Photodynamic Therapy-Current Limitations and Novel Approaches

Abstract

Photodynamic therapy (PDT) mostly relies on the generation of singlet oxygen, via the excitation of a photosensitizer, so that target tumor cells can be destroyed. PDT can be applied in the settings of several malignant diseases. In fact, the earliest preclinical applications date back to 1900's. Dougherty reported the treatment of skin tumors by PDT in 1978. Several further studies around 1980 demonstrated the effectiveness of PDT. Thus, the technique has attracted the attention of numerous researchers since then. Hematoporphyrin derivative received the FDA approval as a clinical application of PDT in 1995. We have indeed witnessed a considerable progress in the field over the last century. Given the fact that PDT has a favorable adverse event profile and can enhance anti-tumor immune responses as well as demonstrating minimally invasive characteristics, it is disappointing that PDT is not broadly utilized in the clinical setting for the treatment of malignant and/or non-malignant diseases. Several issues still hinder the development of PDT, such as those related with light, tissue oxygenation and inherent properties of the photosensitizers. Various photosensitizers have been designed/synthesized in order to overcome the limitations. In this Review, we provide a general overview of the mechanisms of action in terms of PDT in cancer, including the effects on immune system and vasculature as well as mechanisms related with tumor cell destruction. We will also briefly mention the application of PDT for non-malignant diseases. The current limitations of PDT utilization in cancer will be reviewed, since identifying problems associated with design/synthesis of photosensitizers as well as application of light and tissue oxygenation might pave the way for more effective PDT approaches. Furthermore, novel promising approaches to improve outcome in PDT such as selectivity, bioengineering, subcellular/organelle targeting, etc. will also be discussed in detail, since the potential of pioneering and exceptional approaches that aim to overcome the limitations and reveal the full potential of PDT in terms of clinical translation are undoubtedly exciting. A better understanding of novel concepts in the field (e.g. enhanced, two-stage, fractional PDT) will most likely prove to be very useful for pursuing and improving effective PDT strategies.

Keywords: bioengieering; current limitations; novel approaches; photodynamic therapy; photosensitizer; selectivity; targeting; tumor.

FIGURE 1

Basic Mechanisms of Action of PDT on Tumors. PDT can exert a plethora of actions such as inducing immune responses, direct killing of tumor cells, and damaging vascular structures.

FIGURE 2

Effects of PDT on Immune System. PDT can affect immune responses and induce anti-tumor immunity as well as stimulating inflammation at the target tissue. PDT may result in apoptosis and/or necrosis of the tumor cells. It is also capable of inducing immunogenic cell death, which stimulates immune responses against dead cell antigens. The antigens are taken up by antigen presenting cells such as dendritic cells. These cells then travel to secondary lymphoid organs in order to present those antigens to T cells. Activated T cells as well as monocytes, mast cells and neutrophils are recruited to the tumor microenvironment, resulting in inflammation. Effector T cells are capable of eliminating tumor cells.

FIGURE 3

Effects of PDT on Cancer Cells. PDT may result in apoptosis, necrosis, or autophagy.

FIGURE 4

Cell Death by PDT. PDT may induce apoptosis, necrosis, or autophagy via different mechanisms.

FIGURE 5

Light Penetration into Skin. Approximate penetration depths of light into skin according to its wavelength are illustrated.

FIGURE 6

PDT in Cancer. Selected limitations and approaches to improve outcome of PDT in cancer are illustrated.

FIGURE 7

Two Stage PDT. Two stage PDT can overcome the issues of light attenuation and oxygen deficiency in tumors. Reproduced from (Ayan et al., 2020) (published by The Royal Society of Chemistry) with permission from the Royal Society of Chemistry.

FIGURE 8

Fractional PDT. Fractional PDT allows for the continuation of photodynamic process both in the dark and in the light cycles (Turan et al., 2016). Reproduced from ref (Turan et al., 2016) with permission from Wiley, copyright 2016.