Those readers already familiar with the field of photodynamic therapy (PDT)t will consider this title somewhat presumptuous since it implies that the answer to the posed question is known. Indeed, answers to many questions regarding PDT have been found over the past decade, but a comprehensive understanding of all mechanisms involved in PDT tumor destruction has not yet emerged. This paper will attempt to deal with this complex subject by giving a sequential account of the effects occurring during PDT tissue treatment on a cellular and tissue level. Photodynamic therapy is based on the dye-sensitized photooxidation of biological matter in the target tissue (Foote, 1990). This requires the presence of a dye (sensitizer) in the tissue to be treated. Although such sensitizers can be naturally occurring constituents of cells and tissues, in the case of PDT they are introduced into the organism as the first step of treatment. In the second step, the tissuelocalized sensitizer is exposed to light of wavelength appropriate for absorption by the sensitizer. Through various photophysical pathways, also involving molecular oxygen, oxygenated products harmful to cell function arise and eventual tissue destruction results. In keeping with the chronological nature of this review, the subject matter will be divided into the

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1751-1097.1992.tb04222.x

How does photodynamic therapy work

Mechanisms in photodynamic therapy: part one—-photosensitizers, photochemistry and cellular localization

In recent years several review articles and books have been published on the use of porphyrin-based compounds in photodynamic therapy (PDT). This critical review is focused on (i) the basic concept of PDT, (ii) advantages of long-wavelength absorbing photosensitizers (PS), (iii) a brief discussion on recent advances in developing PDT agents, and (iv) the various synthetic strategies designed at the Roswell Park Cancer Institute, Buffalo, for developing highly effective long-wavelength PDT agents and their utility in constructing the conjugates with tumor-imaging and therapeutic potential (Theranostics). The clinical status of certain selected PDT agents is also summarized (205 references).

The role of porphyrin chemistry in tumor imaging and photodynamic therapy

Basic principles of photodynamic therapy

Photodynamic therapy (PDT) is an innovative and attractive modality for the treatment of small and superficial tumours. PDT, as a multimodality treatment procedure, requires both a selective photosensitizer and a powerful light source which matches the absorption spectrum of the photosensitizer. Quadra Logic's Photofrin, a purified haematoporphyrin derivative, is so far the only sensitizer approved for phase III and IV clinical trials. The major drawbacks of this product are the lack of chemical homogeneity and stability, skin phototoxicity, unfavourable physicochemical properties and low selectivity with regard to uptake and retention by tumour vs. normal cells. Second-generation photosensitizers, including the phthalocyanines, show an increased photodynamic efficiency in the treatment of animal tumours and reduced phototoxic side effects. At the time of writing of this article, there were more than half a dozen new sensitizers in or about to start clinical trials. Most available data suggest a common mechanism of action. Following excitation of photosensitizers to long-lived excited singlet and/ or triplet states, the tumour is destroyed either by reactive singlet oxygen species (type II mechanism) and/or radical products (type I mechanism) generated in an energy transfer reaction. The major biological targets of the radicals produced and of singlet oxygen are well known today. Nucleic acids, enzymes and cellular membranes are rapidly attacked and cause the release of a wide variety of pathophysiologically highly reactive products, such as prostaglandins, thromboxanes and leukotrienes. Activation of the complement system and infiltration of immunologically active blood cells into the tumorous region enhance the damaging effect of these aggressive intermediates and ultimately initiate tumour necrosis. The purpose of this review article is to summarize the up-to-date knowledge on the mechanisms responsible for the induction of tumour necrotic reactions.

Photophysical and photobiological processes in the photodynamic therapy of tumours

. We have examined transport, sites of photosensitization, and plasma protein binding by sulfonated derivatives of tetraphenylporphine in vitro and tumor localization of these products in vivo. Studies carried out in culture indicate that the mono-sulfonated porphyrin sensitized mainly at intracellular loci while drugs with 2 or 3 sulfonates caused photodamage at membrane sites. But the number and distribution of sulfonates were majors factor in both accumulation and efficiency of photodamage. The product with 2 adjacent sulfonates was the most potent photosensitizer; the presence of more or fewer sulfonate residues led to reduced uptake and sensitization. Steady-state accumulation of drugs with one, two (opposite), three or four sulfonates was rapid, while uptake of the disulfonated (on adjacent rings) porphine was slower. Products bearing one to four sulfonates localized equally well in vivo, but sites of localization varied considerably. Drugs with one sulfonate, or two sulfonates on adjacent rings partitioned into neoplastic cells, analogs with two (opposite), three or four sulfonates partitioned to tumor stroma. Plasma binding studies show that drugs with one or two (adjacent) sulfonates bound to VLDL, LDL and HDL components of plasma, while the tri and tetra-sulfonated analogs bound progressively more to albumin. These results suggest that tumor localization can occur via two pathways: one mediated by lipoprotein binding and leading to dye accumulation in neoplastic cells, another associated with albumin binding and leading to dye accumulation in stromal elements of neoplastic tissues.

Tumor localization and photosensitization by sulfonated derivatives of tetraphenylporphine

The hematoporphyrin-derived tumor-localizing preparation HPD consists of porphyrin monomers, which are‘inactive’(not tumor-localizing), and a dimer/oligomer fraction which is responsible for the localizing phenomenon. In an organic solvent system, gel-exclusion chromatography can separate HPD into fractions containing porphyrin monomers, dimers or oligomers. The relative amount of the dimer/oligomer fraction of HPD was a function of the pH of the mixture used to transform HP mono/di acetate to HPD. HPD prepared by the‘Upson’procedure contained dimer/oligomer linkages which are labile to 1 M NaOH (in 50% tetrahydrofuran), and are reduced by LiAlH4 to alcohols. These properties are characteristic of esters. But a commercial product, Photofrin II, contained approx. 50% of material refractory to both reagents described above. This behavior is characteristic of an ether linkage. These observations show that the nature of the linkage joining the porphyrin units is sensitive to conditions employed in HPD preparation. Tumor localization derives, in part, from affinity of these oligomers for plasma lipoprotein, and is associated with conformational alterations characteristic of these porphyrin-porphyrin linkages.

Chemistry of hematoporphyrin-derived photosensitizers.

A ternary-solvent HPLC method for analysis of the components of the tumor-localizing product HPD is described. This HPLC system was used to assess the utility of a new method, based on gel exclusion chromatography, for purification of hematoporphyrin.

Paul Thompson

Papers

Tumor localization and photosensitization by sulfonated derivatives of tetraphenylporphine

Chemistry of hematoporphyrin-derived photosensitizers.

PURIFICATION and ANALYSIS OF HEMATOPORPHYRIN and HEMATOPORPHYRIN DERIVATIVE BY GEL EXCLUSION and REVERSE‐PHASE CHROMATOGRAPHY