Dalian University of Technology has realized a new idea of direct use of small molecules as nano-photosensitizing drugs

On May 11, 2023, Professor Sun Wen of Dalian University of Technology and the team of Professor Sylvestre Bonnet of Leiden University in the Netherlands published a research result entitled “In vivo metallophilic self-assembly of a light-activated anticancer drug” in the journal Nature Chemistry.

This achievement verifies how a simple small molecule metal-complex dye uses supramolecular metal-metal interaction to self-assemble into nanophotosensitizers with stable structure in vivo to achieve efficient tumor enrichment and photodynamic anti-cancer effects. The highlight is that it provides new ideas that small molecules can be directly used in vivo as nanomedicines, and introduces metal-metal interactions into the field of nanomedicine.

The corresponding authors of the paper are Professor Sun Wen and Professor Sylvestre Bonnet, and the first author is Dr. Xuequan Zhou. The first communication unit of the paper is Dalian University of Technology. Other partners include Johns Hopkins University in the United States, Fujian Institute of Structure of Matter of the Chinese Academy of Sciences, and Mario Negri Institute of Pharmacology in Italy.

As the most common anti-cancer drugs on the market, small molecule chemotherapy drugs have a definite molecular structure and synthesis pathway, and have advantages in large-scale production. But they also face problems such as excessive metabolic speed, low tumor enrichment rate, and poor targeting. The Nano Drug Delivery System (NDDS) was once considered a “golden strategy” to help small molecule drugs overcome these difficulties. However, in recent years, some in-depth studies on nanocarrier delivery have shown that the proportion of nanocarriers delivering drugs to living tumors is still low, averaging around 0.7%, in part due to the low drug loading rate of nanocarriers. At the same time, the synthesis methods of some nanomaterials are more complex and may face the risk of failure in scale-up experiments. With this in mind, Prof. Wen Sun and Prof. Sylvestre Bonnet focused on self-assembled nanodrugs (SAND). With reasonable design, supramolecular forces can be formed between small molecule photosensitizers and aggregated into nanoparticles with a drug loading rate of up to 100% in the physiological environment, thereby overcoming the low drug loading rate of conventional nanodrug delivery systems.

In this work, the authors used an unconventional supramolecular force, the metal-metal interaction, for small molecule photosensitizer self-assembly. The reason for this is that by introducing metal complexes, small molecules can be imparted with photosensitive properties, making them less toxic in dark conditions; After illuminating the tumor site, the tumor growth can be physically and selectively inhibited by generating reactive oxygen species without damaging other sites. The authors designed and synthesized a palladium complex, and studied in detail the properties of this small molecule in metal-metal interaction, photophysical chemistry and physiological environment self-assembly nano-assembly by means of single crystal diffraction, absorption and emission spectroscopy, cryo-EM and bio-electron microscopy, respectively, from the aspects of solid, liquid, nanoaggregate, blood self-assembly, etc. Cytotoxicity experiments and mouse tumor suppression experiments also proved the excellent photodynamic anti-cancer effect of this metal complex.

Further studies found that 12 hours after tail vein injection, the drug was still enriched in the tumor in the form of nanoparticles, and the tumor enrichment rate could be as high as 10.2% ID/g (that is, 10.2% of the injected drug per gram of tumor), much higher than the average of 0.7% ID reported for nanocarriers. This study also proves that metal-metal interactions have strong biological stability and can be used as a new supramolecular force for nanodrug development, which is worth further exploration. (Source: Science Network)

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