An outline of the history of PDT

J. Moan and Q. Peng

Table of Contents

1.1 Introduction 3
1.2 The 'photodynamic action' 3
1.3 Phototherapy 4
1.4 Photochemotherapy 5
1.5 The early days of photodynamic therapy 5
1.5.1 Hematoporphyrin and hematoporphyrin derivative 6
1.5.2 Other photosensitizers introduced for PDT 8
1.6 Why do some photosensitizers localize selectively in tumors? 8
1.7 The action mechanisms of PDT at the cellular level 12
1.8 The action mechanisms of PDT at the tissue level 12
1.9 Photochemical internalization 13
References 13

1.1 Introduction

Photodynamic therapy, PDT, has now reached the level of being an accepted treatment for a number of diseases, among which are several forms of cancer. Many countries have approved its use. The number of articles on PDT published in a year, both clinical and basic, seems to be steadily increasing. It has, however, been observed that many of the investigators are obviously unaware of the early work done in this field and hence, repeat many of the experiments reported earlier (before the internet and the modern database were established). Therefore, in the present historical review, the early work is weighted more heavily than the recent work that is more easily accessible to the readers.

1.2 The 'photodynamic action'

The term 'photodynamic action' ('photodynamische Wirkung') was introduced in 1904 by one of the pioneers of photobiology: Professor Hermann von Tappeiner, director of the Pharmacological Institute of the Ludwig-Maximilians University in Munich. It is not clear why he called the process 'dynamic'; it might have been to distinguish this biological phenomenon from the reactions taking place in the photographic process that had been discovered a few years earlier. Actually, von Tappeiner was not completely happy with his term, as he says in the foreword of his book Die Sensibilisierende Wirkung Fluorescierender Substanzen: 'Whether or not the name is to be used further or dropped, must be left to the discretion of my colleagues'. Also, Blum in his textbook on photosensitization expresses objections to the term: 'The choice of 'photodynamic action' is not altogether a happy one, but has advantage of priority and usage'. Feeling the need for a more correct and descriptive term we have tried to replace 'photodynamic therapy', PDT, by 'photochemotherapy', PCT without overwhelming success. There may be several reasons for this. First, PDT has the advantage of priority. Secondly, photochemotherapy has a wider definition (see later) including processes not requiring oxygen. Thirdly, PCT is an abbreviation for porphyria cutanea tarda, a disease that involves photosensitivity. However, the name 'photochemotherapy' would have paved the way for clinical applications better than the name 'photodynamic therapy' since all oncologists are familiar with chemotherapy, while 'photodynamic' may give associations to 'biodynamic' which, at the best, is regarded as a quasi-scientific term. According to the original definition, as well as to Blum's later recommendation, the term 'photodynamic action' should be used only for photosensitized reactions requiring oxygen. It should be remarked that oxygen is not only involved in photosensitization of Type II, but also usually involved in photosensitization of Type I. A Type I reaction is a radical or redox reaction in which a photosensitizer, excited to the triplet state (3S), interacts with a neighbouring molecule (A) by exchange of an electron or a hydrogen atom:

3S + A [right arrow] S·- + A·+ (1)

followed by

A·+ + 3O2 [right arrow] Aox (2)

S·- + O2 [right arrow] S0 + O2·- (3)

O2·- + A [right arrow] Aox, (4)

in both cases giving an oxidized biomolecule Aox.

An alternative type I reaction pathway might be:

3S + 3O2 [right arrow] S+ + O2·-, (4)

followed by

S+ + A [right arrow] S0 + A·+ (6)

Reaction (4) may follow after reaction (5), and reaction (2) may follow after reaction (6). Type I reactions may also be independent of oxygen, as is the case for the reactions of psoralens with DNA.

A photosensitized process of Type II is by definition an energy transfer process. The most common Type II process is oxidation via singlet oxygen (1O2) formation:

3S + 3O2 [right arrow] S0 + 1O2

1O2 + A [right arrow] Aox

A further description of 1O2 reactions in biological systems can be found in ref. 5.

Many authors use the expression 'photodynamic action' and 'PDT' synonymously with '1O2 reactions' and even with: 'Type II reactions', but according to the definitions given above this is not strictly correct. However, in most practical cases it may be acceptable since most PDT sensitizers act via 1O2 which is formed in an electron exchange process.

1.3 Phototherapy

Phototherapy can be defined as the use of light alone for therapeutic purposes. However, endogenous sensitizers are usually involved, so phototherapy often relies on photodynamic processes. Solar light has been used to treat a number of disorders such as vitiligo, psoriasis, rickets, skin cancer and even psychosis. Heating, as well as psychological effects mediated by vision, may have played roles in these therapies, but the effect of visible light and ultraviolet radiation on the skin was probably more important. Phototherapy has been applied by humans for 3000 years and was known by the Egyptians, the Indians and the Chinese. In Greece, Herodotes called it 'heliotherapy' and recommended it for 'restoration of health' in the 2nd century BC. In the 18th century the effect of sunlight on rickets was known. In 1815, Carvin wrote that sunlight had a curing effect on 'scrofula', rickets, rheumatism, scurvy, paralysis and muscle weakness. The Polish physician Sniadecki documented in 1822 the...