Remote‐Controlled Release of Singlet Oxygen by the Plasmonic Heating of Endoperoxide‐Modified Gold Nanorods: Towards a Paradigm Change in Photodynamic Therapy

Abstract

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...

Photosensitiser-gold nanoparticle conjugates for photodynamic therapy of cancer

“…14 Kolemen et al reported another system with the potential to solve the hypoxia limitation of PDT. 15 The authors used non-conventional chemical photosensitisers, endoperoxides of arenes, which lead to the production of 1 O2 upon heating via controlled cycloreversion.…”

“…A further advantage of the use of endoperoxides as photosensitisers is their irradiation with NIR light, which can penetrate deeper than commonly used red light into biological tissue, thus opening the possibility to treat deep-lying tumours. 15 In a further attempt to increase light penetration into the tissue, Clement et al…”

Graphene Oxide Wrapped SiO2/TiO2 Hollow Nanoparticles Loaded with Photosensitizer for Photothermal and Photodynamic Combination Therapy

“…The singlet oxygen ( 1 O 2 )g eneration efficiency of photosensitizers is an important factor in PDT. [35,36] AN IR laser and aL ED light were used as the light sourcesi nt his study because of their tissue penetration properties and safety toward the cells. To confirm the photodynamic activity of GO-HNP-PpIX, 1 O 2 generation was detected by ac hemical trappingm ethodw ith 9,10-anthracenediyl bis(methylene)dimalonic acid (ABDA).…”

Deoxyribozyme-nanosponges for improved photothermal therapy by overcoming thermoresistance

“…As a promising alternative or supplement to traditional cancer therapy, PTT is minimally invasive and compensates for the reduced therapeutic efficacy caused by chemodrug resistance. In addition, PTT can be combined with other therapeutic methodologies, such as chemotherapy and gene therapy, to achieve high therapeutic efficacy against cancer [15][16][17] . Nevertheless, recent studies have indicated that PTT is always accompanied by a heat shock response that shields cancer cells from damage by hyperthermia, decreasing its therapeutic efficacy [18][19][20] .…”