Photothermal therapy (PTT) is a safe cancer hyperthermia strategy that utilizes photothermal conversion agents (PCAs) to convert light energy into heat to ablate cancer cells.  

On one hand, high-temperature (>50 ^oC) PTT causes an unavoidable threat to surrounding healthy tissues and could induce inflammatory disease because of the difficulty in blocking heat diffusion. On the other hand, the ablation effect at relative low-temperature(<45 ^oC) is far from sufficient due to the upregulated expression of the heat shock proteins (HSPs), which repair the thermally damaged cells and lead to the thermotolerance of tumor cells upon laser irradiation. It’s imperative to develop new strategy for HSPs silencing for low temperature PTT. 

Now, a research team led by Dr. CAI Lintao from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences has reported a new strategy using carbon oxide gas to inhibit the expression of HSPs and provides an alternative strategy for boosting low-temperature PTT. 

The study was published in Angew. Chem. Int. Ed. on July. 15. 

In the experiment, researchers developed a chemiexcitation-triggered photo-active nanodelivery system (termed AIE nanobomb) based on the self-assembly of NIR-II luminescent polymer with aggregation-induced emission properties (PBPTV) and home-made carbon monoxide (CO) carrier polymer mPEG (CO). The nanobomb could triggered by the high level of H₂O₂ in tumor microenvironment and selectively release CO gas in tumor cells. In the cancerous microenvironment, over-secreted H2O2 diffuses across the nanobomb to preferentially decompose into .OH radicals under the catalysis of FeCO via a Fenton-like reaction, and strongly oxidative .OH radicals further oxidize and competitively coordinate with the Fe centre, causing the release of CO from the Fe centre. The gradually released CO could effectively inhibit the elevated expression of the HSPs to destroy tumor thermal resistance during the low-temperature PTT process and induced the tumor apoptosis. 

"As one of the safe cancer treatment modal, photothermal therapy under mild temperature could not only induced the tumor apoptosis, but also activate the immune system to attack the residue tumor cell in human body and eliminate the tumor recurrence," said Dr. CAI, "we call this treatment as photo-immuno-therapy. It is not doubt that how to selectively inhibit expression of the heat shock proteins in tumor cells 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 inhibitor are either antibiotics or anticancer agents, such as tanespimycin (also known as 17-AAG), gambogic acid, and so on.  

"There are almost hard to be dissolved in water and have side effect to normal cells. Small-interfering RNA (siRNA) seemed to be a good approach. However, they are so easy to be degraded in human body," said Dr. ZHANG Pengfei, the main contributor of this study, "we are also surprised that carbon oxide works. It inspired us nothing is impossible." 

"As a signaling molecule, carbon oxide (CO) could trigger a series of cellular protective mechanisms in stress and inflammation. The mechanism of CO down regulating HSPs protein is still unclear," said Dr. GONG Ping Gong, another main contributor of this study, "according to some literature, we may hypothesized that it might be related with LKB1/AMPK/mTOR pathway, but large amount work is still needed to be done to prove it." 

PBPTV is an ambipolar pyridal thiadiazole-based semiconducting polymer, the use of bis-pyridal-thiadiazole unit enables PBPTV to achieve high electron affinity, low LUMO level, and extended π-conjugation, which has shown great potential for designing high-performance electron-transporting semiconductors in organic electronics. 

"We have never think about it could emit light before, and never thought it could be used in biomedicine area. Thanks to Dr. ZHANG Pengfei Zhang and Dr. CAI’s research team let us know the promising of our materials. I think it is the importance to do interdisciplinary collaboration and I will continue to collaborate with the research team in SIAT", said Dr. Huajie Chen from Xiangtan University, the collaborator in this work. 

"Gas therapy is an emerging and promising field, although there have some report on combination of gas therapy with photo therapy for cancer. The interaction between gas and biological process might open new door to solve some existing problem in disease therapy. Besides, there has been clinical report based on gas therapy. Using gas to solve the problem in photo therapy is also a good example of drug repurposing," said Dr. CAI. 

Schematic illustration of (A) synthesis route of mPEG(CO) and (B) the nanobomb consist of mPEG(CO) and PBPTV. (C) Schematic illustration of low-temperature therapy process of nanobomb. (Image by SIAT)

Media Contact:
ZHANG Xiaomin
Email:xm.zhang@siat.ac.cn