Getting It Right: 3D Cell Cultures for the Assessment of Photosensitizers for Photodynamic Therapy

Abstract

Core quote "Cancer drug screening is rapidly moving towards the use of 3D cell models. The added complexity of PDT action makes this a conditio sine qua non for the screening of new photosensitizers."The quest for the treatment of malignant diseases is ongoing. Classic modalities based on chemo-and radiotherapy and surgery are now supplanted by or used in conjunction with photodynamic therapy (PDT) [1]. PDT involves on the administration of a photosensitizing dye and its accumulation in the affected tissue. After illumination of the respective body part with light (typically low intensity lasers), the photosensitizer transfers its excitation energy to triplet oxygen (the 'regular' form of oxygen in the body) to yield singlet oxygen and other reactive oxygen species (ROS). ROS are highly reactive and cytotoxic, resulting in cell death via apoptosis, necrosis, or autophagy [2]. PDT can be very effective for treating cancers and has found widespread use in dermatology -e.g., as PUVA treatment for actinic keratosis -and is now approved for treating cancer of the esophagus, non-small cell lung cancer and certain types of head & neck cancers or dysplasias. Prime examples for photosensitizers are porphyrins, chlorophyll derivatives, -aminolevulinic acid (precursor for protoporphyrin), simple dyes such as psoralen, and others [3].Yet, despite its promise, widespread clinical use of PDT is only slowly emerging; in part the result of drawbacks of existing drugs and the slow entry of new drugs into the developmental pipeline. Photosensitizers are often classified as 1 st , 2 nd and 3 rd generation drugs, with Photofrin being the classic 1 st generation PDT drug. This was followed by improvements of the photophysical and pharmacological properties in 2 nd generation molecules such as Levulan, Temoporfin or Verteporfin [2]. Currently, a significant number of similar drugs are in preclinical development. Contemporary studies on 3 rd generation agents focus on improved targeting, either via bioconjugate strategies (e.g., carbohydrate or antibody appended porphyrins), as nanoformulations or active transport systems [3,4].An optimum photosensitizer should have a high singlet oxygen quantum yield, not undergo photobleaching, be non-toxic and stable in the dark, water soluble, and be Senge, M. O.; Stafford, S. (2015): Getting it right: 3D cell cultures for the assessment of photosensitizers for photodynamic therapy.

A new valid rhabdomyosarcoma spheroid culture model for in vitro evaluation of hypericin‐based photodynamic therapy

“…For example, the part of PDT effect that can be related to indirect vascular and immunological mechanisms is not considered. 45 Using immunofluorescence labeling, we found that PDTinduced oxygen depletion might contribute to proliferation restriction and induction of apoptosis of hypoxic cells in the center of the spheroid. Functional tumors are interspersed with blood and lymphatic vessels, which do not allow this observation to be entirely translated to the human body.…”

“…Compared to the situation in vivo, this basic spheroid model still has some limitations. For example, the part of PDT effect that can be related to indirect vascular and immunological mechanisms is not considered 45 . Using immunofluorescence labeling, we found that PDT‐induced oxygen depletion might contribute to proliferation restriction and induction of apoptosis of hypoxic cells in the center of the spheroid.…”

Extracellular Matrix Containing in vitro Three‐dimensional Tumor Models in Photodynamic Therapy‐related Research

“…This trend has been introduced also in research related to photodynamic therapy (PDT) (Ref. , other references in this review). This anticancer treatment modality combines selective accumulation of a photosensitizing agent within tumor tissue with subsequent activation of the photosensitizing agent by suitable visible light.…”

Trace Oxygen Sensitive Material Based on Two Porphyrin Derivatives in a Heterodimeric Complex

“…This novel heterodimer complex (compound 3 ), presented in Figure 2c, exhibiting improved fluorescence behavior, based on a non-fluorescent Fe-metalloporphyrin with already proven electrical O 2 sensing capacities [34,35,36,37,38,39,40] and a highly fluorescent phosphor-porphyrin derivative is expected to act as conjugated chemosensor system for O 2 . These properties may also lead to potential future applications in biological fields, for example, as a bio-degradable 1 O 2 -sensitizer [34] and to show photodynamic therapy of cancer (PDT) and bactericidal activity under visible-light irradiation [36,37,38,39].…”

“…These properties may also lead to potential future applications in biological fields, for example, as a bio-degradable 1 O 2 -sensitizer [34] and to show photodynamic therapy of cancer (PDT) and bactericidal activity under visible-light irradiation [36,37,38,39]. …”