New photosensitizers for photodynamic therapy

Abstract

Photodynamic therapy (PDT) was discovered more than 100 years ago, and has since become a well-studied therapy for cancer and various non-malignant diseases including infections. PDT uses photosensitizers (PSs, non-toxic dyes) that are activated by absorption of visible light to initially form the excited singlet state, followed by transition to the long-lived excited triplet state. This triplet state can undergo photochemical reactions in the presence of oxygen to form reactive oxygen species (including singlet oxygen) that can destroy cancer cells, pathogenic microbes and unwanted tissue. The dual-specificity of PDT relies on accumulation of the PS in diseased tissue and also on localized light delivery. Tetrapyrrole structures such as porphyrins, chlorins, bacteriochlorins and phthalocyanines with appropriate functionalization have been widely investigated in PDT, and several compounds have received clinical approval. Other molecular structures including the synthetic dyes classes as phenothiazinium, squaraine and BODIPY (boron-dipyrromethene), transition metal complexes, and natural products such as hypericin, riboflavin and curcumin have been investigated. Targeted PDT uses PSs conjugated to antibodies, peptides, proteins and other ligands with specific cellular receptors. Nanotechnology has made a significant contribution to PDT, giving rise to approaches such as nanoparticle delivery, fullerene-based PSs, titania photocatalysis, and the use of upconverting nanoparticles to increase light penetration into tissue. Future directions include photochemical internalization, genetically encoded protein PSs, theranostics, two-photon absorption PDT, and sonodynamic therapy using ultrasound.

Keywords: naturally occurring photosensitizers; photochemical mechanisms; photodynamic therapy; photosensitizers; synthetic dyes; tetrapyrroles.

Figure 1. Jablonski diagram

When light (hv) is absorbed by the PS, the electron moves from a non-excited low-energy singlet state into a high-energy singlet state. This excited state can lose energy by emitting a photon (fluorescence) or by internal conversion (non-radiative decay). The process known as intersystem crossing involves flipping of the spin of the high-energy electron, leading to a long-lived excited triplet state. In the presence of molecular oxygen, superoxide and hydroxyl radicals are formed in Type I reactions and singlet oxygen in a Type II reaction. These ROS can damage most types of biomolecules (amino acids, lipids, nucleic acids).

Figure 2. Cell death mechanisms

The subcellular localization of the PS in different organelles (mitochondria, lysosomes, endoplasmic reticulum, plasma membrane, etc.) plays a major role in the type of cell death mechanism that dominates, but other factors such as the overall PDT dose (PS concentration × light fluence) and DLI also play a role.

Figure 3. Structure and absorption spectra of tetrapyrrole photosensitizers

Tetrapyrrole absorption spectrum showing porphyrins, chlorins and bacteriochlorins.