JACS: a new idea of PDT -- Design and synthesis of non heavy atom photosensitizer

Photodynamic therapy (PDT) is a photochemical based therapy, which combines photosensitizers (PS) with light, and plays an important role in cancer therapeutics So far, many PS have been used in preclinical and clinical research However, the triplet quantum yield of traditional PS is very low, and it is usually necessary to add heavy atoms to enhance its inter system channeling (ISC), which may lead to increased cost and "dark toxicity" Therefore, the design of triplet PS without heavy atoms is still a challenge Recently, Professor juyoung Yoon of Lihua women's University in Korea and Professor Sungnam Park of Koryo University in Korea jointly proposed a new design strategy of highly efficient and activated photosensitizer, which uses sulfur atom to replace two oxygen atoms in rni-o to make the obtained rni-s ）The results show that sulfur substitution enhances the transition from singlet excited state to triplet excited state More importantly, the resulting compound mani-s still produces a large amount of reactive oxygen species (ROS) under severe hypoxia (1% O2) In addition, ROS production ability can be restored in cancer cells because of inhibition of self-assembly under physiological conditions Relevant achievements were published on J am Chem SOC Under the title of "an emerging molecular design approach to heavy atom freephotosensors for enhanced photodynamic therapy under hypoxia" (DOI: 10.1021 / JACS 9b0920) (source: J am Chem SOC.) firstly, the author synthesized compound rni-o according to the method of literature Under the condition of Lawson reagent and toluene, rni-s was synthesized by one pot method and characterized by NMR and mass spectrometry (scheme 1) Then, the UV and fluorescence spectra of rni-o and rni-s were measured (Table 1, figure 1a and 1b) The results show that with the enhancement of the electron delivery ability of 4-R group, the absorption band moves red gradually; in addition, the maximum absorption value of rni-s has a red shift of 100 nm compared with that of rni-o and the molar absorption coefficient increases Therefore, by changing the donor group and substituting the sulfur atom for the oxygen atom, an effective Homo de stabilization and LUMO stabilization can take place, thus making the absorption spectrum redshift to the biological window (Figure 1c) On the other hand, all rni-o compounds show strong fluorescence with good quantum yield (Φ = 0.04-0.99); rni-s has no fluorescence (Φ = 0.04-0.09), which indicates that sulfur substitution can enhance the ISC process from singlet to triplet excited states (source: j.am Chem SOC.) then, the author measured the singlet quantum yield (Φ) of rni-o and rni-s to elucidate the formation of their triplet states There is almost no Φ ∆ in rni-o, but there is a higher Φ ∆ in rni-s, which increases with the enhancement of the electron supplying ability of 4-R group (Table 1) In order to further understand the mechanism of the formation of triplet, the author calculated the optimized structure of RNI: after substituting sulfur for oxygen, the spin orbit coupling (SOC) constant increased significantly, and the triplet energy gap (∆ EST) decreased, resulting in the increase of ISC rate constant (KISC) of rni-s, indicating that ISC from S1 to T3 is the main reason for the formation of triplet（ Figure 1d ）。 (source: J am Chem SOC.) in order to further confirm the generation of triplets and evaluate the potential of rni-s for PDT, the authors explored its ability of ROS generation in water In the water / DMSO system, rni-s self-assembled into nanoparticles, and nanomani-s has good stability in aqueous solution due to the hydrophilicity of amino group, so it can be tested later In addition, the author found that the absorption spectrum of nanomani-s in water was blue shifted and widened compared with that of mani-s monomer in DMSO, which indicated that H-aggregate generated by quenching ROS was generated, so mani-s was also allowed to be used in "switch" PS In order to verify its ability of "turning off" ROS generation, we used albumin as the target protein to decompose the complete nanomani-s into monomer destroyed nanomani-s (Figure 2D, 2e); then we tested the ROS generation rate of intact and destroyed nanomani-s with MB as reference The results show that the ROS generation rate of the destroyed nanomani-s is significantly higher than that of the intact nanomani-s, and 2.5 times higher than that of MB All of these indicate that mani-s is a good PS with switchable optical activity (Figure 2a) At the same time, the author studied the o 2-production of mani-s, and observed that the o 2-production of damaged nanomani-s was significantly higher than that of intact nanomani-s, which was 3.0 times of MB (Figure 2b) In addition, the production of 1O2 was also observed during the experiment, which indicated that mani-s also produced ROS through type II mechanism In conclusion, mani-s may act through type II and type I mechanisms at the same time (source: J am Chem SOC.) finally, the antitumor effect of mani-s on HeLa cells was analyzed by MTT Under the light condition, the therapeutic effect of mani-s is significantly better than that of MB, and with the increase of concentration, the therapeutic effect is enhanced (Figure 3a) In order to evaluate the photodynamic potential of mani-s in the treatment of hypoxic tumors, the authors explored the PDT effect of mani-s under hypoxia (1% O2) The results showed that the mortality of HeLa cells induced by mani-s was almost the same under hypoxia as that under normal oxygen (20% O2) The results showed that mani-s had excellent phototoxicity to cancer cells (source: J am Chem SOC.) in a word, the author designed a triplet photosensitizer without heavy atom based on thiocarbonyl naphthalene dicarbonimide The substitution of sulfur makes the absorption spectrum red shift and increases the ROS generation rate of rni-s; the incorporation of electron group 4-R significantly enhances the ROS generation ability What's more, even under the condition of severe hypoxia (1% O2), mani-s still plays an excellent role in PDT, which provides some help for the development of derivatives based on this method.