Sono-Photo Dynamic Therapy (SPDT)

Sono-photodynamic therapy, or SPDT, is a promising new alternative cancer treatment, which utilizes sound (sono) and light (photo) to selectively target and eliminate cancer cells. It combines photodynamic therapy (PDT) with sonodynamic therapy (SDT) in a synergistic manner, which increases efficacy when compared to the application of either treatment individually.

PDT involves the use of photosensitive agents (photosensitizers), which are drugs that are activated by certain wavelengths of laser light and kill cancer cells. PDT has been widely used in clinical settings for many years, but is only effective for surface level tumors due to the limited penetrability of visible light [1].

SDT is a more recent development in cancer care, which is thought to overcome the disadvantages of PDT [1]. It involves the use of sonosensitive agents (sonosensitizers), which are drugs that are activated by certain ultrasound frequencies to target cancer cells. SDT provides many advantages such as deeper tissue penetration, high precision and fewer side-effects [2]. It gives the ability to target deep-seated solid tumors and eradicate them in a non-invasive and site-directed manner [3].

In sono-photodynamic therapy, the combined use of ultrasound and laser light can make cancer treatment more effective [4]. SPDT has been shown in small scale studies to improve treatment outcomes in cancer patients with various cancer types, and may provide benefits even for advanced metastatic (widespread) cancers that are resistant to chemotherapy [5]. Many other cancer treatment approaches, such as chemotherapy and radiation, cause systemic toxicity, suppress immunity, or can only be used infrequently. SPDT provides a promising alternative clinical approach that is non-invasive, non-toxic, can be applied frequently without causing harm and often improves immune function. It has also been shown in experimental studies with limited patient numbers to have synergistic effects that may enhance the efficacy of standard of care treatments [6].

Overall, SPDT is an emerging strategy that shows great potential as an adjunct therapy, or for inoperable tumors and late-stage cases that have not responded well to conventional treatment.

History of Sono-Photodynamic Therapy

The knowledge of the powerful healing effects of sunlight date back to antiquity. Many ancient cultures worshiped the sun and utilized light as a therapy for different diseases [16]. Records of phototherapy, classically referred to as heliotherapy, date back thousands of years to the ancient civilizations of Egypt, China, Greece, India and Rome [16].

Phototherapy disappeared for centuries, only to be rediscovered in the West at the start of the 20th Century in Germany by Arnold Rikli, Oscar Raab, Niels Finsen and Herman von Tappeiner [17]. These early pioneers discovered the tumor-localizing ability of compounds called porphyrins and their toxic effects on tumor tissues when combined with light [18]. This led to the development of modern-day photodynamic therapy (PDT).

Although PDT was first discovered over a hundred years ago, it only became a focus of mainstream cancer research in the 1970s. Thomas J. Dougherty, PhD successfully treated cancer with PDT in preclinical models in 1975 at Roswell Park Cancer Institute in Buffalo, New York [19]. In 1978 he conducted the first of a series of clinical studies in humans, which confirmed the efficacy and safety of the method [20]. In 1980 Dougherty and his team performed PDT on early-stage bronchial squamous cell carcinoma and achieved a complete cure [20]. Since then the treatment attracted major attention and Dougherty’s clinical data eventually led to FDA approval of the procedure in 1995 [21].

In the late 1980s it was reported that a variety of photosensitizing agents administered in conjunction with ultrasound also had anti-cancer effects [13]. In 1990, Shin-ichiro Umemura, PhD et al. introduced the concept of sonodynamic therapy to target cancer cells in mice with ultrasonically activated sensitizing agents [22]. From that point onwards, SDT developed into the promising non-invasive cancer therapy that it is today [13]. Sono-photodynamic therapy as a synergistic combination of PDT and SDT is a novel therapeutic modality with research only beginning to emerge in the last decade or two.

Research on Sono-Photodynamic Therapy

Photodynamic therapy has been applied widely in clinical settings for many years. Research confirms that PDT induces cell death by apoptosis and necrosis, increases oxidative stress, alters cancer cell death signaling pathways, increases cytotoxicity and damages DNA in tumor cells [12].

The scientific literature shows that SDT disrupts tumor growth, induces cell death, and elicits an immune response [13]. The treatment can be effectively combined with targeted therapy and immunotherapy. Given its minimally invasive nature, synergistic effects, safety and efficacy, it could be a powerful tool in the future for treating previously incurable cancers [13].

A 2017 review of the literature on SDT states that recent studies have shown that SDT can selectively target cancer cells and has the potential to treat solid tumors, leukemia, atherosclerosis, remove proliferative scars, and kill pathogenic microorganisms [14].

SPDT treatment has been shown in a 2017 case study (small-scale patient reports) carried out over 4 years to result in a significant drop in circulating tumor cells in 17 patients with various cancer types and stages. Results indicate that SPDT could be an effective and well-tolerated treatment for a wide variety of primary and metastatic tumors, including those that have become resistant to chemotherapy [5]. Another case study on SPDT reported significant partial or complete responses in all 3 patients treated with advanced refractory (treatment-resistant) breast cancer [9].

A small 2017 study on SPDT treatment in 12 patients with advanced metastatic breast cancer showed a 75% response rate and concluded that the treatment had no significant side-effects and may significantly increase the efficacy of chemotherapy in advanced refractory cases [6]. Preliminary data from another study on 3 patients with advanced refractory esophageal and gastric cancers suggests that SPDT may dramatically enhance the efficacy of standard of care treatments without toxic side-effects [15].

Researchers agree that SPDT shows promise as a new systemic strategy in cancer care and as an adjunct therapy[6]. It merits further investigation as a therapeutic tool for advanced metastatic cancers of various types, which have become resistant to first line treatment approaches [5].

Potential Applications of Sono-Photodynamic Therapy

SPDT has been shown to be safe and effective. It is a beneficial non-invasive and non-toxic therapy that has potential application as an adjunct treatment for most cancer types and stages of disease. It has a wide range of clinically-supported benefits. Studies show it can be as effective as surgery or radiation in certain cases.

Sono-photodynamic therapy has been used in combination with other therapies to treat a range of cancer types, including but not limited to the following:

• Bone Cancer
• Brain Cancer
• Breast Cancer
• Cervical Cancer
• Colon Cancer
• Esophageal Cancer
• Head and Neck Cancers
• Leiomyosarcoma
• Leukemia
• Liver Cancer
• Lung Cancer
• Lymphoma
• Melanoma
• Ovarian Cancer
• Pancreatic Cancer
• Prostate Cancer
• Rectal Cancer
• Stomach Cancer
• Thyroid Cancer
• Urinary Bladder Cancer
• Uterine Cancer
• Vaginal Cancer

Potential benefits of SPDT include:

• No long-term side effects when administered correctly
• Non-invasive compared to surgery
• Non-toxic compared to conventional treatments
• Can be repeated frequently at same location (unlike radiation)
• Can be targeted precisely
• Little or no scarring
• Synergistic effects with standard of care treatments
• Normalized or improved tumor markers
• Reduced circulating tumor cells
• Selectively kills cancer cells
• Inhibits tumor growth
• Reduction or elimination of solid tumors and blood cancers
• Highly synergistic with low-dose and high-dose chemotherapy
• Suitable for early-stage and advanced metastatic cancer
• Promising solution for treatment-resistant or otherwise incurable cancers
• Pain reduction
• Improved quality of life
• Longer survival rates
• Palliative benefits

Mechanism of Action Explained:

Photodynamic therapy requires the combination of three components: a photosensitive drug, laser light and molecular oxygen. In PDT the patient is administered a photosensitizer (molecule activated by light), which is preferentially absorbed by cancer cells. When irradiated with a specific wavelength of laser light, the photosensitizer absorbs the light energy and activates [7]. When activated, it generates cytotoxic oxygen free radicals, known as reactive oxygen species (ROS), which in turn damage DNA and induce apoptosis (programmed cell death) of cancerous cells without damaging healthy cells [8]. Light at specific wavelengths can be targeted to a tumor site or systemically to treat a large area of the body.

Sonodynamic therapy also requires the combination of three components: a sonosensitive drug, low-intensity ultrasound and molecular oxygen. In SDT the patient is administered a sonosensitizer (molecule activated by sound), which is then almost exclusively uptaken by cancer cells. When exposed to ultrasound waves of a specific frequency, the sonosensitizer activates and releases a cascade of endogenous cytotoxic agents, such as ROS, which damage DNA and induce apoptosis in cancer cells, selectively destroying the tumor cells from inside [6].

The advantage of ultrasound is that it penetrates more deeply than light, which means it is more effective for the treatment of deep-rooted tumors than PDT [6]. The successful application of PDT has been limited to superficial cancers such as skin, head, neck, mouth, throat or breast, because of the limited penetration of laser light into tumor tissues [9]. SDT was developed as a complementary or alternative therapy to PDT in order to resolve shortfalls of the treatment. Ultrasound allows for non-invasive targeted treatment of deeper tumor sites throughout the body, which is not possible with photodynamic therapy [5].

Certain sensitizers have both photodynamic and sonodynamic effects, which means they are activated by both light and sound [10]. In sono-photodynamic therapy for cancer, PDT and SDT are combined with a carefully selected sensitizing drug that is activated by both light and sound frequencies. This results in powerful synergistic effects. Research has demonstrated that SPDT generates much greater cytotoxicity in cancer cells than either SDT or PDT alone and that ROS are significantly increased with the combined therapy [6].

SPDT can be targeted locally or administered systemically to treat cancers throughout the whole body. The therapy may also damage blood vessels in tumors, cutting off the blood supply and therefore inhibiting tumor growth [11]. It may also have a systemic anti-cancer effect and trigger the immune system to attack cancerous cells throughout the body [11].

Risks and side-effects of Sono-Photodynamic Therapy

In general, sono-photodynamic therapy has been shown to be safe in terms of serious adverse effects and relatively harmless even with frequent applications [23]. Damage to healthy cells generally remains limited as the sensitizing agents are preferentially absorbed by cancer cells. There are no serious risks or long-term side-effects commonly associated with the treatment, but there can be some short-term side-effects with photodynamic therapy and photosensitizers.

While damage to normal cells is limited, PDT can occasionally cause issues at the targeted site of treatment such as:

• Burns
• Swelling
• Redness or itching
• Pain
• Scarring

Other side effects may include:

• Cough
• Breathing difficulties
• Trouble swallowing
• Stomach pain

Certain photosensitizers, such as porfimer sodium, are known to make the skin and eyes sensitive to light for about 6 weeks. During this time patients are advised to avoid direct sunlight and stay inside as much as possible [11].

Occasionally PDT treatments can alter immune function, either stimulating or weakening the immune system for a certain period of time. In extremely rare cases, PDT has been known to cause skin cancer at the site where treatment was given. This is believed to only happen if the immune system was suppressed by the treatment [24].

The majority of reported side effects improve soon after the treatment is finished, and overall, SPDT is considered to be a well-tolerated and low-toxicity therapy compared to other conventional treatments [11].