Sono-Photodynamic Therapy (SPDT) in Cancer Care

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 adjunctAnother treatment used together with the primary treatment. Its purpose is to assist the primary treatment. therapy, or for inoperable tumors and late-stage cases that have not responded well to conventional treatment.

Historical Perspective

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 20^th 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

Photodynamic therapy has been applied widely in clinical settings for many years. Research confirms that PDT induces cell death by apoptosisA type of cell death in which a series of molecular steps in a cell lead to its death. This is one method the body uses to get rid of unneeded or abnormal cells. The process of apoptosis may be blocked in cancer cells. Also called programmed cell death. 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

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

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].

FAQs

1. How does SPDT work?

SPDT is a new technology that uses full body and targeted ultrasound combined with specific wavelengths of light. Before treatment, you take a drug that selectively accumulates in cancer cells. The drug activates when exposed to specific frequencies and wavelengths of sound and light, which in turn kills cancer cells without damaging healthy cells.

2. How is SPDT administered?

In SPDT the drug can be taken by mouth, applied directly on the skin or injected depending on the location of the cancer. After 24 to 72 hours the drug will have left all healthy cells and will remain only in the cancer cells. Treatment with light and ultrasound can then begin.

3. Is SPDT safe and effective?

In general, sono-photodynamic therapy has been shown to be safe and effective for a range of cancer types. The treatment is well tolerated in most cases without major side effects. Any adverse effects are normally superficial and resolve soon after the completion of treatment.

References

[1] Chen H, Zhou X, Gao Y, Zheng B, Tang F, Huang J. Recent progress in development of new sonosensitizers for sonodynamic cancer therapy. Drug Discov Today. 2014 Apr;19(4):502-9. https://pubmed.ncbi.nlm.nih.gov/24486324/

[2] Pan X, Wang H, Wang S, Sun X, Wang L, Wang W, Shen H, Liu H. Sonodynamic therapy (SDT): a novel strategy for cancer nanotheranostics. Sci China Life Sci. 2018 Apr;61(4):415-426. https://pubmed.ncbi.nlm.nih.gov/29666990/

[3] Wan GY, Liu Y, Chen BW, Liu YY, Wang YS, Zhang N. Recent advances of sonodynamic therapy in cancer treatment. Cancer Biol Med. 2016 Sep;13(3):325-338. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069838/

[4] Sadanala KC, Chaturvedi PK, Seo YM, Kim JM, Jo YS, Lee YK, Ahn WS. Sono-photodynamic combination therapy: a review on sensitizers. Anticancer Res. 2014 Sep;34(9):4657-64. https://ar.iiarjournals.org/content/34/9/4657/

[5] Kenyon JN. Outcome measures following Sono and Photodynamic Therapy – A Case Series. Journal of Cancer Treatment and Diagnosis. 2021 Mar;5(1):23-29. https://doi.org/10.29245/2578-2967/2021/1.1195

[6] Zhang W, Li K, Lu J, Peng Z, Wang X et al. (2017) Sonodynamic and Photodynamic Therapy in Breast Cancer – A Pilot Study. Int J Complement Alt Med 9(5): 00313. DOI: 10.15406/ijcam.2017.09.00313

[7] Sivasubramanian M, Chuang YC, Lo LW. Evolution of Nanoparticle-Mediated Photodynamic Therapy: From Superficial to Deep-Seated Cancers. Molecules. 2019 Jan 31;24(3):520. https://pubmed.ncbi.nlm.nih.gov/30709030/

[8] Henderson BW, Dougherty TJ. How does photodynamic therapy work? Photochem Photobiol. 1992 Jan;55(1):145-57. https://pubmed.ncbi.nlm.nih.gov/1603846/

[9] Wang X, Zhang W, Xu Z, Luo Y, Mitchell D, Moss RW. Sonodynamic and photodynamic therapy in advanced breast carcinoma: a report of 3 cases. Integr Cancer Ther. 2009 Sep;8(3):283-7. https://journals.sagepub.com/doi/pdf/10.1177/1534735409343693

[10] Zheng, Yilin & Jinxiang, Ye & Li, Ziying & Chen, Haijun & Gao, Yu. (2020). Recent progress in sono-photodynamic cancer therapy: From developed new sensitizers to nanotechnology-based efficacy enhancing strategies. Acta Pharmaceutica Sinica B. 11. 10.1016/j.apsb.2020.12.016. https://doi.org/10.1016/j.apsb.2020.12.016

[11] Photodynamic Therapy to Treat Cancer. https://www.cancer.gov/about-cancer/treatment/types/photodynamic-therapy

[12] Senapathy GJ, George BP, Abrahamse H. Exploring the Role of Phytochemicals as Potent Natural Photosensitizers in Photodynamic Therapy. Anticancer Agents Med Chem. 2020;20(15):1831-1844. https://pubmed.ncbi.nlm.nih.gov/32619181/

[13] Yamaguchi T, Kitahara S, Kusuda K, Okamoto J, Horise Y, Masamune K, Muragaki Y. Current Landscape of Sonodynamic Therapy for Treating Cancer. Cancers (Basel). 2021 Dec 8;13(24):6184. https://doi.org/10.3390/cancers13246184

[14] Rengeng L, Qianyu Z, Yuehong L, Zhongzhong P, Libo L. Sonodynamic therapy, a treatment developing from photodynamic therapy. Photodiagnosis Photodyn Ther. 2017 Sep;19:159-166. https://pubmed.ncbi.nlm.nih.gov/28606724/

[15] Lucy Qing Li, Xiaohuai Wang, Iris Wenyin Zhang, and Douglas Mitchell. Primary clinical use of the sono-photo-dynamic therapy for advanced esophagocadiac and gastric adenocarcinomaCancer that begins in glandular (secretory) cells. Most cancers of the breast, pancreas, lung, prostate, and colon are adenocarcinomas.. Journal of Clinical Oncology 2014 32:15. https://ascopubs.org/doi/abs/10.1200/jco.2014.32.15_suppl.e15024

[16] Mahmoud H. Abdel-kader, CHAPTER 1:The Journey of PDT Throughout History: PDT from Pharos to Present , in Photodynamic Medicine: From Bench to Clinic, 2016, pp. 1-21 DOI: 10.1039/9781782626824-00001

[17] Daniell MD, Hill JS. A history of photodynamic therapy. Aust N Z J Surg. 1991 May;61(5):340-8. https://pubmed.ncbi.nlm.nih.gov/2025186/

[18] Ackroyd, Roger & Kelty, Clive & Brown, Nicola & Reed, Malcolm. (2007). The History of Photodetection and Photodynamic Therapy. Photochemistry and Photobiology. 74. 656 – 669. https://www.researchgate.net/publication/229731546_The_History_of_Photodetection_and_Photodynamic_Therapy

[19] Dougherty, T.J. (2007). A Personal History of Photodynamic Therapy. In: Schlag, P.M., Stein, U., Eggermont, A.M.M. (eds) Regional Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-225-0_9

[20] Kato H. [History of photodynamic therapy–past, present and future]. Gan To Kagaku Ryoho. 1996 Jan;23(1):8-15. Japanese. https://pubmed.ncbi.nlm.nih.gov/8546474/

[21] Kessel D. Photodynamic Therapy: A Brief History. J Clin Med. 2019 Oct 2;8(10):1581. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832404/

[22] Umemura S, Yumita N, Nishigaki R, Umemura K. Mechanism of cell damage by ultrasound in combination with hematoporphyrin. Jpn J Cancer Res. 1990 Sep;81(9):962-6. https://pubmed.ncbi.nlm.nih.gov/2172198/

[23] Miyoshi N, Kundu SK, Tuziuti T, Yasui K, Shimada I, Ito Y. Combination of Sonodynamic and Photodynamic Therapy against Cancer Would Be Effective through Using a Regulated Size of Nanoparticles. Nanosci Nanoeng. 2016 Feb;4(1):1-11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827930/[24] The American Cancer Society medical and editorial content team. Getting Photodynamic Therapy. American Cancer Society. Last Revised: November 19, 2021. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/radiation/photodynamic-therapy.html

Photodynamic therapy (PDT) is a treatment that uses a drug, called a photosensitizer or photosensitizing agent, and a particular type of light. When photosensitizers are exposed to a specific wavelength of light, it is theorized they produce a form of oxygen that kills nearby cells. [1]

Each photosensitizer is activated by light of a specific wavelength. This wavelength determines how far the light can travel into the body . Therefore, doctors use specific photosensitizers and wavelengths of light to treat various areas of the body with PDT.

In addition to potentially killing cancer cells, PDT appears to shrink or destroy tumors in two other ways. The photosensitizer may cause damage to the blood vessels in the tumor, thereby preventing cancer from receiving necessary nutrients. PDT may also activate the immune system to attack the tumor cells.

Photodynamic Therapy (PDT) and Sono-Dynamic Therapy (SDT) have been innovatively combined into the Sono-Photo Dynamic Therapy (SPDT) method. The possibility that SPDT may help even the most advanced cancers, SPDT could provide a powerful and non-toxic method to destroy aberrant cancer cells. [2]

Sono-Photo Dynamic Therapy combines two therapies suggested to destroy cancer cells. SPDT involves getting an agent into the whole body, (originally by injection, now orally), which adheres to cancer cells, so that when light and now, sound, of the correct frequency is applied, the agent “explodes” into free radical oxygen, essentially killing the cancer cells which cannot survive in oxygen. It is suggested to be followed up by cleansing of toxinsA poison made by certain bacteria, plants, or animals, including insects. from the body, especially including all of the just killed cancer cells.

In this treatment, a patient ingests an oral, non-toxic, photosensitive dietary supplementA product, generally taken orally, that contains one or more ingredients (such as vitamins or amino acids) that are intended to supplement one's diet and are not considered food. called SP-Activate (SP-A). SP-A preferentially absorbs into cancer cells. At precise sound (sono) and light (photo) frequencies, SP-Activate produces a high energy molecule that induces free radical oxygen, destroying the cancer cell. The sound and light frequencies are directed locally at a tumor site, or systemically (treating a large area of the body).

It is important to note that the origin of the cancer must still be dealt with.

SPDT is recently approved in the U.S., UK, and has been adopted by the Chinese Government. Experimental projects have recently been published in Toronto, Canada, and other countries.

Sono-Photo Dynamic Therapy has been used in combination with other therapies to treat a number of cancers, including but not limited to the following: [2]

• 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

Research continues on ways to increase PDT effectiveness and expand it to other cancers. Clinical trials are under way to evaluate the use of PDT for cancers of the brain, skin, prostate, cervix, and peritoneal cavity. Other studies are focused on the development of more powerful and targeted photosensitizers that are activated by light which can penetrate tissue and treat deep or large tumors. Researchers are also working toward ways to improve equipment and the delivery of the activating light.