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Efficient near-infrared second-region photodynamic one-type photosensitizers obtained by adjusting chalcogen elements


In clinical treatment, some malignant tumors with deep infiltration, large volume, complex location and low possibility of surgery/radiotherapy are difficult to cure. Photodynamic/photothermal therapy (PDT/PTT) is used to treat such tumors due to its noninvasiveness, significant tumor penetration depth, and negligible side effects. On the one hand, near-infrared region II (NIR-II) laser irradiation has the advantages of deep penetration (1064 nm laser is greater than 1 cm) and high maximum allowable exposure (1064 nm laser is 1.0 W cm−2). On the other hand, the hypoxic microenvironment of hypoxic tumors requires that the photosensitizer should be a PDT type I material. So, is it possible to develop a type I photosensitizer for PDT in the near-infrared second region and apply it to cancer treatment? Recently, the team of Professor Huang Hui from the University of Chinese Academy of Sciences (click to view the introduction) has prepared a photosensitive agent of near-infrared second-region photodynamic type 1 which can be used under hypoxic conditions by regulating chalcogen elements, and found that it has good properties. effect of tumor treatment.

     Triplet organic semiconductor materials have important application prospects in biology, luminescence, photovoltaics, etc. The generation of triplet excitons requires an increase in the rate constant (kISC) of intersystem crossing (ISC). Generally speaking, there are two ways to enhance the ISC process. One is to reduce the energy level difference (ΔEST) between singlet and triplet states by enhancing intramolecular charge transfer (ICT) states, which has been widely used to develop thermally activated delayed fluorescence and PDT materials. Another approach is to enlarge the spin-orbit coupling (SOC) constant (ξ) between singlet and triplet states by introducing heavy atoms, such as iodine, selenium, tellurium, etc., into semiconducting polymers. Type I PDTs are triplet excitons of photosensitizers that transport electrons to ground-state oxygen (3O2) to form superoxide anion radicals (O2•−), which also include hydrogen peroxide and hydrogen peroxide through superoxide disproportionation and Franck-Condon transformation. hydroxyl radical (HO•), which requires electron transfer to be allowed (Gibbs free energy change, ΔG < 0). In contrast, type II PDT transfers the energy of the triplet excitons of the photosensitizer to 3O2 to form singlet oxygen (1O2), which requires the energy of the lowest triplet excited state (T1) to be above the oxygen sensitization threshold of 0.98 eV. In general, Type II PDT is much faster than Type I PDT. When the energy levels meet the requirements, PDT favors type II PDT over type I PDT. Therefore, although some NIR-II region PDT/PTT photosensitizers have been used for cancer therapy, there are no reports of NIR-II type I PDT/PTT organic/polymer photosensitizers.

      In the previous work, Professor Huang Hui's team took tellurium-containing materials as the starting point, designed and synthesized a series of tellurium-containing semiconductor organic/polymer materials, and systematically studied the triplet properties and applications of such materials. (Angew. Chem. Inter. Ed., 2020, 59, 12756; 2018, 61, 1359. Sci. Bull., 2020, 65, 1580. Sci. China Chem., 2019, 62, 897. ACS Appl. Mater. Interfaces, 2019, 19, 17884; 2018, 10, 1917; 2016, 8, 34620. ChemPhysChem, 2019, 20, 2600. J. Power Sources, 2018, 401, 13.)

       In this work, the team of Prof. Hui Huang developed three narrow-bandgap semiconducting polymers (PTS, PTSe and PTTe) with thiophene isoindigo derivatives as electron acceptor units and thiophene, selenophene and tellurium as electron donor units, respectively. )(figure 1). The powerful ICT function realized by the donor-acceptor strategy not only extends the light absorption range to the NIR-II region, but also through the introduction of heavy atoms (selenium and tellurium), the kISC is significantly enhanced, which promotes the generation of triplet excitons. By comparing the energy levels of the highest occupied molecular orbital and the lowest unoccupied molecular orbital of nanoparticles with the redox potentials of reactive oxygen species, it is shown that PTS, PTSe and PTTe are capable of producing O2•−. After tuning the chalcogen, the energy of the lowest triplet excited state is not sufficient to sensitize 3O2 to 1O2. The Gibbs free energy change between PTS, PTSe or PTTe and 3O2 is less than zero, which favors the realization of type I PDT via intermolecular electron transfer (IET) (Fig. 2). As expected, telluride-based PTTe nanoparticles exhibit excellent biocompatibility and unprecedented NIR-II (1064 nm) type I photodynamic/photothermal properties under both normoxic and anoxic conditions in vitro, which can Effectively inhibits 4T1 tumor proliferation in vivo.


 Figure 1. Near-infrared second-region photodynamic therapy type I photosensitizers for photothermal and photodynamic therapy under hypoxic conditions. Image credit: Adv. Mater.

     Professor Huang Hui's team pointed out that the appropriate lowest unoccupied molecular orbital energy level and the criterion that the Gibbs free energy change is less than zero not only provide a solution for the design of the near-infrared second region type I photosensitizer, but also promote the design of photosensitizers. theoretical development.



Figure 2. Excitation energies of excited states of PTS (a), PTSe (b) and PTTe (c) and spin-orbit coupling constants between them; PTS (d), PTSe (e) and PTTe (f) Gibbs free energy change.

Image credit: Adv. Mater.


    This achievement was recently published in Advanced Materials. The first author of the article is Wen Kaikai, a postdoctoral fellow at the School of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences and Shenzhen Second People's Hospital, and the co-first author is Tan Hui from Shenzhen Second People's Hospital. The corresponding authors are Professor Huang Hui and Professor Peng Qian of the University of Chinese Academy of Sciences, and Professor Tan Hui and Director Cai Xiaodong of Shenzhen Second People's Hospital.

    The project was supported by the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong Province, the Natural Science Foundation of Beijing Municipality, the Shenzhen Science and Technology Innovation Committee, and the special funds for the basic scientific research business expenses of the central universities.

   Paper information:

Achieving Efficient NIR-II Type-I Photosensitizers for Photodynamic/Photothermal Therapy upon Regulating Chalcogen Elements. Kaikai Wen, Hui Tan, Qian Peng, Hao Chen, Han Ma,Lu Wang, Aidong Peng, Qinqin Shi,  Xiaodong Cai, Hui Huang. Adv. Mater. 2022, 2108146. DOI: 10.1002/adma.202108146

About Dr. Wong Fai

    Huang Hui, professor and doctoral supervisor of University of Chinese Academy of Sciences. Winner of the National Science Fund for Distinguished Young Scholars. Graduated from the Institute of Chemistry, Chinese Academy of Sciences with a master's degree, and received a Ph.D. in chemistry from Dartmouth College in 2008. He then followed up with Professor Tobin Marks of Northwestern University for postdoctoral research. In 2010, he joined the Global R&D Center of ConocoPhillips (now Phillips 66 Oil Company) to engage in the research and development of organic solar cells. He returned to China in November 2013 and has worked since then.



     He has been engaged in the synthesis and application of organic/polymer semiconductor materials for a long time, mainly including photovoltaic materials and devices, photoelectric sensing, biological detection and treatment, etc. He has published more than 90 papers in international journals including Nature Chem., Nature Commun., J. Am. Chem. Soc., Angew. Chem. Inter. Ed., Adv. Mater. He has won the Chinese Academy of Sciences Frontier Research-Young Top-notch Talent, the Chinese Academy of Sciences Outstanding Mentor Award, and the Zhu Liyuehua Outstanding Teacher Award.

Analysis of scientific research ideas

    Q: What was the original purpose of this research? Or how did the idea come about?

    A: As mentioned above, the original purpose was to design novel photosensitizers with high penetration depth that can be used in hypoxic tumor environments. The near-infrared second-region conjugated polymer material can meet the requirements of high penetration depth of photosensitizers, and the first-type photosensitizers are very suitable for working effectively in an oxygen-deficient environment. Therefore, we selected thiophene isoindigo with strong electron withdrawing ability as the electron acceptor unit, and selected thiophene, selenophene and telluride as the electron donor unit respectively, and designed a semiconducting polymer material in the near-infrared second region. The strong intramolecular charge transfer ensures the near-infrared second-region absorption of semiconducting polymer materials and narrows the energy level difference between the singlet excited state and triplet excited state; the introduction of heavy atoms promotes the increase of the spin-orbit coupling constant, which together The intersystem crossing rate constant is enhanced, which lays the foundation for the generation of triplet excitons. The energy level of the lowest triplet excited state is less than the threshold value of ground state oxygen sensitization, and singlet oxygen cannot be generated. The electron transfer process between the photosensitizer and the ground state oxygen is allowed, which is conducive to the occurrence of the electron transfer process. Therefore, a novel photosensitive agent of the photodynamic type I in the near-infrared second region was designed for photothermal and photodynamic therapy of deep tumors.

     Q: What challenges did you encounter in the research process?

     A: The biggest challenge in this study is how to control the UV-Vis-NIR absorption, the appropriate highest occupied molecular orbital energy level and the lowest unoccupied molecular orbital energy level of the semiconducting conjugated polymer to obtain a suitable electron transfer process photosensitizer. During this process, our team's accumulated experience in designing semiconducting polymer processes has played a crucial role.

In addition, this research is an interdisciplinary research, which requires a lot of background knowledge in theoretical calculations and ultrafast dynamics, and our team is mainly from polymer chemistry and semiconductor materials, so there is a challenge of insufficient knowledge reserve. In the future, it is hoped that researchers in related fields will work together to promote research to a higher level.

     Q: What important applications might this research result have? Which fields of business or research institutions might benefit from the results?

        A: The type I photosensitizer in the near-infrared region not only has suitable biocompatibility and is non-toxic and harmless to healthy mice, but also has excellent photothermal and photodynamic properties, which are excellent in mouse tumor treatment. Therefore, it has potential application prospects for malignant tumors with deep infiltration, large volume, complex location, and low possibility of surgery/radiotherapy. We believe that this research result will provide reliable support for the clinical application scenarios of photosensitizers with high penetration depth, such as liver cancer, pancreatic cancer and skin cancer, and will greatly promote the development of medical photosensitizers.