Photobiology Lab
Photodynamic therapy (PDT) is a novel antineoplastic treatment modality. At the physicochemical level, the principle of PDT resides in the administration of a photosensitizer that itself is rather inert, yet acquires cytotoxic potential upon absorption of photons that cause the generation of reactive oxygen species (ROS), hence damaging cellular structures. At the practical level, the photosensitizing drug is injected systemically or intratumorally. After a defined time, named the drug-to-light interval (DLI), light with appropriate wavelength is applied to the targeted area. High DLI facilitates optimal redistribution of the compound into organellar, cellular, or subcellular compartments, whereas low DLI is mainly used to target the tumor vasculature. Photodynamic therapy allows to limit the overall side effects and to control the spatial and temporary extension of the treatment with unprecedented precision. It is minimally invasive with superior functional outcome as compared to surgery. Both in preclinical models and in the clinical context, PDT-elicited anti-tumor immunity has been observed.
Courtesy of Ana Mata
PDT is gaining increasing attention due to its immunomodulatory properties, which can instruct the host immune system to recognize and effectively eliminate cancer cells. The increased awareness of PDT as a new form of immunotherapy is based on a large body of preclinical evidence that have been collected in the last two decades, including by our group.
The development of anti-tumor immunity by PDT is being associated to the ability of this therapy to induce immunogenic cell death (ICD). ICD is considered as any form of cell demise that can mount an adaptive immune response in immunocompetent syngeneic hosts without the need of any immunoadjuvant. Cell-based assays show that PDT induces cell death by different mechanisms (apoptosis, necrosis, autophagy, paraptosis, necroptosis, etc.). Thereof, the investigation of the mechanisms of cell death under the oxidative stress of PDT is of paramount importance as they can have different impact on the way how the immune cells perceived the PDT-dying cancer cells. PDT-stressed cells appear to have the aptitude to release/expose, in a spatial-temporal manner, a specific set of intracellular molecules that acquired immune-stimulatory effects when located outside of the cells. These molecules, named as damage-associated molecular patterns (DAMPs), are recognized by pattern recognition receptors (PRRs) expressed on immune cells which result in the activation of immune cell of the different arms of immune system. Altogether, DAMPs activate the recruitment of immune cells to the tumor bed, where they facilitate the presentation of tumor associated antigens (TAA) to antigen presenting cells (APC). In the lymph nodes, APC mediated the presentation of tumor antigens to tumor-specific cytotoxic CD8+ T cells, which are then released from the lymph nodes and enter in the bloodstream being able to recognize remaining tumour cells, both at the primary (and illuminated) tumour or distant metastases.
PDT treatments offer some tumor selectivity and specificity as a function of the illumination region. Additionally, PSs (namely amphiphilic and lipophilic PSs) are known to have preferential accumulation at tumor sites due to their interaction with low density lipoproteins (LDL), which have overexpressed receptors on cancer cells. Despite this, significant improvements for PDT treatment might be achieved by means of drug delivery strategies can mediate higher and more specific PS tumor accumulation. In this regard, one of our research activities is the development of advanced pharmaceutical formulations, ranging from simple strategies (e.g. cremophor, pluronics) to sophisticated nanocarriers like liposomes and hydrogels.
Some examples of concluded projects include:
- pH-sensitive chitosan-based hydrogel for sustained and controlled release of a derivative of temoporfin, a potent photosensitizer used for cancer treatment;
- lipid-based nanoparticles (delivery technology of mRNA COVID-19 vaccines) with improved endosomal release triggered by an external light source at 750 nm;
- formulations based on cremophor or pluronic for intravenous administration of highly lipophilic molecules, one is currently in clinical trials for photodynamic therapy of cancer (NCT02070432)
