The photodynamic therapy of cancer is contingent upon the sustained generation of singlet oxygen in the tumor region. However, tumors of the most metastatic cancer types develop a region of severe hypoxia, which puts them beyond the reach of most therapeutic protocols. More troublesome, photodynamic action generates acute hypoxia as the process itself diminishes cellular oxygen reserves, which makes it a self-limiting method. Herein, we describe a new concept that could eventually lead to a change in the 100 year old paradigm of photodynamic therapy and potentially offer solutions to some of the lingering problems. When gold nanorods with tethered endoperoxides are irradiated at 808 nm, the endoperoxides undergo thermal cycloreversion, resulting in the generation of singlet oxygen. We demonstrate that the amount of singlet oxygen produced in this way is sufficient for triggering apoptosis in cell cultures.
The photosensitized generation of reactive oxygen species, and particularly of singlet oxygen [O2 (a(1) Δg )], is the essence of photodynamic action exploited in photodynamic therapy. The ability to switch singlet oxygen generation on/off would be highly valuable, especially when it is linked to a cancer-related cellular parameter. Building on recent findings related to intersystem crossing efficiency, we designed a dimeric BODIPY dye with reduced symmetry, which is ineffective as a photosensitizer unless it is activated by a reaction with intracellular glutathione (GSH). The reaction alters the properties of both the ground and excited states, consequently enabling the efficient generation of singlet oxygen. Remarkably, the designed photosensitizer can discriminate between different concentrations of GSH in normal and cancer cells and thus remains inefficient as a photosensitizer inside a normal cell while being transformed into a lethal singlet oxygen source in cancer cells. This is the first demonstration of such a difference in the intracellular activity of a photosensitizer.
Tropomyosin-related kinase (Trk) C, a member of the Trk family of neurotrophin receptors, has been implicated in the growth and survival of human cancer tissues. Here, we report that TrkC is frequently overexpressed in human breast cancers and plays an essential role in tumor growth and metastasis. Ectopic expression of TrkC in non-malignant mammary epithelial cells suppressed anoikis, which correlated with activation of the Ras-mitogen-activated protein kinase and phosphatidylinositol-3-OH kinase (PI3K)/Akt pathways, and reduced expression of the metastatic regulator Twist. Furthermore, suppression of TrkC expression in highly metastatic mammary carcinoma cells inhibited their growth in vitro, as well as their ability to metastasize from the mammary gland to the lung in vivo. These results have identified TrkC as a critical regulator of breast cancer cell growth and metastasis.
The photodynamic therapyo fc ancer is contingent upon the sustained generation of singlet oxygen in the tumor region. However,t umors of the most metastatic cancer types develop ar egion of severe hypoxia, whichp uts them beyond the reach of most therapeutic protocols.M ore troublesome, photodynamic action generates acute hypoxia as the process itself diminishes cellular oxygen reserves,whichmakes it aselflimiting method. Herein, we describe anew concept that could eventually lead to ac hange in the 100 year old paradigm of photodynamic therapyand potentially offer solutions to some of the lingering problems.W hen gold nanorods with tethered endoperoxides are irradiated at 808 nm, the endoperoxides undergo thermal cycloreversion, resulting in the generation of singlet oxygen. We demonstrate that the amount of singlet oxygen produced in this way is sufficient for triggering apoptosis in cell cultures.The photodynamic therapy (PDT) of cancer has been considered ap romising therapeutic approach for decades. Principal requirements for photodynamic action were established by the experiments of Raab and von Tappeiner at the turn of the 20th century.[2] Based on their work, which was followed up by many others, [3,4] aphotosensitizer that can be excited by light in the visible,but more preferably in the red or near-IR region of the spectrum could sensitize groundstate molecular oxygen and generate as hort-lived, cytotoxic reactive oxygen species,that is,singlet oxygen (O 2 : 1 D g ). This process is inherently regioselective,a st he singlet-oxygen generation will take place only in the region at which the light beam is directed. In combination with the enhanced permeation and retention (EPR) effect, [5] which leads to sensitizer accumulation in tumors,t his non-invasive,o rm inimally invasive,t reatment protocol, with tolerable side effects and ab onus of enhanced immune response, [6] has tremendous therapeutic potential. However,t he full promise of PDT has not been realized except perhaps for some niche applications such as superficial lesions.[7] Thel imited applicability is not necessarily due to the lack of optimal sensitizers or smart delivery/activation processes; [8][9][10][11][12][13][14][15] the problem unfortunately lies at the core of the PDT paradigm. First, even at the optimum wavelengths,t he tissue penetration of light is very ineffective beyond the first few millimeters.[16] Thes econd issue is oxygen concentration. Most tumors develop ahypoxic region, and this is more common in aggressive metastatic tumors.[17] Such hypoxic tissues are highly resistant to chemotherapy and radiotherapy.[18] PDT,o nt he other hand, is inhibited even more severely,b ecause normoxic oxygen concentrations are essential for effective singlet-oxygen generation. Furthermore,e ven in normal tissues,t he PDT process itself decreases the cellular oxygen concentration, Figure 1. New photodynamics concept. Top: Synthesis of the targeted anthracene endoperoxide derivative (EPT1) for gold nanorod functionalization. The PEG...
The photosensitized generation of reactive oxygen species, and particularly of singlet oxygen [O 2 (a 1 D g )], is the essence of photodynamic action exploited in photodynamic therapy. The ability to switch singlet oxygen generation on/off would be highly valuable, especially when it is linked to a cancer-related cellular parameter. Building on recent findings related to intersystem crossing efficiency, we designed a dimeric BODIPY dye with reduced symmetry, which is ineffective as a photosensitizer unless it is activated by a reaction with intracellular glutathione (GSH). The reaction alters the properties of both the ground and excited states, consequently enabling the efficient generation of singlet oxygen. Remarkably, the designed photosensitizer can discriminate between different concentrations of GSH in normal and cancer cells and thus remains inefficient as a photosensitizer inside a normal cell while being transformed into a lethal singlet oxygen source in cancer cells. This is the first demonstration of such a difference in the intracellular activity of a photosensitizer.
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