Systemic effects

Photodynamic therapy (PDT) is a clinically approved practice for treatment of cancer and infectious diseases. PDT involves systemic or topical administration of a photosensitizer (PS), followed by irradiation of the target area with light of a wavelength matching the absorption band of the PS. In the presence of oxygen, photochemical reactions trigger the production of reactive oxygen species and, consequently, cell death by oxidative stress. Besides causing direct cytotoxicity to tumor cells, PDT induces destruction of the tumor vasculature releasing pro-inflammatory cytokines. Current literature supports that PDT is able to affect both the innate and adaptive responses of the immune system. In addition, PDT-induced adaptive immunity may attack distant untreated tumor cells and lead to development of antitumor memory immunity, which can potentially avoid the cancer relapse. Conversely, pro-inflammatory activity of PDT can also collaborate to resolve local infections since more neutrophils are recruited to the infected region. When photosensitizer (PS) preparations are injected into the bloodstream, they tend to bind to various serum proteins, and this binding can dramatically affect their pharmacokinetics and biodistribution [1]. Different PSs can have very different pharmacokinetics and this can directly affect the illumination parameters and particularly the pharmacokinetics will determine the drug-light interval [2]. Intravenously injected PSs undergo a gradual transition from being bound to serum proteins, then becoming bound to endothelial cells, and then they are bound to the adventitia of the vessels, then bound either to the extracellular matrix or to the cells within the tumor. Eventually, they will be cleared from the tumor tissue by removal by lymphatic system or by blood vessels, and they will be excreted either by the kidneys or the liver. The effect of PDT on the tumor largely depends at which stage of this continuous process light is delivered. The antitumor effects of PDT are divided into three main mechanisms. Direct tumor cell death by apoptosis or necrosis can occur, if the PS has been allowed to be taken up by tumor cells. Powerful anti-vascular effects can lead to thrombosis and hemorrhage in tumor blood vessels that subsequently lead to shutdown of tumor blood vessels, which kill the tumor by deprivation of oxygen and nutrients. Finally the release of damage-associated molecular patterns (DAMPs) leads to acute inflammation and the release of cytokines [3]. The DAMPs, cytokines, and stress-response proteins induced in the tumor by PDT work together and lead to an influx of leukocytes that can both contribute to tumor destruction and to stimulate the immune system to recognize and destroy tumor cells even at distant locations.