A review and outlook in the treatment of osteosarcoma and other deep tumors with photodynamic therapy: from basic to deep

Abstract

Photodynamic therapy, one of the most promising minimally invasive treatments, has received increasing focus in tumor therapy research, which has been widely applied in treating superficial tumors. Three basic factors - photosensitizer, the light source, and oxidative stress - are responsible for tumor cell cytotoxicity. However, due to insufficient luminous flux and peripheral tissue damage, the utilization of photodynamic therapy is facing a huge limitation in deep tumor therapy. Osteosarcoma is the typical deep tumor, which is the most commonly occurring malignancy in children and adolescents. Despite developments in surgery, high risks of the amputation still threatens the health of osteosarcoma patients. In this review, we summarize recent developments in the field of photodynamic therapy and specifically PDT research in OS treatment modalities. In addition, we also provide some novel suggestions, which could potentially be a breakthrough in PDT-induced OS therapies. PDT has the potential to become an effective therapy while the its limitations still present when applied on the treatment of OS or other types of deep tumors. Thus, more researches and studies in the field are required.

Keywords: immunotherapy; nanotechnology; osteosarcoma; photodynamic; target therapy.

Figure 1. The light-induced PSs activating and ROS producing in PDT

Photodynamic is activated with the irradiation of specific light source, which was transit to high energy level and release the electron when the PSs return to the ground state. The electrons lead to the two types of oxidation reactions. Type I is substrate or solvent induced oxygen radical generation, which is also called reactive oxygen specie (ROS). Type II is the activation of singlet oxygen (¹O₂) by oxygen molecule and which also promote the producing of ROS. Both ROS and ¹O₂ contribute to the apoptosis of cancer cells.

Figure 2. The antitumor effect of various wavelength light sources

The light in NISR can get through the skin and have the cytotoxicity to the tumor cells while UV light will be block in epidermis layer. However, the attenuation of NISR light in different layers of skin and soft tissues will weaken the antitumor effect and cause the Invalidation of PDT. This is the largest barrier of PDT in deep tumor therapy.

Figure 3. The summarization of various PSs in different PDT researches of OS

This figure summarizes the total PSs of PDT in OS. There are only 31 articles and 14 types of PSs involved in the PDT in OS.

Figure 4. The relevant pathways involved in PDT-induced antitumor effect

The ROS is activated by the combination of light source, PSs and oxygen, which cause the necrosis, apoptosis and the activation of DCs in tumor cells. With the recognition of antigen on the surface of tumor cells, DCs activate the CTL and lead to the specific cellular immune to the tumor. At the same time, the ROS will promote the autophagy in cancer cells, which will reverse the cell death with the inhibition of necrosis and apoptosis. On the other hands, the tumor vessels injury and cell cycle arrest will also cause the apoptosis of cancer cells.

Figure 5. The summarization of seven feasible improvements to PDT in OS

A. The employment of X-ray, which has the high penetrating in various tissues B. Using the optical fiber as the conductor of laser in the skin, which avoid the epithelial tissue injury and lead to the cytotoxicity directly. C. Designing the PSs in a nano size to enhance the cycling time in body and gathering in tumor tissue induced by EPR effect. D. Combining with the target molecule and result to the gathering effect in tumor tissue. E. The combination of RE elements induced by upconversion with the core-shell structure of PSs. F. Utilization of tumor vaccine induced by PDT. G. Adjuvant- related CTL activation in PDT.