The Dark Side: Photosensitizer Prodrugs

Abstract

Photodynamic therapy (PDT) and photodiagnosis (PD) are essential approaches in the field of biophotonics. Ideally, both modalities require the selective sensitization of the targeted disease in order to avoid undesired phenomena such as the destruction of healthy tissue, skin photosensitization, or mistaken diagnosis. To a large extent, the occurrence of these incidents can be attributed to "background" accumulation in non-target tissue. Therefore, an ideal photoactive compound should be optically silent in the absence of disease, but bright in its presence. Such requirements can be fulfilled using innovative prodrug strategies targeting disease-associated alterations. Here we will summarize the elaboration, characterization, and evaluation of approaches using polymeric photosensitizer prodrugs, nanoparticles, micelles, and porphysomes. Finally, we will discuss the use of 5-aminolevulinc acid and its derivatives that are selectively transformed in neoplastic cells into photoactive protoporphyrin IX.

Keywords: 5-aminolevulinic acid; photodynamic therapy; prodrugs; quenching.

Figure 1

Photodynamic therapy (PDT) diagram. The therapy starts with photosensitizer (PS) administration. The drug is accumulated in the target tissue, and only when irradiated with light does leads to cell death.

Figure 2

Improving the signal-to-background ratio (SBR): Upper row: Intrinsically active targeted photosensitizers (PSs) have a low SBR during administration and distribution within the body. Only during the elimination phase does the SBR become higher. Lower row: Optically silent PSs already have a high SBR during the distribution phase. Red spheres represent photoactive photosensitizers; Grey spheres represent non-active photosensitizers.

Figure 3

(A) Molecular beacon. In its initial conformation, the PS is quenched thanks to the proximity between the PS and quencher linked to a synthetic chain, which could be a peptide, DNA, or RNA. After the proper digestion or complement sequence hybridization, the PS is activated by the physical separation between the two components. (B) Regioselectively-Addressable Functionalized Templates (RAFTs). The molecular structure is based in a cyclopeptidic scaffold. We can differentiate two main domains, one functionalized with different PSs, and the second domain containing a chemical chain to increase the solubility. In its initial conformation, the molecule is quenched, until the linker encounters a specific digestion, becoming active.

Figure 4

Heme biosynthesis. 5-aminolevulinic acid (5-ALA) resulting from the condensation of succynil-CoA and glycine. It can pass through the mitochondrial membrane. Once inside the cytosol after different enzymatic reactions it is converted into coproporphyrinogen III, which in turn re-enters the inner mitochondrial membrane. Then, after two consecutive reactions it is transformed into heme. This heme group works functions as a negative feedback for the 5-ALA synthesis.