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Body Distribution of Dextrin and D-2-S and Evaluation of Their Potential As Novel Polymeric-Drug Carriers

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Body Distribution of Dextrin and D-2-S and Evaluation of Their Potential As Novel Polymeric-Drug Carriers Body distribution of dextrin and D-2-S and evaluation of their potential as novel polymeric-drug carriers b y Lisa German, BSc (Hons) A thesis submitted to the University of London in partial fulfilment of the requirements for the degree of Doctor of Philosophy Centre for Polymer Therapeutics School of Pharmacy Faculty of Medicine University of London February 2001 ProQuest Number: 10104133 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10104133 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 This Thesis is Dedicated To My Parents 11 Acknowledgements Firstly, I would like to thank my supervisor Prof R. Duncan for giving me the opportunity to work in such an interesting field and also for her patience, continuous advice and encouragement throughout my PhD. I would also like my second supervisor Dr. S. Shaunak for his continuous enthusiasm and energy that he has shown with this project throughout the past three years. I would like to thank Prof. A. Perkins and Dr. A. Murray in Nottingham, for their friendliness and support during the imaging work. If there is a next time Andrea I will bring the vallium. Thanks go to my colleagues (past and present) at the Centre of Polymer Therapeutics both in London and Cardiff. I would like to thank Alan Keddle for teaching me all of the in vivo techniques and Dr. Simon Richardson and John Latigo for helpin vitro and Dr. Navid Malik who always had time. Special thanks go to Dr. Dale Hirst whom I had the pleasure working alongside for over two years for his help, advice and for always being relaxed and level headed. Finally I would like to thank Samantha Kneller for being there at all times (good and bad) and for being a truly great friend “thanks Sam”. Proof readers of this thesis include Dr. Shaunak, Dr S. Conroy (ML Laboratories) and Ryan Tomlinson. Financial support I would like to thank the BBSRC and ML Laboratories. Most of all I would like to thank my family for their unfailing support and love throughout all that I have achieved so far in life. Without your financial and emotional support and continuing faith in me I would not be where I am today. Ill Abstract Water soluble polymers, including natural polymers (e.g. polyamino acids and polysaccharides) and synthetic polymers (e.g. polyethyleneglycol (PEG)) and N-(2- hydroxypropyl)methacrylamide (HPMA) copolymers) are finding increasing use as polymer therapeutics. Dextrin and dextrin-2-Sulphate (D-2-S) are poly(al-4 glucose) polymers that have entered into clinical use: dextrin as a peritoneal dialysis solution and D-2-S as an anti-HIV treatment. The aim of this study was (1) to quantitate the biodistribution of dextrin and D-2-S and (2) to evaluate the potential of these polymers for use as drug carriers. First, pendant groups were introduced by succinoylation (1-60 mol %). To study biodistribution (after s.c., i.v. or i.p. administration) probes were then synthesised containing either -TyrNH2 or -DTPA (~1 mol %) to allow labelling with iodine or [*“ln]indium respectively. After i.p. administration *^^I-labelled D-2-S remained longer in the peritoneal cavity (-27 times) than ^^^I-labelled dextrin (ti/2 = 2.3 h and 5 min respectively). Maximum tissue accumulation was seen in the liver, for *^^I-labelled dextrin approximately 20 % administered dose (2 min) and for *^^I-labelled D-2-S (15.3 % administered dose (24 h). Gamma camera images obtained using ‘“ in-labelled polymers were consistent with the data obtained using “^I-labelled compounds. Using the succinoylated intermediate, dextrin- and D-2-S-amphotericin B conjugates (AmpB) were prepared containing 0.01-3.50 wt % and 0.01-16.0 wt % AmpB respectively. Conjugation increased drug solubility approximately 10 fold. Preliminary in vitro testing showedIC 50 values for AmpB, dextrin- and D-2-S-AmpB (IC50 of 11.0 >50, and >50 pg/ml respectively) and haemolytic activity at 24 h (Hbso of 0.06 mg/ml, >50 pg/ml and 8.0 p-g/ml respectively). Additionally, experiments were carried out with dextrin-doxorubicin (Dox) (9 wt %, Dox-equiv) to ascertain its tumour targeting potential and antitumour activity. Whereas free Dox was inactive (T/C= 105 %) in a s.c. B16F10 tumour model dextrin- Dox had a T/C = 144 %. Dextrin and D-2-S have shown that they have potential for further development as water soluble drug carriers. IV Thesis Index Page Number Thesis Title i Dedication ii Acknowledgements iii Abstract iv Thesis Index V List of Figures xi List of Tables xvii Abbreviations xix Chapter 1: General Introduction 1 1.0 Introduction 2 1.1 Drug delivery 8 1.2 Passive tumour targeting by the EPR effect 9 13 Endocytosis 12 1.4 Polymeric drug carriers 14 1.5 Polymeric drug delivery systems 15 1.6 Polymer therapeutics 17 1.7 Polysaccharides 20 1.8 Peritoneal dialysis 25 1.9 Icodextrin (Extraneal TM, Baxter Health care Inc; 27 ML Laboratories PLC) 1.10 Icodextrin- Based products 29 1.11 D-2-S 30 1.12 Doxorubicin (Dox) and Amphotericin B (AmpB) 31 1.13 Aims of this thesis 36 Chapter 2: Materials and Methods 39 2.1. Materials 40 2.1.1 Equipment 40 2.1.2 Animals and Cells 40 2.2 Cell Culture 40 2.2.1 Cell bank 40 2.2.2 Maintainance of cell lines 4 1 2.2.3 Splitting of cells 41 2.2.4 Evaluation of cell viability/ density using Trypan blue 41 2.3 Polymers and reagents 41 2.4 Synthesis and chemical characterisation 42 2.4.1 Succinoylation of dextrin 42 2.4.2 Succinoylation of D-2-S 45 2.4.3 Modification of succinoylated dextrin and D-2-S with 45 tyrosinamide 2.4.4 Conjugation of biotin to dextrin and D-2-S 47 2.4.5 Conjugation of AmpB to succinoylated dextrin and D-2-S 50 2.4.6 Conjugation of diethylenetriaminepentaacetic acid 50 anhydride to succinoylated dextrin and D-2-S 2.5 Biological evaluation of dextrin and D-2-SIn Vitro 54 2.5.1 Assessment of cell viability using the M i l assay 54 2.5.2 Red blood cell (RBC) lysis assay 57 2.5.3 Scanning electron microscopy 57 2.6 Biological evaluation of dextrin and D-2-S and their conjugates 58 In Vivo 2.6.1 Body distribution of ^^^I-labelled dextrin and ^^^I-Iabelled 58 D-2-S 2.6.2 Radioiodination of polymers using the Chloramine T method 58 2.6.3 Determination of the purity of radioiodinated polymers by 59 paper electrophoresis 2.6.4 Body distribution of ^^^I-labelled polymers in Wistar rats 60 and S.C. tumour-bearing mice 2.6.5 Pharmacology of dextrin-Dox 61 2.7 In vivo studies using ^"in-labelled dextrin and D-2-S 61 2.7.1 Radiolabelling of dextrin and D-2-S using [^^^In]indium 61 2.7.2 Imaging of "^In-labelled dextrin and "^In-labelled D-2-S 61 2.8 Expression of data and statistical analysis 63 VI Chapter 3: Dextrin and D-2-S: Introduction of pendant groups 65 by succinoylation 3.1 Introduction 66 3.1.1 Succinoylation 68 3.1.2 Biotin 71 3.13 Tyrosinamide and DTPA 73 3.2 Materials and Methods 75 3.2.1 Optimisation of succinoylated of dextrin 75 3.2.2 Succinoylation of D-2-S 75 3.23 Conjugation of tyrosinamide to dextrin and D-2-S 76 3.2.4 Conjugation of biotin to dextrin and D-2-S 76 3.2.5 Conjugation of DTPA to succinoylated dextrin 76 and succinoylated D-2-S 3.3 Results 76 3.3.1 Succinoylation of dextrin 73 33.2 Succinoylation of D-2-S 83 3 3 3 Conjugation of dextrin-tyrosinamide and D-2-S-tyrosinamide 83 3.3.4 Conjugation of dextrin-biotin and D-2-S-biotin 83 3.3.5 Conjugation of DTPA to succinoylated dextrin and 87 succinoylated D-2-S 3.4 Discussion 87 Chapter 4: Biodistribution of dextrin and D-2-S 92 4.1 Introduction 93 4.2 Materials and Methods 96 4.2.1 ^^^I-Labelled probes: Labelling efficiency and 96 purity assessment 4.2.2 Body distribution of ^^^I-labelled dextrin and *^^I-labelled 96 D-2-S after administration s.c., i.v. and i.p. 4.23 Urine analysis using a PDIO column 97 4.2.4 In-Labelled probes: Labelling efficiency and 97 purity assessment Vll 4.2.5 Body distribution of In-labelled dextrin and In-labelled 97 D-2-S: Evaluation using gamma camera imaging and dissection analysis 4.3 Results 99 4.3.1 ^^^I-Labelled probes: Labelling efficiency and purity 99 assessment 4.3.2 Biodistribution of *^^I-labelled dextrin and ^^^I-labelled 99 D-2-S after s.c. administration 4.3.3 Biodistribution of ^^^I-labelled dextrin and ^^^I-labelled 99 D-2-S after i.v. administration 4.3.4 Biodistribution of ^^^I-labelled dextrin and D-2-S after 104 i.p.
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