Selective Cell Death by Photochemically Induced pH Imbalance in Cancer Cells

Abstract

Singlet oxygen sensitized photodynamic therapy (PDT) relies on the concentration of oxygen in the tissue to be treated. Most cancer lesions, however, have poor vasculature and, as a result, are hypoxic, significantly hindering PDT efficacies. An oxygen-independent PDT method may circumvent this limitation. To address this, we prepared sulfonium salts that produced a pH drop within HCT 116 cells via the generation of photoacid within the cytosol. This process was driven by one- or two-photon absorption (1PA or 2PA) of the endocytosed photoacid generators (PAGs). One of these PAGs, which had a significantly lower dark cytotoxicity and was more efficient in generating photoacid, effectively induced necrotic cell death in the HCT 116 cells. The data suggests that PAGs may be an attractive alternative PDT modality to selectively induce cell death in oxygen-deprived tissue such as tumors.

Pegylated and nanoparticle-conjugated sulfonium salt photo triggers necrotic cell death

“…Fadhel et al As demonstrated in our previous study, 6 time-lapsed micrographs ( Figure 6) of HCT-116 cells incubated with PEG-PAG9 and SiNP-PAG9 (Figures 6 and 7, respectively) show significant cell swelling, loss of cell adhesion that is followed by a "blebbing"-like activity, which is a characteristic of necrotic cell death. Figure 8 shows a simplified Jablonski diagram summarizing the process of photoacid generation by either one-photon or two-photon (2P) excitation.…”

“…Next, we verified the reduced lysosomal pH by employing LysoSensor Green as a suitable intracellular pH sensor. 6 Since the fluorescence quantum yield of LysoSensor Green increases in increasingly acidic environments, 11 International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 54.245.13.81 on 11-May-2018 For personal use only.…”

“…Rather than producing ROS as the main "damaging" component, we used a non-toxic sulfoniumbased photoacid generator (PAG) to cause intracellular pH imbalance. 6 Upon proper light excitation, the PAG lowers the pH in the moderately pH-sensitive intracellular environment; the acidic environment thus created leads to the malfunction and destruction of many cellular components, likely including key enzymes. This process is considered an oxygen-independent PDT (OI-PDT) and, essentially, relies on two main components, the sulfonium salt distribution in the affected area and a proper source of excitation, rather than the three components mentioned earlier.…”

“…Given the hydrophobic nature of PAGs prepared in our preliminary study, 6 we opted to introduce a polyethylene glycol (PEG) unit that can confer hydrophilicity to the PDT agent while maintaining its photo-induced cytotoxicity. Along the same line, we prepared highly monodispersed silica nanoparticles (SiNPs) functionalized with amines that served as handles to covalently bond PAG molecules via an amide linkage.…”

Fluorenyl porphyrins for combined two-photon excited fluorescence and photosensitization

“…Multiphotonics has gained increasing popularity in the life sciences over the last decade, in relation with the many advantages molecular multiphoton absorption [1][2][3][4] provides for biological or biomedical applications, such as multiphoton excited fluorescence imaging, [5][6][7] and photodynamic therapy (PDT), [8][9][10][11][12][13][14] . The advantages of two-photon absorption (2PA) M a n u s c r i p t 2 include the ability for highly selective excitation in biological media, intrinsic threedimensional resolution as well as increased penetration depth in tissues.…”