay (ELIS A) 104 5.3.7 Ovalbumin-specific enzyme-linked- immunosorbent-assay (ELISA) 105 5.3.8 Lysozyme activity test 106 5.4 Results 107 5.4.1 Stability of tetanus toxoid 107 5.4.2 Stability of ovalbumin 112 5.4.3 Stability of lysozyme 118 5.5 Conclusions 122 5.6 Acknowledgments 124 5.7 References 125 CHAPTER 6 THE ROLE OF MICROSPHERE FABRICATION METHODS ON THE STABILITY AND RELEASE KINETICS OF OVALBUMIN ENCAPSULATED IN POLY ANHYDRIDE MICROSPHERES 128 6.1 Abstract 128 6.2 Introduction 129 6.3 Materials and Methods 132 6.3.1 Materials 132 6.3.2 Polymer synthesis & characterization 132 6.3.3 Ovalbumin lyophilization 133 6.3.4 W/O/W microsphere fabrication method 133 6.3.5 W/O/O microsphere fabrication method 134 6.3.6 S/O/O microsphere fabrication method 134 6.3.7 Cryogenic atomization method for microsphere fabrication 135 6.3.8 Microsphere characterization 135 6.3.9 Encapsulation efficiency 136 6.3.10 In vitro release studies 136 6.3.11 Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) 137 vi 6.3.12 Fourier transform infrared spectroscopy (FTIR) 138 6.4 Results and Discussion 139 6.4.1 Ovalbumin atomization 139 6.4.2 Microsphere characterization 139 6.4.3 Encapsulation efficiency 144 6.4.4 In vitro release of ovalbumin 145 6.4.5 SDS-PAGE analysis 147 6.4.6 FTIR analysis 148 6.5 Conclusions 150 6.6 Acknowledgements 151 6.7 References 151 CHAPTER 7 UTEROCALIN-LOADED POLYANHYDRIDE MICROSPHERES EXPEDITE CELL MIGRATION FOR WOUND HEALING APPLICATIONS 154 7.1 Abstract 154 7.2 Introduction 155 7.3 Materials and Methods 157 7.3.1 Materials 157 7.3.2 Polymer synthesis & characterization 158 7.3.3 Protein purification 158 7.3.4 Protein lyophilization 160 7.3.5 Microsphere fabrication 160 7.3.6 Microsphere characterization 161 7.3.7 Sodium dodecyl sulfate gel electrophoresis (SDS- PAGE) 162 7.3.8 In vitro release 162 7.3.9 Incubation of microspheres for cell migration assay 163 7.3.10 Cell migration assay 164 7.3.11 Data analysis 166 7.4 Results 166 7.4.1 Uterocalin lyophilization 166 7.4.2 Microsphere characterization 167 7.4.3 SDS-PAGE analysis 168 7.4.4 In vitro release kinetics 170 7.4.5 Cell migration assay 171 7.5 Conclusions 173 7.6 Acknowledgments 175 7.7 References 176 CHAPTER 8 CONCLUSIONS AND FUTURE DIRECTIONS 178 8.1 References 183 vii ACKNOWLEDGMENTS Before reading my dissertation, I would like to acknowledge the faculty, staff, and students who helped make my time as a graduate student a little easier. I would first like to thank my graduate advisors Balaji Narasimhan and Marit Nilsen-Hamilton for the guidance they gave me and for the different perspectives that they provided. I would also like to thank the members of Dr. Narasimhan and Dr. Nilsen-Hamilton's research groups. In particular I owe much thanks to Dr. Matt Kipper and Lee Bendickson for the invaluable assistance that they gave me. I also cannot forget to thank all of the undergraduate students who have helped me (Elizabeth Schmerr, Quentin Leigh, Angie Clark, Jennifer Graham, Katherine Pfeiffer, Martin Gran, Lindsey Boland, Michelle Sukup, and Laura Miller) by synthesizing polymers, doing electrophoresis, or washing dishes your time was much appreciated. As you read the following chapters please note the numerous co-authors whose expertise added more depth to my project. Without their help this work would not have been possible. I also want to acknowledge Warren Straszheim and Jerry Amenson in the MARL laboratories at Iowa State University for their assistance with the scanning electron microscope. And I would like to thank Dr. Robert Doyle in the Carver Laboratory at Iowa State University for the assistance he offered me with my confocal and optical microscopy experiments. I would like to thank the members of my POS committee (Dr.
Load more

Recommended publications
  • Polyanhydride-Based Nanomedicine Platform for Combating Neurodegeneration Benjamin W
    Polyanhydride-based Nanomedicine Platform for Combating Neurodegeneration Benjamin W. Schlichtmann1, Shivani Ghaisas2, Vellareddy Anantharam2, Anumantha Kanthasamy2, Surya Mallapragada1, and Balaji Narasimhan1. 1Chemical & Biological Engineering and 2Biomedical Sciences, Iowa State University, Ames, IA 50011 Statement of Purpose: Treatment for exposure to (blue arrows). The average NP size of NF-NPs and CPTP- chemical toxins such as pesticides has resulted in an NPs was 397 ± 143 nm and 287 ± 99 nm, respectively, estimated annual cost of $200 million in recent years [1]. which is in agreement with previous work [4]. Surface Exposure to these toxins leads to neurodegeneration, zeta potential measurements demonstrated a negligible including development of chronic conditions such as effect of functionalization on surface charge, as expected. Parkinson’s and Alzheimer’s diseases. Drugs that combat Non-functionalized neurodegeneration, such as antioxidants, must effectively pass through the blood-brain barrier (BBB), and then target diseased neurons and their mitochondria. The efficacy of drugs administered alone to do so is significantly hindered by drug metabolism and limited CPTP bulk-functionalized localization. Polyanhydride nanoparticles (NPs) have several favorable characteristics for drug delivery to overcome these issues and improve treatment of neurodegeneration [2]. Localization can be further Pre-CPTP (control) improved using targeting ligands by directly functionalizing the polyanhydrides to ensure that the ligand persists throughout NP degradation. The lipophilic cationic ligand triphenylphosphonium (TPP) has recently shown enhanced targeting of the BBB and mitochondria Figure 1. FTIR of functionalized and non-functionalized [3]. In this work, a derivative of TPP, (3-carboxypropyl) polymer showing functionalization by the relative triphenylphosphonium (CPTP) was used to functionalize decrease (red) of non-functionalized polymer end-group polyanhydrides.
    [Show full text]
  • Acetic Anhydride Cyclodehydration Agent, 220 Acetoamides Synthesis
    INDEX Acetic anhydride Acrylic acid cyclodehydration agent, 220 biomer polymer activity, 309 Acetoamides Acrylonitrile synthesis, 277 purification, 409 Acetone sodium naphthalene polymerized, polyanhydride solvent, 193 410 Acetone cyanohydrin N-Acryloyl-a-aminoisobutyrate azlactone raw material, 225 synthesis, 225 a-Acetoxypropionic acid N-Acryloylmethylalanine ring closure to lactone, 443 ethyl chloroformate reaction, 206 Acetyl acetone, 464 Activation energy manganese decarbonyl coordi­ styrene anoinic dispersion nating agent, 300 polymerization, 392, 296 Acetyl chloride a-Acylamino-a-aminopropionic acid coumalic acid reaction, 61 conversion to a-lactone, 445 polystyrene living particle N-Acylurea, 307 reaction, 400 Adhesives, hot melt Acetylene carbonyls synthesis concept, 480 amine condensations, 276 Adipic acid, 192 Acrolein Adipic acid, metal salts acetal formation, 62, 74 phosphorus acid chloride Acrylamide condensation, 195 hydrophilic grafts on polymers, Aldehydes 293 anionic polymerization, 322 functionalized oligomers, 205, Alkenes 211, 215-217 triazolinedione ene reaction, 2 ORTEP plots, 212 Alkenyl azalactone purification, 308 amine oligomer reaction, 208, telechelic oligomers, 203 210, 211 Acrylamides, bis type 2-Alkenyl-2-oxazoline-5-ones amine reaction, 215 amine reactions, 205, 211 Acrylamides, telechelic Alkoxides characterization, 208 catalyst for oxazolidone synthesis from azlactones, formation, 252 219, 221 Alkoxides, polymeric Acrylates, alkyl ethylene oxide polymerization, anionic polymerization, 327 330 alkali
    [Show full text]
  • Introduction of Polymer Nanoparticles for Nanoparticles Generally Have the Following Properties [13-17]: Drug Delivery Applications
    Wang H and Rempel GL, J Nanotechnol Nanomed Nanobiotechnol 2015, 2: 008 DOI: 10.24966/NTMB-2044/100008 HSOA Journal of Nanotechnology: Nanomedicine & Nanobiotechnology Review Article human beings. Until now, the main techniques to fight cancer are Introduction of Polymer non-targeted chemotherapy and radiation. However, it is unavoidable to prevent systematic side effects to the human body due to Nanoparticles for Drug non-specific uptake by normal, healthy, noncancerous tissues because of the instinctive properties of the chemotherapy chemical agent Delivery Applications featured with high toxicity and a lack of tumor specificity. Hui Wang and Garry L Rempel* In order to overcome the limitations of free chemotherapeutic agents, targeting of tumors with nanoparticulate drug carriers has Department of Chemical Engineering, Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, Ontario received much attention and expectance [1,2]. Nanocarriers can offer N2L 3G1, Canada many avenues over free drugs for the following aspects [3]:(1) protect the drug from premature degradation; (2) prevent drugs from prematurely interacting with the biological environment; (3) enhance absorption of the drugs into a selected tissue (for example, solid tumour); (4) control the pharmacokinetic and drug distribution profile; and (5) improve intracellular penetration. Abstract Let us first recall the important moments in the short but rapid The past half of a century has seen increasing attention focused development history of drug delivery systems (Figure 1). Lipid is on the development of polymer nanoparticle based drug delivery the first nanotechnology based drug delivery system, which was systems as being capable of improving the efficacy and obviating discovered in the 1960s and later known as liposomes [4].
    [Show full text]
  • Surface Modification of Polyanhydride Microspheres
    COMMUNICATIONS Surface Modification of Polyanhydride Microspheres JINMING GAO†,‡,LAURA NIKLASON†,‡,XIAO-MEI ZHAO§, AND ROBERT LANGER*,† Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, Department of Anesthesia, Massachusetts General Hospital, Boston, Massachusetts 02114, and Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138 Received July 25, 1997. Final revised manuscript received October 31, 1997. Accepted for publication November 6, 1997. Polyanhydrides are emerging as a new class of biode- gradable polymers for drug delivery.1-3 The degradation of polyanhydride delivery systems is largely through surface erosion, potentially leading to zero-order release Scheme 1sSurface modification of pSA microspheres with ligands con- of encapsulated drugs.4,5 Recently, the Food and Drug taining amino groups via amide formation. Administration has approved the use of the polyanhydride poly[sebacic acid-co-1,3-bis(p-carboxyphenoxy)propane] to The microspheres were collected after centrifugation (10 000 deliver drugs for treatment of brain cancer.6 This is one rpm for 10 min) at 4 °C, washed with 2 M aqueous NaCl, of the few examples where an implantable synthetic distilled water (twice), and ethanol, and dried in vacuo. The degradable polymer has been approved for human use. The surface density of argininamide was analyzed by X-ray use of polyanhydride polymers in oral delivery of insulin photoelectron spectroscopy (XPS), and its bulk concentra- and genes further broadens the scope of their applications tion was analyzed by 1H NMR (400 MHz) of microspheres in drug delivery.7 Despite numerous studies on polyan- dissolved in CDCl3. The size of the microspheres was hydrides, the compositions thus far developed do not have measured by a Coulter Multisizer (Coulter Electronic the capability to target specific organs or cell types.
    [Show full text]
  • Design and Evaluation of Single-Dose Polyanhydride Nanovaccines Against Bacterial Respiratory Pathogens Danielle Ann Wagner Iowa State University
    Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2019 Design and evaluation of single-dose polyanhydride nanovaccines against bacterial respiratory pathogens Danielle Ann Wagner Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Allergy and Immunology Commons, Immunology and Infectious Disease Commons, and the Medical Immunology Commons Recommended Citation Wagner, Danielle Ann, "Design and evaluation of single-dose polyanhydride nanovaccines against bacterial respiratory pathogens" (2019). Graduate Theses and Dissertations. 17116. https://lib.dr.iastate.edu/etd/17116 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Design and evaluation of single-dose polyanhydride nanovaccines against bacterial respiratory pathogens by Danielle Ann Wagner A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Immunobiology Program of Study Committee: Michael Wannemuehler, Co-major Professor Balaji Narasimhan, Co-major Professor Bryan Bellaire Marian Kohut Randy Sacco The student author, whose presentation of the scholarship herein was approved by the program of study committee, is solely responsible for the content of this dissertation. The Graduate College will ensure this dissertation is globally accessible and will not permit alterations after a degree is conferred. Iowa State University Ames, Iowa 2019 Copyright © Danielle Wagner, 2019. All rights reserved.
    [Show full text]
  • Polyanhydride Nanoparticles Induce Low Inflammatory Dendritic Cell Activation Resulting in CD8+ T Cell Memory and Delayed Tumor Progression
    University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Faculty Publications in Food Science and Technology Food Science and Technology Department 2020 Polyanhydride Nanoparticles Induce Low Inflammatory Dendritic Cell Activation Resulting in CD8+ T Cell Memory and Delayed Tumor Progression Ross Darling Sujata Senapati John Christiansen Luman Liu Amanda E. Ramer-Tati See next page for additional authors Follow this and additional works at: https://digitalcommons.unl.edu/foodsciefacpub Part of the Food Science Commons This Article is brought to you for free and open access by the Food Science and Technology Department at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Faculty Publications in Food Science and Technology by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. Authors Ross Darling, Sujata Senapati, John Christiansen, Luman Liu, Amanda E. Ramer-Tati, Balaji Narasimhan, and Michael Wannemuehler International Journal of Nanomedicine Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Polyanhydride Nanoparticles Induce Low Inflammatory Dendritic Cell Activation Resulting in CD8+ T Cell Memory and Delayed Tumor Progression This article was published in the following Dove Press journal: International Journal of Nanomedicine Ross Darling 1 Introduction: Adjuvants and immunotherapies designed to activate adaptive immunity to Sujata Senapati 2 eliminate infectious disease and tumors have become an area of interest aimed at providing John Christiansen1 a safe and effective strategy to prevent or eliminate disease. Existing approaches would fi fi Luman Liu2 bene t from the development of immunization regimens capable of inducing ef cacious cell- + fi Amanda E Ramer-Tait 3 mediated immunity directed toward CD8 T cell-speci c antigens.
    [Show full text]
  • Grafting with RAFT—Graft Strategies to Prepare Hybrid Nanocarriers with Core-Shell Architecture
    polymers Article Grafting with RAFT—gRAFT Strategies to Prepare Hybrid Nanocarriers with Core-shell Architecture José L. M. Gonçalves , Edgar J. Castanheira ,Sérgio P. C. Alves , Carlos Baleizão * and José Paulo Farinha * Centro de Química Estrutural and Department of Chemical Engineering, Instituto Superior Técnico, University of Lisbon, 1049-001 Lisboa, Portugal; [email protected] (J.L.M.G.); [email protected] (E.J.C.); [email protected] (S.P.C.A.) * Correspondence: [email protected] (C.B.); [email protected] (J.P.F.) Received: 10 July 2020; Accepted: 17 September 2020; Published: 23 September 2020 Abstract: Stimuli-responsive polymer materials are used in smart nanocarriers to provide the stimuli-actuated mechanical and chemical changes that modulate cargo delivery. To take full advantage of the potential of stimuli-responsive polymers for controlled delivery applications, these have been grafted to the surface of mesoporous silica particles (MSNs), which are mechanically robust, have very large surface areas and available pore volumes, uniform and tunable pore sizes and a large diversity of surface functionalization options. Here, we explore the impact of different RAFT-based grafting strategies on the amount of a pH-responsive polymer incorporated in the shell of MSNs. Using a “grafting to” (gRAFT-to) approach we studied the effect of polymer chain size on the amount of polymer in the shell. This was compared with the results obtained with a “grafting from” (gRAFT-from) approach, which yield slightly better polymer incorporation values. These two traditional grafting methods yield relatively limited amounts of polymer incorporation, due to steric hindrance between free chains in “grafting to” and to termination reactions between growing chains in “grafting from.” To increase the amount of polymer in the nanocarrier shell, we developed two strategies to improve the “grafting from” process.
    [Show full text]
  • Novel Biodegradable Polyanhydrides Based on Betulin Disuccinate and Sebacic Acid for Medical Purpose †
    Proceedings Novel Biodegradable Polyanhydrides Based on Betulin Disuccinate and Sebacic Acid for Medical Purpose † Daria Niewolik 1,*, Barbara Bednarczyk-Cwynar 2, Piotr Ruszkowski 3 and Katarzyna Jaszcz 1 1 Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, M. Strzody 9, 44-100 Gliwice, Poland; [email protected] 2 Department of Organic Chemistry, Poznan University of Medical Science, Grunwaldzka 6, 60-780 Poznan, Poland; [email protected] 3 Department of Pharmacology, Poznan University of Medical Science, Rokietnicka 5a, 60-806 Poznan, Poland; [email protected] * Correspondence: [email protected] † Presented at the 1st International Electronic Conference on Applied Sciences, 10–30 November 2020; Available online: https://asec2020.sciforum.net/. Published: 9 November 2020 Abstract: The paper describes synthesis and the characterization of novel biodegradable betulin- based polyanhydrides, exhibiting anti-cancer activity. Polyanhydrides were obtained by a melt polycondensation of a disuccinate betulin (3,28-di-O-succinyl betulin) and sebacic acid with the use of acetic anhydride. Mentioned polyanhydrides were then thoroughly characterized by 1H NMR and 13C NMR, size exclusion chromatography, differential scanning calorimetry and FT-IR spectroscopy. The content of sebacic acid in obtained copolymers was from 20 to 80 wt%. The use of sebacic acid as a comonomer increases the crystallinity of polymers. Under physiological conditions copolymers undergo hydrolytic degradation to betulin disuccinate, whose biological activity is known and confirmed and to sebacic acid approved by the US Food and Drug Administration (FDA) for use in drug delivery systems. Polyanhydrides were also tested for cytostatic activity against a wide range of cancer cell lines (HeLa, A-549, U-87MG, KB and HepG2), proving its efficiency in inhibiting the growth of selected cell lines.
    [Show full text]
  • The Institute of Paper Chemistry
    The Institute of Paper Chemistry Appleton, Wisconsin Doctor's Dissertation Anhydride Derivatives of Trimellitic Anhydride Richard G. Barker June, 1963 ANHYDRIDE DERIVATIVES OF TRIMELLITIC ANHYDRIDE A thesis submitted by Richard G. Barker B.A. 1958, Hamilton College M.S. 1960, Lawrence College in partial fulfillment of the requirements of The Institute of Paper Chemistry for the degree of Doctor of Philosophy from Lawrence College Appleton, Wisconsin June, 1963 TABLE OF CONTENTS Page GENERAL SUMMARY 1 INTRODUCTION 3 Trimellitic Anhydride 3 Unsymmetrical Anhydrides 5 Preparation of Unsymmetrical Anhydrides 6 Disproportionation of Unsymmetrical Anhydrides 8 Hydrolysis of Unsymmetrical Anhydrides 11 Reactions of Unsymmetrical Anhydrides 12 Previous Investigations on the Esterification of Unsymmetrical Anhydrides 12 The Mechanism of Acylation by Unsymmetrical Anhydrides 13 Trifluoroacetic Anhydride as an Esterification Promoter 16 PRESENTATION AND APPROACH TO THE PROBLEM 22 PROCEDURES AND RESULTS 24 The Trimellitic Anhydride-Trifluoroacetic Anhydride Reaction System 24 Preparation of the Unsymmetrical Anhydride of TMA and TFAA 24 Purification and Analysis of the Unsymmetrical Anhydride of TMA and TFAA 25 Disproportionation of the Unsymmetrical Anhydride of TMA and TFAA 27 Hydrolysis of the Unsymmetrical Anhydride of TMA and TFAA 28 Esterification of the Unsymmetrical Anhydride of TMA and TFAA 29 The Unsymmetrical Anhydride of Trimellitic and Acetic Anhydrides 31 Preparation of the Unsymmetrical Anhydride 31 Purification and Analysis of the
    [Show full text]
  • A Study on Xylitol Based Copolyester for in Vitro Degradation Applications
    International Journal of ChemTech Research CODEN (USA): IJCRGG, ISSN: 0974-4290, ISSN(Online):2455-9555 Vol.11 No.09, pp 69-76, 2018 A Study on Xylitol Based Copolyester for In vitro Degradation Applications Deepa K and Jaisankar V* PG and Research Department of Chemistry, Presidency College, Chennai –600005, Tamil Nadu, India. Abstract : In this paper, we report on the synthesis and characterization of copolyesters from xylitol, lactic acid and sebacic acid through a catalyst free melt polycondensation method. The synthesized aliphatic random copolyesters were characterized by means of fourier transform infrared (FTIR), viscosity measurements, 1H and 13C nuclear magnetic resonance, differential scanning calorimetry (DSC) and gel permeation chromatography (GPC) studies. The effect of copolymer composition on the physical and thermal properties as well as degradation test was investigated. The mechanical properties evaluated for the polyester films in the tensile mode shows that the polymer has characteristics of elastomers and stiff thermosets. The degradation test was carried out in alkali medium. The phase behaviour of the polymers was studied by differential scanning calorimetry. As all the monomers used in these materials are component of other biomaterials, the synthesised xylitol based triblock copolyesters could be excellent candidates as future biomaterials. Keywords : Catalyst free melt polycondensation, spectral and degradation studies. Introduction Recent developments in the synthetic biodegradable polymers have substantial
    [Show full text]
  • POLYANHYDRIDE BLENDS AS DRUG DELIVERY MATRICES to CONTROL BIOFILMS, BONE, and NERVE REGENERATION by MICHELLE LINETTE JOHNSON
    POLYANHYDRIDE BLENDS AS DRUG DELIVERY MATRICES TO CONTROL BIOFILMS, BONE, AND NERVE REGENERATION by MICHELLE LINETTE JOHNSON A Dissertation submitted to the Graduate School-New Brunswick Rutgers, The State University of New Jersey in partial fulfillment of the requirements for the degree of Doctor of Philosophy Graduate Program in Chemistry and Chemical Biology written under the direction of Professor Kathryn E. Uhrich and approved by ________________________ ________________________ ________________________ ________________________ New Brunswick, New Jersey May, 2008 ABSTRACT OF THE DISSERTATION Polyanhydride Blends for Drug Delivery, Biofilm Prevention, and Tissue Engineering By MICHELLE LINETTE JOHNSON Dissertation Director: Kathryn E. Uhrich Biodegradable polyanhydrides were fabricated into disks, coatings, microspheres, and tubes for controlled drug delivery as well as enhanced thermal and mechanical properties. The polymer systems were evaluated as potential treatments for periodontal disease, orthopedic injuries, nerve regeneration, and biofilm formation. The polymers contained the non-steroidal anti-inflammatory drug (NSAID), salicylic acid and the antibiotic, ampicillin, in the polymer backbone, which are subsequently released as the polymers degrade. Significantly, the polymers can be fabricated into these different geometries that would not be possible with the drug molecules alone. This dissertation characterizes the in vitro degradation of the polyanhydrides specifically for the multiple applications. Polymer degradation was monitored by high pressure liquid chromatography (HPLC) for final degradation products. The effect of physically admixing additional drugs into the polymer matrix was studied as well, where the admixed drugs were delineated from the chemically incorporated drugs by HPLC. Accelerated in vitro degradation rates were developed using highly basic media. ii Mechanical and thermal properties were examined for potential orthopedic and nerve applications.
    [Show full text]
  • Therapeutic Polyanhydride Compounds for Drug Delivery
    (19) TZZ ¥¥_ T (11) EP 2 233 155 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 29.09.2010 Bulletin 2010/39 A61K 47/48 (2006.01) A61P 29/00 (2006.01) (21) Application number: 10006142.3 (22) Date of filing: 27.07.2001 (84) Designated Contracting States: (72) Inventor: Uhrich, Kathryn, E. AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Plainfield, NJ 07060 (US) MC NL PT SE TR Designated Extension States: (74) Representative: Grünecker, Kinkeldey, AL LT LV MK RO SI Stockmair & Schwanhäusser Anwaltssozietät (30) Priority: 27.07.2000 US 627215 Leopoldstrasse 4 80802 München (DE) (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: Remarks: 01956010.1 / 1 307 233 This application was filed on 14-06-2010 as a divisional application to the application mentioned (71) Applicant: Rutgers, The State University of New under INID code 62. Jersey New Brunswick, NJ 08903 (US) (54) Therapeutic polyanhydride compounds for drug delivery (57) A polymer comprising a backbone, wherein the backbone comprises an anhydride linkage, and wherein the backbone comprises one or more groups that will yield diflunisal upon hydrolysis of the polymer. EP 2 233 155 A2 Printed by Jouve, 75001 PARIS (FR) EP 2 233 155 A2 Description Priority of Invention 5 [0001] This application is a Continuation -in-Part of U.S. Patent Application Number 09/627,215, filed 27 July 2000), which is incorporated herein by reference. Background of the Invention 10 [0002] Polymers comprising aromatic or aliphatic anhydrides have been studied extensively over the years for a variety of uses.
    [Show full text]