IR-Click

Nanomaterials have integrated the most exciting advances of this decade. In the cancer field, nanomedicines are emerging due to their capacity for accumulating at the tumor site, potentially increasing the treatments’ efficacy and safety. In particular, the IR780-loaded nanostructures have a groundbreaking potential for cancer therapy. These nanostructures can produce, upon irradiation with Near Infrared (NIR) light, a temperature increase (photothermal therapy) and singlet oxygen (photodynamic therapy). Due to this multimodality, the IR780-nanostructures produced by our team could photo-ablate the cancer cells at an ultralow concentration. Owed to the unique features of NIR light, phototherapies mediated by IR780-nanomaterials are circumscribed to the tumor site, thus having low side-effects. In the last 5 years, our team synthesized several amphiphilic polymers that could self-assemble into nanomaterials that loaded non-covalently IR780. In 2022, our team pioneered in the synthesis of poly(2-oxazoline)-IR780 covalent conjugates, which could self-assemble into nanoparticles. Due to the IR780 covalent loading, these hydrophilic polymer-IR780 conjugate nanoparticles displayed an enhanced stability. Such is crucial since non-covalently loaded drugs are prone to premature detachment during circulation, hindering their tumor uptake. We also disclosed that nanomaterials’ photothermal/photodynamic effects can trigger the release of Damage-associated molecular patterns from cancer cells. Such ground-breaking effect stimulates Dendritic cells’ maturation/activation, which can then prime Cytotoxic T cells. Ultimately, this domino-effect may unlock an immune response towards metastases. Despite the nanomedicines’ potential, their clinical translation has been scarce. It was recently reported that only 0.7% of the intravenously injected nanomaterials’ dose reaches the tumor site. This harsh reality derives from the fact that nanomaterials rely on the EPR effect to accumulate at the tumor. However, the EPR effect is not present on most human solid tumors, thus explaining the nanomedicines’ limited translation. To explore the potential of hydrophilic polymer-IR780 conjugates for cancer immuno-photothermal/photodynamic therapy, it is urgent to address the nanomedicines’ systemic administration problems. We identified that Tetrazine-Norbornene click injectable in situ forming hydrogels (IIFH) are a potential candidate to perform the direct delivery of hydrophilic polymer-IR780 conjugate nanomaterials into the tumor site. The aim of the IR-Click project is to engineer hydrophilic polymer-IR780 conjugates that self-assemble into IIFH through the Tetrazine-Norbornene click chemistry, and perform the in vitro validation of their potential for cancer immuno-photothermal/photodynamic therapy. Overall, the hydrophilic polymer-IR780 based Tetrazine-Norbornene click IIFH are a cutting-edge, scalable and ecologic technology that may establish a novel strategy for i) tumor-confined delivery of nanomaterials and ii) metastatic breast cancer treatment. Hence, this project will impact the scientific community, industry, society and economy.