Chemical Aspects of Photodynamic Therapy ADVANCED CHEMISTRY TEXTS A series edited by DAVID PHILLIPS, Imperial College, London, UK, PAUL O’BRIEN, Imperial College, London, £//T and STAN ROBERTS, University of Liverpool, UK Volume 1 Chemical Aspects of Photodynamic Therapy Raymond Bonnett This book is part of a series. The publisher will accept continuation orders which may be cancelled at any time and which provide for automatic billing and shipping of each title in the series upon publication. Please write for details. Chemical Aspects of Photodynamic Therapy Raymond Bonnett Queen Mary and Westfield College University of London, UK Gordon and Breach Science Publishers Australia • Canada • France • Germany • India • Japan Luxembourg • Malaysia • The Netherlands • Russia Singapore • Switzerland Copyright © 2000 Raymond Bonnett. The right of Raymond Bonnett to be identified as the author of this work has been asserted by him in accordance with the Copyrights, Designs and Patents Act 1988. Published by license under the Cordon and Breach Science Publishers imprint. All rights reserved. No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying and recording, or by any information storage or retrieval system, without permission in writing from the publisher. Printed in Singapore. Amsteldijk 166 1st Floor 1079 LH Amsterdam The Netherlands British Library Cataloguing in Publication Data Bonnett, Raymond Chemical aspects of photodynamic therapy. - (Advanced chemistry texts ; v. 1) 1. - Photochemotherapy I. Title 615.8'31 ISBN: 90-5699-248-1 ISSN: 1029-3654 For Patrick, Anna and Louis Contents Preface xiii Acronyms xv Chapter 1 Introduction 1 1.1 Definition of Area of Study 1 1.2 Historical Aspects 3 1.2.1 Vitamin D and Rickets 4 1.2.2 Phototherapy of Psoriasis 6 1.2.3 Neonatal Hyperbilirubinemia 7 1.2.4 Cancer 9 Bibliography 13 Chapter 2 Physical Matters 15 2.1 Light 15 2.2 Light Sources 19 2.2.1 Sunlight 19 2.2.2 Incandescent Lamps 19 2.2.3 Arc Lamps 19 2.2.4 Light-emitting Diodes 20 2.2.5 Lasers 21 2.3 Light Absorption 23 2.3.1 The Beer-Lambert Law 23 2.3.2 Excitation 24 2.3.2.1 Multiplicity 24 2.3.2.2 Probability 25 2.4 Emission 27 2.5 Jablonski Diagram 28 2.6 Quantum Efficiency 30 2.7 Intermolecular Electronic Excitation Transfer 31 2.8 Singlet Oxygen Quantum Yields 32 Bibliography 37 Chapter 3 Singlet Oxygen 39 3.1 General 39 3.2 Generation of Singlet Oxygen 42 3.2.1 Chemical Methods 42 3.2.2 Physical Methods 42 CHEMICAL ASPECTS OF PHOTODYNAMIC THERAPY CONTENTS 3.3 Chemical Reactions 47 3.3.1 Alkenes — the "ene" Reaction 47 3.3.2 Electron-rich Alkenes 49 3.3.3 Conjugated Dienes — Diels-Alder Addition 52 3.3.4 Miscellaneous Reactions 54 Bibliography 56 Chapter 4 Photodynamic Action 57 4.1 Definition 57 4.2 Discovery and Development 57 4.3 Photodynamic Agents — Structural Types 64 4.3.1 General Considerations 64 4.3.2 Structural Types 64 4.4 Mechanism of Photodynamic Action 70 4.4.1 The Type I Mechanism — Electron Transfer 70 4.4.2 The Type II Mechanism — Energy Transfer 74 4.4.3 Distinguishing between Type I and Type II Photooxygenation Processes 76 4.4.3.1 Tests for radical intermediates (Type I mechanism) 80 4.4.3.2 Tests for singlet oxygen (Type II mechanism) 81 4.4.4 The Overall Mechanistic Picture 83 Bibliography 87 Chapter 5 Some Other Examples of Photomedicine 89 5.1 Introduction 89 5.2 Sunscreens 89 5.2.1 Sunlight and the Skin 89 5.2.2 Artificial Sunscreens 92 5.3 Skin Carcinogenesis 93 5.4 Phototherapy of Rickets (Osteomalacia) 94 5.5 Psoriasis 100 5.5.1 Photosensitisers for PUVA 100 5.5.2 Mechanism 102 5.6 Phototherapy of Neonatal Hyperbilirubinemia 103 5.6.1 Photofragmentation 104 5.6.2 Photoisomerisation / Photosolubilisation 107 5.6.2.1 Photochemical configurational isomerisation (Photobilirubins I) 107 5.6.2.2 Photocyclisation (Photobilirubins If lumirubins) 109 Bibliography 113 CHEMICAL ASPECTS OF PHOTODYNAMIC THERAPY CONTENTS Chapter 6 The Chemistry of Haematoporphyrin Derivative (HpD) 115 6.1 Introduction 115 6.2 Chemistry of HpD Stage I 117 6.3 Chemistry of HpD Stage II 118 6.4 Clinical Development 126 Bibliography 128 Chapter 7 Second Generation Photosensitisers 129 7.1 First Generation Photosensitisers 129 7.1.1 Advantages 129 7.1.2 Disadvantages 129 7.2 Design Criteria for Second GenerationP hotosensitisers 130 7.2.1 Dark Toxicity 130 7.2.2 Composition 130 7.2.3 Synthesis 130 7.2.4 Solution Behaviour 130 7.2.4.1 Tetraphenylporphyrin sulphonic acids 131 7.2.4.2 Sulphonated metallophthalocyanines 132 7.2.4.3 3-(1 -Alkyloxyethyl)-3-devinylpyropheo- phorbide a 135 7.2.4.4 Spacing of hydrophilic substituents on the hydrophobic framework 136 7.2.5 Delivery Systems 137 7.2.6 Photophysical Properties 143 7.2.7 Red Absorption 144 Bibliography 147 Chapter 8 Porphyrin Photosensitisers 149 8.1 Introduction 149 8.2 Porphyrin Sources 149 8.3 Porphyrins Derived from Haemoglobin 156 8.4 Synthetic Porphyrins 159 8.4.1 General Approaches 159 8.4.2 Specific Examples 166 8.5 Endogenous Porphyrin: 8-ALA as a Pro-drug 173 Bibliography 174 Chapter 9 Chlorins and Bacteriochlorins 177 9.1 Structural Definition 177 9.2 Absorption Spectra 178 9.3 Naturally Derived Chlorins and Bacteriochlorins 183 9.4 Chlorins Derived from Protohaem 186 9.4.1 From Deuteroporphyrin (88) 187 9.4.2 From Protoporphyrin (61) 188 9.4.3 From Photoprotoporphyrin (132) 189 CHEMICAL ASPECTS OF PHOTODYNAMIC THERAPY