The upregulated expression of heat shock proteins (HSPs) impairs the therapeutic efficacy of photothermal therapy (PTT). Inhibition of HSPs repair is crucial for improving the efficiency of low-temperature PTT.
A new study by the Chinese Academy of Sciences has suggested a new strategy to inhibit the expression of HSPs. The approach involves using carbon oxide gas. It offers an alternative strategy for boosting low-temperature PTT.
Scientists started by developing a chemiexcitation-triggered photo-active nano delivery system called AIE nanobomb. This system is based on the self-assembly of NIR-II luminescent polymer with aggregation-induced emission properties (PBPTV) and homemade carbon monoxide (CO) carrier polymer MPEG(CO). The high concentration of H2O2 in the tumor microenvironment could set off the nano bomb, which would then selectively release CO gas in the tumor cells.
Oversecreted H2O2 diffuses across the nano bomb in the cancerous microenvironment to preferentially decompose into OH radicals via a Fenton-like reaction, and strongly oxidative OH radicals further oxidize and competitively coordinate with the Fe center, resulting in the release of CO from the Fe center. During the low-temperature PTT procedure, the progressively released CO could efficiently suppress the increased production of HSPs to decrease tumor thermal resistance and promote tumor apoptosis.
Dr. CAI Lintao from the Shenzhen Institute of Advanced Technology (SIAT) of CAS said, “As a safe cancer treatment modal, photothermal therapy under mild temperature could not only induce the tumor apoptosis but also activate the immune system to attack the residue tumor cell in the human body and eliminate the tumor recurrence. e call this treatment photo-immuno-therapy. There is no doubt that how to selectively inhibit expression of the heat shock proteins in tumor cells and reverse thermotolerance of the cell is the key.”
“Small molecular HSPs inhibitor and small-interfering RNA (siRNA) have been widely co-loaded with photothermal conversion agents to improve the therapeutic effect of low-temperature PTT. Small molecular HSPs inhibitors are antibiotics or anticancer agents, such as tanespimycin (also known as 17-AAG), gambogic acid, and so on.”
Dr. ZHANG Pengfei, the main contributor to this study, said, “They are almost hard to be dissolved in water and have a side effect to normal cells, and siRNA seems to be a good approach. However, they are so easy to be degraded in the human body. We are also surprised that carbon oxide works. It inspires us that nothing is impossible.”
Dr. GONG Ping Gong, another main contributor to this study, said, “As a signaling molecule, carbon oxide (CO) can trigger a series of cellular protective mechanisms in stress and inflammation. The mechanism of CO down-regulating HSPs protein is still unclear. According to some literature, we may hypothesize that it might be related to the LKB1/AMPK/mTOR pathway, but a lot of work is still needed to prove it.”
Using the bis-pyridal-thiadiazole unit in PBPTV, an ambipolar pyridal thiadiazole-based semiconducting polymer allows for high electron affinity, a low LUMO level, and extended -conjugation. This has shown great promise for developing high-performance electron-transporting semiconductors in organic electronics.
Dr. Huajie Chen from Xiangtan University, a collaborator in this work, said, “We had never thought it could emit light before, and never thought it could be used in biomedicine. This work gives us an idea of the promise of our material. I think it’s important to work across disciplines, and I will continue to work with the research team at SIAT.”
Dr. CAI said, “Gas therapy is an emerging and promising field, although there are some reports on combining gas therapy with phototherapy for cancer. The interaction between gas and the biological process might open a new door to solve some existing problems in disease therapy. Besides, there are also clinical reports based on gas therapy. Using gas to solve the problem in phototherapy is also a good example of drug repurposing.”
- Gongcheng Ma, Zhongke Liu, Chunguang Zhu, et al. H2O2-Responsive NIR-II AIE Nanobomb for Carbon Monoxide Boosting Low-Temperature Photothermal Therapy. Angewandte Chemie. DOI: 10.1002/anie.202207213