Cancer remains one of the most formidable challenges in the field of modern medicine. While various treatment modalities have been developed, chemotherapy continues to be at the forefront of cancer treatment. However, traditional chemotherapy often leads to nonspecific drug delivery, rapid clearance from the bloodstream, and low accumulation in tumors, causing severe side effects for patients. To address these limitations, researchers have explored the use of nanocarriers for targeted drug delivery. In a new study published in the Journal Nature Chemistry, Professor Sylvestre Bonnet from Leiden University in Netherlands and a team of international collaborators have introduced a novel approach to cancer therapy based on a metallophilic interaction, offering promising results for highly effective photodynamic therapy (PDT). PDT is a medical treatment that uses a combination of light and a photosensitizing drug to target and destroy cancer cells and other abnormal tissues. It is a minimally invasive procedure that is used to treat various types of cancer, as well as certain non-cancerous conditions. However, photodynamic therapy also has some limitations, such as the limited depth of light penetration (which restricts its use to superficial or accessible tumors), potential side effects like skin sensitivity to light, and the need for careful coordination between drug administration and light exposure.
The authors developed a new light-sensitive drug delivery system based on a metallophilic interaction, where the PdL molecule self-assembles into nanoparticles. This unique approach distinguishes itself from conventional drug delivery systems. The PdL molecule, characterized by its bis-cyclometalated palladium structure, exhibits metallophilic interactions that play a pivotal role in self-assembly. This self-assembly process occurs in the presence of water, depending on the specific composition of the solvent. Importantly, this self-assembly property is retained even under biologically relevant conditions. The PdL molecule demonstrates outstanding photodynamic properties, a crucial factor for its potential application in cancer therapy. It efficiently generates superoxide radicals (O2 •−) through electron transfer upon exposure to light. This mechanism positions PdL as a PDT type I photosensitizer, capable of inducing cell death in cancer cells through the generation of reactive oxygen species (ROS) within cellular organelles.
The research team conducted comprehensive in vitro and in vivo experiments to evaluate the efficacy of PdL as a cancer treatment agent. In vitro studies demonstrated that PdL exhibited high phototoxicity when exposed to green light, resulting in cancer cell death via both apoptotic and necrotic pathways. Furthermore, 3D multicellular tumor spheroid models confirmed the enhanced cytotoxicity of PdL under light irradiation. Remarkably, in vivo experiments using a mouse tumor model highlighted the potential of PdL for cancer treatment. PdL exhibited low systemic toxicity, with no significant adverse effects on vital organs. The results revealed that PdL efficiently inhibited tumor growth when combined with light irradiation. Histological analyses confirmed the damage to tumor tissues in the PdL plus light group. PdL’s exceptional tumor-targeting capability was explored through detailed uptake, biodistribution, and tumor accumulation studies. It was observed that PdL self-assembled into nanoparticles upon injection into the bloodstream. These nanoparticles demonstrated a prolonged circulation time in the blood, allowing for high tumor accumulation, even in the absence of active tumor-targeting molecules. This phenomenon was attributed to the enhanced permeability and retention effect.
The study led by Professor Sylvestre Bonnet and his international team presents a groundbreaking approach to cancer therapy through a metallophilic interaction-based drug delivery system. PdL, a self-assembling molecule, exhibits remarkable photodynamic properties, making it an effective PDT type I photosensitizer. In vitro and in vivo experiments demonstrated its potent anticancer efficacy with low systemic toxicity. The unique self-assembly behavior and long circulation time in the bloodstream provide PdL with a significant advantage over traditional drug delivery systems. This breakthrough has the potential to revolutionize cancer treatment by offering a highly efficient and targeted therapy that minimizes side effects on healthy tissues.
Zhou XQ, Wang P, Ramu V, Zhang L, Jiang S, Li X, Abyar S, Papadopoulou P, Shao Y, Bretin L, Siegler MA, Buda F, Kros A, Fan J, Peng X, Sun W, Bonnet S. In vivo metallophilic self-assembly of a light-activated anticancer drug. Nat Chem. 2023 ;15(7):980-987. doi: 10.1038/s41557-023-01199-w