Photodynamic therapy: current status and future directions

Abstract

Photodynamic therapy (PDT) is a minimally invasive therapeutic modality used for the management of a variety of cancers and benign diseases. The destruction of unwanted cells and tissues in PDT is achieved by the use of visible or near-infrared radiation to activate a light-absorbing compound (a photosensitizer, PS), which, in the presence of molecular oxygen, leads to the production of singlet oxygen and other reactive oxygen species. These cytotoxic species damage and kill target cells. The development of new PSs with properties optimized for PDT applications is crucial for the improvement of the therapeutic outcome. This review outlines the principles of PDT and discusses the relationship between the structure and physicochemical properties of a PS, its cellular uptake and subcellular localization, and its effect on PDT outcome and efficacy.

Fig. 1

Photoexcitation and participation of a PS in type I and type II processes.

Fig. 2

Schematic representation of the electron configuration and energetic levels of ground and excited molecular oxygen states.

Fig. 3

Photo-induced cross-linking of erythrocyte membrane proteins. Hemoglobin-free erythrocyte membranes were illuminated for 30 min in the presence of Zn(II) meso-tetrakis(N-butylpyiridinium-2-yl)porphyrin (ZnTnBu-2-PyP⁴⁺). Proteins were separated by sodium dodecyl sulfate gel electrophoresis and stained with Coomassie brilliant blue. Lanes: 1 - molecular weight markers; 2 - untreated erythrocyte membranes; 3 - dark control (incubated with 32 µM ZnTnBu-2-PyP⁴⁺ in the dark); 4-9 - erythrocyte membranes illuminated in the presence of different concentrations of ZnTnBu-2-PyP⁴⁺ (lanes: 4-32 µM; 5-16 µM; 6-8 µM; 7-4 µM; 8-2 µM; 9-1 µM). Arrows point to protein aggregates.

Fig. 4

Main groups of PSs used in PDT.

Fig. 5

Structures of anionic and cationic PSs. a Hematoporphyrin derivative (monomer). b Zn(II) meso-tetrakis(4-carboxyphenyl)porphyrin (ZnTBAP^4-). c Zn(II) meso-tetrakis(N-methylpyridinium-4-yl)porphyrin (ZnTM-4-PyP⁴⁺).

Fig. 6

The optical (phototherapeutic) window, where the absorption and scattering of light by tissues is minimal. For simplicity, only absorption by hemoglobin and water is presented in the logarithmic scale [modified from [102]].

Fig. 7

Uptake of isomeric ZnPs by human colon adenocarcinoma cells (LS174T). After 24 h of incubation with 20 μM ZnPs the cells were washed and lysed. PSs were determined in cell-free extracts by estimating the area under the florescence emission peaks. Mean ± SE is presented (n = 3). ZnTBAP = Zn(II) meso-tetrakis (4-carboxyphenyl)porphyrin; ZnTM-2-PyP = Zn(II) meso-tetrakis(N-methylpyridinium-2-yl)porphyrin; ZnTE-2-PyP = Zn(II) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; ZnTnBu-2- PyP = Zn(II) meso-tetrakis(N-butylpyiridinium-2-yl)porphyrin; ZnTnHex-2-PyP = Zn(II) meso-tetrakis(N-hexylpyiridinium-2-yl)porphyrin.

Fig. 8

Structures of cationic Zn(II) N-alkylpyridylporphyrins with progressively increasing lipophilicity. For simplicity, only ortho-isomers are shown. a Zn(II) meso-tetrakis(N-methylpyridinium-2-yl)porphyrin (ZnTM-2-PyP⁴⁺). b Zn(II) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (ZnTE-2-PyP⁴⁺). c Zn(II) meso-tetrakis(N- butylpyiridinium-2-yl)porphyrin (ZnTnBu-2-PyP⁴⁺). d Zn(II) meso-tetrakis(N-hexylpyiridinium-2-yl)porphyrin (ZnTnHex-2-PyP⁴⁺).

Fig. 9

Isomers of the hydrophilic methyl and the amphiphilic hexyl Zn-porphyrin derivatives. aOrtho, Zn(II) meso-tetrakis(N-methylpyridinium-2-yl)porphyrin (ZnTM-2-PyP⁴⁺). bMeta, Zn(II) meso-tetrakis(N-methylpyridinium-3-yl)porphyrin (ZnTM-3-PyP⁴⁺). cPara, Zn(II) meso-tetrakis(N-methylpyridinium-4-yl)porphyrin (ZnTM-4-PyP⁴⁺). dOrtho, Zn(II) meso-tetrakis(N-hexylpyiridinium-2-yl)porphyrin (ZnTnHex-2-PyP⁴⁺). eMeta, Zn(II) meso-tetrakis(N-hexylpyiridinium-3-yl)porphyrin (ZnTnHex-3-PyP⁴⁺). fPara, Zn(II) meso tetrakis(N-hexylpyiridinium-3-yl)porphyrin (ZnTnHex-4-PyP⁴⁺).

Fig. 10

Schematic representation of the three-dimensional shapes of the ortho-, meta- and para-hexyl isomers. The porphyrin core is represented by a blue ellipse, pyridyl substituents at meso-position by yellow hexagons and aliphatic chains by dotted red lines. For simplicity, only αααα and αβαβ atropisomers of ortho-isomer are presented. a ZnTnHex-2-PyP αααα. b ZnTnHex-2-PyP αβαβ. c ZnTnHex-3-PyP. d ZnTnHex-4-PyP [modified from [111]].