Modulation of Photosensitization Processes for an Improved Targeted Photodynamic Therapy

M.      Verhille; P.      Couleaud; R.      Vanderesse; D.      Brault; M.      Barberi-Heyob; C.      Frochot

Abstract

Photodynamic therapy (PDT) is a cancer treatment modality involving the combination of light, a photosensitizer (PS) and molecular oxygen, which results in the production of cytotoxic reactive oxygen species (ROS). Singlet oxygen (1O2) is one of the most important of these ROS. Because the lifetime and diffusion of 1O2 is very limited, a controllable singlet oxygen generation with high selectivity and localization would lead to more efficient and reliable PDT. The lack of selective accumulation of the PS within tumour tissue is a major problem in PDT. Targeted PDT would offer the advantage to enhance photodynamic efficiency by directly targeting diseased cells or tissues. Many attempts have been made to either selectively deliver light to diseased tissues or increase the uptake of the photoactive compounds by the target cells. The review will survey the literature regarding the multi-level control of 1O2 production for PDT applications. The mechanisms of ROS formation are described. The different strategies leading to targeted formation of 1O2 are developed. Some active PDT agents have been based on energy transfer between PS by control of the aggregation/ disaggregation. The concept of molecular beacon based on quenching – dequenching upon protease cleavage is capable of precise control of 1O2 by responding to specific cancer-associated biomarkers.

Keywords: Reactive oxygen species, Photodynamic therapy, molecular beacon, targeting, Photodynamic therapy (PDT), photosensi-tizer (PS), reactive oxygen species (ROS), photodynamic efficiency, photoactive compounds, dermatolog-ical, ophthalmic, cardiovascular, photosensitizing, tumour neovasculature, intratumoural hypoxic state, lactic acid, lipophilic characteristic, vascular-targeting, coreceptor neuropilin-1 (NRP-1), transmembrane, photophysical, photochemical, photosensi-tizer, Vibrational relaxation, intersystem crossing (ISC), triplet state (T1), oxyradicals, higher occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), electrostatic effects, oligonucleotide, quenchers, Carotenoids, pro-vitamin A, photoprotective, dye-sensitized photooxygenations, Black Hole Quencher 3, stilbene quinones, azomethine dyes, Tumour, aggregation, porphyrin, phthalocyanine, nanoagent, glioblastoma, B16 melanoma, BT breast carci-noma cells, neovascularization, matrix metalloproteinases, MMPs, urokinase plasminogen activator (uPA), Fibroblast activation protein (FAP), chemotactic molecules, collagenases, gelatinases, stromelysins, matrilysins, tissue inhibitors of metalloproteinases (TIMPs), pharmacophore, coupled multiple chlorin e6 (Ce6), cathepsin B, xenographic tu-mour model, stem-loop structure (hairpin), pyropheophorbide (Pyro), single-walled carbon nanotubes (SWNT), R-thrombin, pyropheophorbide, carotenoid, fluorescence quencher, Asparagine, human embryonic kidney cells (HEK293), 1, 4-diazabicyclo[2, 2, 2]octane, Goeppert-Mayer, Neuropilin-1, Protoporphyrin IX, N, N-dimethyl-4-nitrosoaniline, 2, 2, 6, 6-tetraethyl-4-piperidone