Designing Photosensitizers for Photodynamic Therapy: Strategies, Challenges and Promising Developments

Abstract

Photodynamic therapy (PDT) and photodynamic antimicrobial chemotherapy (PACT) are techniques that combine the effects of visible light irradiation with subsequent biochemical events that arise from the presence of a photosensitizing drug (possessing no dark toxicity) to cause destruction of selected cells. Despite its still widespread clinical use, Photofrin(®) has several drawbacks that limit its general clinical use. Consequently, there has been extensive research into the design of improved alternative photosensitizers aimed at overcoming these drawbacks. While there are many review articles on the subject of PDT and PACT, these have focused on the photosensitizers that have been used clinically, with little emphasis placed on how the chemical aspects of the molecule can affect their efficacy as PDT agents. Indeed, many of the PDT/PACT agents used clinically may not even be the most appropriate within a given class. As such, this review aims to provide a better understanding of the factors that have been investigated, while aiming at improving the efficacy of a molecule intended to be used as a photosensitizer. Recent publications, spanning the last 5 years, concerning the design, synthesis and clinical usage of photosensitizers for application in PDT and PACT are reviewed, including 5-aminolevulinic acid, porphyrins, chlorins, bacteriochlorins, texaphyrins, phthalocyanines and porphycenes. It has been shown that there are many important considerations when designing a potential PDT/PACT agent, including the influence of added groups on the lipophilicity of the molecule, the positioning and nature of these added groups within the molecule, the presence of a central metal ion and the number of charges that the molecule possesses. The extensive ongoing research within the field has led to the identification of a number of potential lead molecules for application in PDT/PACT. The development of the second-generation photosensitizers, possessing shorter periods of photosensitization, longer activation wavelengths and greater selectivity for diseased tissue provides hope for attaining the ideal photosensitizer that may help PDT and PACT move from laboratory investigation to clinical practice.

Activatable Photosensitizers: Agents for Selective Photodynamic Therapy

“…Because of their 18 π-electron aromatic macrocyclic structures, porphyrins typically have characteristic electronic absorption spectra with characteristic Q bands in the 500-700 nm region and a Soret band around 400 nm. [6,7] With appropriate modification, the basic structure can be transformed into porphyrin derivatives or other porphyrinoids that have specific photoactivities. For example, chlorin is a reduced form of porphyrin, which is obtained by reduction of one the peripheral cross-conjugated bond.…”

Platelets, photosensitizers, and PDT

“…However, other classes of compounds such as anthraquinones and phenothiazines are suitable as well [18,19]. A well studied example for a nonporphyrin OS is hypericin (4,5,7,4',5',7'-hexahydroxy-2,2'-dimethylnaphthodianthrone) [20].…”

Photodynamic Therapy for Cancer: Principles, Clinical Applications, and Nanotechnological Approaches

“…The presence of Al (III), Zn (II), Si (IV), Ru (II), and other diamagnetic metal ions with axial ligands gives hexacoordination and guarantees a satisfactory yield of singlet oxygen generation, thus decreasing the tendency to form PS self-aggregates and inducing high photodynamic effi ciency and reduced phototoxic side effects (Garland et al 2009 ).…”

“…Finally, toxicity to skin and internal organs in the absence of light (the so-called "dark" toxicity) is absent or minimal. PS currently under investigation belong to two chemical groups: the chlorins and the phthalocyanines (Pc) (Garland et al 2009 ).…”