Next Article in Journal
Correction: Kazimir et al. Metallodrugs against Breast Cancer: Combining the Tamoxifen Vector with Platinum(II) and Palladium(II) Complexes. Pharmaceutics 2023, 15, 682
Next Article in Special Issue
Indole Antitumor Agents in Nanotechnology Formulations: An Overview
Previous Article in Journal
Precision Vaccinology Approaches for the Development of Adjuvanted Vaccines Targeted to Distinct Vulnerable Populations
Previous Article in Special Issue
New Ruthenium-Cyclopentadienyl Complexes Affect Colorectal Cancer Hallmarks Showing High Therapeutic Potential
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pharmaceutics
Volume 15
Issue 6
10.3390/pharmaceutics15061767
pharmaceutics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Shining a Light on Prostate Cancer: Photodynamic Therapy and Combination Approaches

by
Hicham Wahnou
1,
Ibtissam Youlyouz-Marfak
2,
Bertrand Liagre
3,
Vincent Sol
3,
Mounia Oudghiri
1,
Raphaël Emmanuel Duval
4,* and
Youness Limami
1,2,*
1
Laboratory of Immunology and Biodiversity, Faculty of Sciences Ain Chock, Hassan II University, B.P. 2693, Maarif, Casablanca 20100, Morocco
2
Laboratory of Health Sciences and Technologies, Higher Institute of Health Sciences, Hassan First University of Settat, Settat 26000, Morocco
3
Univ. Limoges, LABCiS, UR 22722, F-87000 Limoges, France
4
Université de Lorraine, CNRS, L2CM, F-54000 Nancy, France
*
Authors to whom correspondence should be addressed.
Pharmaceutics 2023, 15(6), 1767; https://doi.org/10.3390/pharmaceutics15061767
Submission received: 26 May 2023 / Revised: 15 June 2023 / Accepted: 16 June 2023 / Published: 19 June 2023
(This article belongs to the Special Issue Novel Anticancer Strategies (Volume III))
Browse Figures
Versions Notes

Abstract

:
Prostate cancer is a major health concern worldwide, and current treatments, such as surgery, radiation therapy, and chemotherapy, are associated with significant side effects and limitations. Photodynamic therapy (PDT) is a promising alternative that has the potential to provide a minimally invasive and highly targeted approach to treating prostate cancer. PDT involves the use of photosensitizers (PSs) that are activated by light to produce reactive oxygen species (ROS), which can induce tumor cell death. There are two main types of PSs: synthetic and natural. Synthetic PSs are classified into four generations based on their structural and photophysical properties, while natural PSs are derived from plant and bacterial sources. Combining PDT with other therapies, such as photothermal therapy (PTT), photoimmunotherapy (PIT), and chemotherapy (CT), is also being explored as a way to improve its efficacy. This review provides an overview of conventional treatments for prostate cancer, the underlying principles of PDT, and the different types of PSs used in PDT as well as ongoing clinical studies. It also discusses the various forms of combination therapy being explored in the context of PDT for prostate cancer, as well as the challenges and opportunities associated with this approach. Overall, PDT has the potential to provide a more effective and less invasive treatment option for prostate cancer, and ongoing research is aimed at improving its selectivity and efficacy in clinical settings.

Graphical Abstract

1. Introduction

With over 1.4 million new cases and more than 375,000 deaths worldwide in 2020, prostate cancer is a major public health concern [1]. Prostate cancer is the second most commonly occurring cancer in men and the fourth most common cancer overall. In addition, the rising incidences of prostate cancer in the last decade are concerning, even if it is likely attributed to earlier detection through increased screening [1]. Conventional treatment options such as surgery, radiation therapy, hormone therapy, chemotherapy, and immunotherapy have limitations, including high invasiveness, poor specificity, and adverse effects. In this context, PDT has emerged as an innovative and promising treatment option for prostate cancer due to its high specificity, low invasiveness, and reproducibility [2,3].
PDT involves the use of photosensitizing agents and light to activate them, leading to localized cancer cell death [2]. However, PDT alone may not be sufficient to eradicate prostate cancer completely. Thus, the combination with other therapeutic options may provide opportunities to draw on the strong points of each option and offset their weaknesses, leading to additive or synergistic therapeutic effects [4].
This review article aims to explore the potential of PDT as a treatment for prostate cancer, including its mechanism of action, limitations, photosensitizers, and combination with other therapies. It also provides insights into the future directions of PDT in the context of prostate cancer treatment.
To ensure the accuracy and comprehensiveness of our review, our team embarked on a rigorous data collection and search process from a wide range of reputable databases, including Google Scholar, Pubmed, Springer, Elsevier ScienceDirect, and Web of Science. We focused on scrutinizing studies published from 2000 to 2023 and we included one older study for contextualization. In order to maintain consistency and ensure a thorough analysis, only articles containing English texts were selected, and we conducted keyword and heading searches for the following terms: prostate cancer, photodynamic therapy, natural photosensitizers, synthetic photosensitizers, prostate cancer treatment complications, and combination cancer therapies.
Then, a thorough selection process was conducted, starting with 2101 records. Before proceeding to screen full-text documents, duplicate papers and irrelevant works were eliminated. The inclusion criteria were strict and consisted of original articles, review papers, book chapters or websites that met specific factors, thus ensuring the accuracy and quality of the information presented in this paper. Overall, 96 references were selected for our study, which included articles or websites specifically dedicated to providing context, epidemiological data, and reports of clinical studies.

2. Conventional Treatments for Prostate Cancer and Complications

2.1. Surgery

Surgery is a common treatment option for prostate cancer and involves the partial or radical removal of the prostate gland. This procedure, known as a prostatectomy, can be performed using various techniques [5]. Nevertheless, many potential complications may arise in this procedure, such as incontinence and erectile dysfunction resulting from surgical damage to the urinary sphincter and erectile nerves [6]. These adverse effects can greatly impact a patient’s quality of life and are important considerations in prostate cancer treatment decision-making [6].

2.2. Radiation Therapy

Radiation therapy is a cancer treatment that uses high-energy X-rays or other types of radiation to eliminate cancer cells. Two types of radiation therapy are used: external and internal [5]. External radiation therapy involves using a machine to direct radiation toward the cancer site, while internal radiation therapy places a radioactive substance directly into or near the cancer site [5,7]. Radiation therapy for prostate cancer increases the risk of developing bladder and/or gastrointestinal cancer. Furthermore, a higher rate of long-term complications, such as impotence and urinary problems, can also occur [5,8].

2.3. Hormone Therapy

Hormone therapy, also known as androgen deprivation therapy (ADT), is a treatment that aims to remove or block male hormones, which can cause cancer cells to grow. This can be achieved through drugs such as abiraterone acetate and luteinizing hormone-releasing hormone agonists, or surgery to remove the testicles (orchiectomy), or the use of antiandrogens that block the action of male hormones [5]. Hormone therapy can help shrink the tumor and slow the growth of cancer, but it may also cause side effects including hot flashes, loss of libido, and weakened bones [5,7].

2.4. Chemotherapy

Chemotherapy is a treatment that uses powerful drugs to destroy cancer cells. In prostate cancer, chemotherapy is usually reserved for advanced cases that no longer respond to hormone therapy [5]. Chemotherapy can cause side effects such as hair loss, nausea, vomiting, fatigue, and an increased risk of infection due to a weakened immune system. However, these side effects can be managed with medications and other supportive therapies [7,9].

2.5. Cellular Immunotherapy

Immunotherapy is a cancer treatment that harnesses the patient’s own immune system to attack cancer cells. It involves the use of substances or cells, either naturally produced by the body or created in a lab, to enhance or restore the body’s natural defenses against cancer [5]. In the case of prostate cancer, Sipuleucel-T, an autologous cellular immunological agent, is intended for patients with metastatic hormone-refractory prostate cancer. It consists of exposing the patient’s peripheral blood mononuclear cells to a recombinant fusion protein composed of prostatic acid phosphatase, an antigen that is highly expressed in most prostate cancer cells, and a granulocyte-macrophage colony-stimulating factor. The mechanism of action is not fully elucidated, but it is likely to work through antigen-presenting cells (APCs) to stimulate a T-cell immune response [10]. The most reported side effects, including chills, fever, headache, myalgia, sweating, and influenza-like symptoms, were attributed to cytokine release usually within the first 24 h of infusion. However, no increased risk of autoimmune complications has been reported to date [5].

2.6. Other Therapeutic Approaches

Prostate cancer treatment has come a long way, with several innovative therapies reported in clinical studies [5]. Cryosurgery, or cryotherapy, involves the use of an instrument to freeze and destroy cancerous prostate cells. High-intensity-focused ultrasound therapy, on the other hand, uses ultrasound waves to break down cancer cells. Additionally, proton beam radiation therapy employs tiny, positively charged particles to target and kill tumor cells [5].
Besides these therapeutic approaches, another promising treatment for prostate cancer is PDT. The principle of this alternative treatment is the use of a photoactivated drug to selectively destroy cancer cells while minimizing damage to healthy tissues and side effects.

3. PDT

3.1. Mechanism of Action

PDT uses a photosensitizer (PS), molecular oxygen, and light to generate reactive oxygen species (ROS) that can trigger tumor cell death [11]. PDT can cause tumor destruction by three mechanisms: direct cell death, tumor vascular damage, and an immune response (Figure 1) [11,12].
Direct cell death (Figure 1A) occurs through both programmed cell death (apoptosis) and non-programmed cell death (necrosis) pathways [13]. Necrosis is characterized by rapid cell death leading to the release of cellular components and molecules that promote inflammation, while apoptosis is a genetically encoded, energy-dependent process that can initiate an immune response [14,15]. PDT can also induce unconventional modes of cell death in cancer cells, including paraptosis, parthanatos, mitotic catastrophe, pyroptosis, necroptosis, and ferroptosis [13]. In addition, a growing body of evidence suggests that PDT can also trigger immunogenic cell death (ICD) [16], which has emerged as a promising strategy for eliminating tumor cells by promoting T-cell adaptive immune responses and inducing durable immunological memory [13,16,17].
PDT can also damage the tumor microvasculature (Figure 1B), leading to the interruption of the tumor’s feeding and, consequently, to the death of the tumor cells. This vascular mechanism is achieved by concentrating the PS in the vascular system and using a short drug-light interval [18]. PDT vascular effect can be selectively applied to the tumor and surrounding healthy tissue, with important advantages over PDT protocols that require PS accumulation in the tumor cells [17,18].
Finally, PDT can induce an immune response (Figure 1C) that can contribute to long-term tumor control [18]. PDT has been shown to influence the adaptive immune response through either stimulation or suppression, depending on the treatment protocol [6]. The oxidative damage inflicted by PDT on the tumor stroma triggers an acute inflammatory response initiated by the release of pro-inflammatory mediators. These mediators attract the host’s innate immune cells, which can activate a systemic antitumor immune response. PDT-induced necrosis of tumors and their vasculature can activate CD8 cytotoxic T lymphocytes that can specifically destroy tumor cells and circulate throughout the body for long periods [18].
Pharmaceutics 15 01767 g001 550
Figure 1. PDT destroys tumor cells by three mechanisms of action. (A) Induction of cell death through various pathways depends on the location of the photosensitizer (PS) and the extent of damage to the organelles. Mitochondrial damage caused by PDT results in the loss of membrane permeability and the release of pro-apoptotic mediators, while damage to the endoplasmic reticulum (ER) leads to the release of cellular calcium deposits. Lysosomal damage, on the other hand, causes the release of proteolytic enzymes upon illumination, and can also trigger autophagy. In cases where apoptosis is dysfunctional, necrosis and autophagy may be the primary modes of cell death after PDT. It is important to note that multiple PSs may localize in multiple organelles, and therefore, simultaneous activation of death pathways may occur (adapted from Mroz, P et al. [19]). (B) PDT can induce vascular damage, leading to the interruption of the tumor’s feeding causing its death through various mechanisms. (C) PDT can also activate innate and adaptative immunity, leading to a systemic antitumor immune response and the destruction of tumor cells.
Figure 1. PDT destroys tumor cells by three mechanisms of action. (A) Induction of cell death through various pathways depends on the location of the photosensitizer (PS) and the extent of damage to the organelles. Mitochondrial damage caused by PDT results in the loss of membrane permeability and the release of pro-apoptotic mediators, while damage to the endoplasmic reticulum (ER) leads to the release of cellular calcium deposits. Lysosomal damage, on the other hand, causes the release of proteolytic enzymes upon illumination, and can also trigger autophagy. In cases where apoptosis is dysfunctional, necrosis and autophagy may be the primary modes of cell death after PDT. It is important to note that multiple PSs may localize in multiple organelles, and therefore, simultaneous activation of death pathways may occur (adapted from Mroz, P et al. [19]). (B) PDT can induce vascular damage, leading to the interruption of the tumor’s feeding causing its death through various mechanisms. (C) PDT can also activate innate and adaptative immunity, leading to a systemic antitumor immune response and the destruction of tumor cells.
Pharmaceutics 15 01767 g001

3.2. Photosensitizers (PSs)

PSs are molecules that can absorb light and transfer the absorbed energy to the surrounding molecules (e.g., oxygen), leading to the generation of reactive oxygen species (ROS) that can cause cell death. These PSs are generally divided into two categories: tetrapyrrolic macrocycles (i.e., porphyrins, chlorins, bacteriochlorins, phthalocyanines, and their derivates) and no tetrapyrrolic macrocycles (i.e., methylene blue, curcumin, phenalenon, coumarin, anthraquinone, boron-dipyrromethene florophore (bodipy), and their derivatives) [20,21,22,23]. Tetrapyrrolic macrocycles are the most widely used PSs in anticancer PDT and, among them, porphyrins are the most studied. Thus, porphyrin-derived PSs are further classified into three generations [24].
The first-generation PS, such as the hematoporphyrin derivative (HpD) and Photofrin®, were the first photosensitizers to be used clinically in PDT. However, these molecules have some drawbacks, such as a mixture of PSs, prolonged skin photosensitization, no selectivity, and suboptimal tissue penetration [25].
Second-generation PSs were developed to address these issues. These compounds are chemically pure, absorb light at a longer wavelength, and cause significantly less skin photosensitization post-treatment. They must also be at least as efficient in eradicating tumors as Photofrin®, which is currently the gold standard for PDT [26].
Third-generation PSs, which are bound to targeting agents (antibodies, sugar, folic acid, polyamine, peptide, etc.), are able to be selectively accumulated within tumor tissues and represent an active research area in the field [27,28,29,30,31,32,33,34,35].
Of note, fourth-generation PSs are still in the early stages of development and are characterized by their ability to be associated with nanoparticles and/or activated by specific stimuli, such as light at a specific wavelength, changes in pH or temperature, ultrasound, or X-rays [36]. This allows for even greater control over the location and timing of the PS activation, potentially reducing side effects and improving treatment efficacy. Fourth-generation PSs are still a relatively new area of research but have shown promising results in preclinical studies [37,38,39,40].

3.3. Natural and Synthetic PS

Herbal medicines have been used for centuries to treat various human ailments, and many modern medicines are derived from medicinal plants. There is a growing interest in using natural products, including herbal extracts and compounds, as possible lead components in cancer drug discoveries. Natural products are a valuable source for the development of drugs and the discovery of new PSs [41,42,43,44]. In recent decades, efforts have been made to isolate new products of natural origin from microbes, plants, and other living organisms, leading to the discovery of a number of anti-cancer drugs [41]. Researchers have found new active chemical compounds in natural extracts that display efficient PS properties, and numerous compounds have already been identified as potential candidates to be used as PSs [44]. Furthermore, screening studies of natural extracts have identified new PSs with cyclic tetrapyrrole structures [45]. Additionally, in a 2022 review published by Kubrak TP et al., various photochemicals were described for their light-absorbing properties and their anticancer activity including furanocoumarins, polyacetylenes, thiophenes, curcumins, alkaloids, and anthraquinones [20].
On the other hand, synthetic PSs are those that are created in the laboratory through chemical synthesis. These PSs are designed to have specific properties that allow them to effectively target cancer cells and destroy them upon exposure to light. They are often optimized to have higher light absorption at longer wavelengths, improved tissue penetration, and reduced toxicity compared to earlier generations of PSs [37,46]. Synthetic PSs can be produced in large quantities and with a high degree of purity, making them a reliable and cost-effective option for PDT. Some examples of synthetic PSs include benzoporphyrins, texaphyrins, purpurin, chlorin e6, bacteriochlorin. and pyropheophorbide.
Figure 2 presents some natural and synthetic PSs according to their absorption wavelengths.
An updated summary of natural and synthetic PSs and their potential mechanism of action to target prostate cancer are presented in Table 1 and Figure 3.

3.4. Ongoing Clinical Studies in Prostate Cancer

In clinical settings, the implementation of PDT for prostate cancer involves several key steps. First, a photosensitizing agent is administered to the patient, either systemically or directly into the tumor site. The choice of photosensitizer depends on factors such as its absorption and distribution properties, as well as its ability to selectively accumulate in tumor tissues [74]. Once the photosensitizer has been adequately distributed, a specific light source is selected, considering factors, such as wavelength and power output [74]. Light delivery techniques may vary, including intraluminal or interstitial illumination [75]. For instance, intraluminal light sources can be used for prostate cancer by inserting light-emitting devices through catheters or endoscopes. Interstitial PDT involves the placement of optical fibers or diffusers directly into the prostate tissue, allowing for light delivery to deeper tissue layers [75]. These techniques aim to achieve optimal light distribution and tumor coverage.
PDT is a promising treatment option for prostate cancer, with the potential to provide a safe and effective alternative to conventional therapies. However, in order to fully evaluate the safety and efficacy of PDT for prostate cancer, clinical trials are needed. These trials can provide valuable insights into the effectiveness of PDT, as well as help to identify any potential side effects or limitations of the treatment.
To date, several clinical trials have been conducted on the use of PDT for prostate cancer, with promising results.
By conducting research on clinical trials to further explore the potential of PDT for the treatment of prostate cancer [76], we found that out of the 14 studies conducted (Table 2), using the keywords “Photodynamic therapy” and “Prostate cancer”, only one study posted their results [77].

3.5. Multimodal Synergistic Therapies to Overcome PDT Limitations

Combination approaches in PDT for cancer treatment address limitations related to tumor size and location [78]. Larger tumors and tumors located in challenging anatomical areas can pose difficulties in achieving complete eradication with PDT alone due to the limited light penetration depth [79]. However, by combining PDT with other treatment modalities, such as surgery, sonodynamic therapy, photoimmunotherapy, chemotherapy, and photothermal therapy, these limitations can be overcome [80]. For larger tumors, combination approaches can sensitize the tumor or target residual cancer cells, thus enhancing the therapeutic effect. Multimodal therapies that combine PDT with other treatments have shown promise in the treatment of multidrug-resistant and hypoxia-related prostate cancers (Figure 4) [4,81]. However, challenges arise in terms of complexity, potential side effects and the requirement for rigorous testing of optimal sequencing and timing strategies.

3.5.1. PDT/Surgery

Surgery is a common treatment for prostate cancer, but it is not always successful in eradicating all cancer cells. Recent studies have explored the potential benefits of combining surgery with PDT in the treatment of prostate cancer. A retrospective study published in 2019 by Pierrard V et al. [82] investigated the safety and effectiveness of salvage radical prostatectomy (surgical removal of the prostate gland) after vascular-targeted photodynamic therapy (VTP) treatment. The study included 45 patients who underwent a salvage prostatectomy followed by VTP salvage due to persistent or recurrent cancer. The results showed that the combination was a safe and effective treatment option for localized prostate cancer. The study also reported that the combination therapy did not result in any severe complications or adverse events [82]. Furthermore, the feasibility, safety, and effectiveness of this combination in treating most locally recurrent prostate cancer were also reported by a previous study where various outcomes were reported including operation time, blood loss, complications, urethral catheterization time, functional outcomes, and short-term oncologic outcomes [83].

3.5.2. PDT/Sonodynamic Therapy

Although there are no specific studies on the use of PDT and sonodynamic therapy (SDT) for prostate cancer treatment, these therapies are currently being studied for their potential in cancer treatments [39,84]. PDT and SDT utilize sensitizers that can produce ROS, which can cause damage to cancer cell membranes. The combination of these therapies has demonstrated promising results in preclinical studies for various types of cancer, such as brain cancer [39]. In fact, in the prostate cancer context, the penetrating power of ultrasound avoids the use of an endoscope (and light) in the bladder while allowing the activation of the PS [84]. Ongoing research aims to identify effective sensitizers and optimal delivery methods to enhance the effectiveness of PDT and SDT in prostate cancer treatments. While further studies are necessary to determine the safety and efficacy of these therapies for prostate cancer, the potential benefits of PDT and SDT offer a promising avenue for the development of effective cancer treatments.

3.5.3. PDT/Photoimmunotherapy

Photoimmunotherapy (PIT) is an innovative treatment that harnesses the power of phototherapy and immunotherapy to combat cancer by inducing antitumor immune responses and preventing cancer recurrence [85]. Among the different approaches to PIT, one of the most promising and rapidly expanding is near-infrared (NIR)-PIT. This approach selectively and locally destroys cancer cells by releasing damage-associated molecular patterns (DAMPs) and tumor-associated antigens (TAAs), which trigger an antitumor immune response. NIR-PIT has demonstrated remarkable results in preclinical and clinical applications for various types of cancer including prostate cancer [85,86]. In fact, in a study using a prostate-specific membrane antigen (PSMA)-expressing a prostate cancer cell line, NIR-PIT with a fully human IgG1 anti-PSMA monoclonal antibody (mAb) conjugated to a specific photoabsorber resulted in specific binding and cell-specific killing after exposure to NIR light [86].

3.5.4. PDT/Chemotherapy

In the last few years, researchers have developed a new treatment strategy for prostate cancer known as photochemotherapy. This approach combines the benefits of PDT and chemotherapy to deliver cancer-fighting drugs selectively to tumor cells. Unlike traditional chemotherapy, photochemotherapy can target cancerous tissues without damaging surrounding healthy cells, potentially reducing unwanted side effects. By combining these two therapies, the effectiveness of the treatment is enhanced, with chemotherapy compensating for the limited light penetration in the PDT. Furthermore, chemotherapy may increase the sensitivity of cancer cells to ROS or hyperthermia, resulting in a synergistic effect [87]. Furthermore, in vivo studies using athymic nude mice and BALB/c nude mice, have also demonstrated the effectiveness of photochemotherapy in treating prostate cancer [88,89].

3.5.5. PDT/Photothermal Therapy

Photothermal therapy (PTT) is a form of phototherapy that uses light energy to produce heat energy, which can kill cancer cells [4]. PTT has been used to treat prostate cancer by irradiating a photothermal agent with an external light source of a specific wavelength, typically NIR light. PTT has been combined with PDT to enhance the effects of both therapies. The thermal effect of PTT can improve local blood flow and increase the oxygen concentration in the tumor tissue, making up for the deficiency of PDT in a hypoxic environment [90]. Many studies have reported the combination of PDT and PTT using nanomaterials as drug carriers [4,90]. Some studies have used self-assembled nanoparticles, such as melanin-like polydopamine nanoparticles, to deliver photothermal and photodynamic agents for synergistic therapy [4,90]. However, the low photoconversion efficiency of some materials used in these therapies raises issues about how to maximize the synergistic effect of PDT and PTT.
Pharmaceutics 15 01767 g004 550
Figure 4. Schematic illustration of mechanisms of the multimodal synergistic therapies targeting prostate cancer using PDT.
Figure 4. Schematic illustration of mechanisms of the multimodal synergistic therapies targeting prostate cancer using PDT.
Pharmaceutics 15 01767 g004

4. Conclusions

In the last decades, steady progress in prostate cancer patients’ care has been noted due to the broad application of early detection and progress in therapeutic approaches. In this context, PDT is a promising approach to treat prostate cancer that has the potential to provide a minimally invasive, highly targeted approach and negligible side effects on normal tissues when compared to conventional therapies. Several PDT approaches have already been approved by regulatory authorities including the FDA and the European Medicines Agency. Furthermore, combining PDT with other therapy modalities such as chemotherapy, radiotherapy, surgery, and immunotherapy seems to be more effective against tumor growth. Advances in therapeutic approaches to develop innovative organic PSs for enhanced PDT are being reported worldwide [91]. Recently, PDT has entered the era of vectorization and encapsulation into drug delivery systems using innovative strategies to increase the delivery of PSs to tumor tissues [89,92,93,94,95]. Furthermore, several research studies reported the use of PDT to treat different cancer types, including colorectal cancer, melanoma, and glioblastoma as well as other diseases such as rheumatoid arthritis [92,93,94,95,96,97]. Despite considerable progress in understanding the underlying mechanisms of photodynamic therapy, further clinical studies are still needed to improve its modalities.

Author Contributions

Conceptualization, H.W., R.E.D. and Y.L.; data curation, H.W., I.Y.-M., M.O. and Y.L.; Figures conception, H.W.; writing—original draft preparation, H.W. and Y.L.; writing—review and editing, I.Y.-M., B.L., V.S., M.O., R.E.D. and Y.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
  2. Algorri, J.F.; Ochoa, M.; Roldan-Varona, P.; Rodriguez-Cobo, L.; Lopez-Higuera, J.M. Photodynamic Therapy: A Compendium of Latest Reviews. Cancers 2021, 13, 4447. [Google Scholar] [CrossRef] [PubMed]
  3. Windahl, T.; Andersson, S.O.; Lofgren, L. Photodynamic therapy of localised prostatic cancer. Lancet 1990, 336, 1139. [Google Scholar] [CrossRef] [PubMed]
  4. Xue, Q.; Zhang, J.; Jiao, J.; Qin, W.; Yang, X. Photodynamic therapy for prostate cancer: Recent advances, challenges and opportunities. Front. Oncol. 2022, 12, 980239. [Google Scholar] [CrossRef]
  5. PDQ® Adult Treatment Editorial Board. Prostate Cancer Treatment: Health Professional Version. Updated: 13 February 2023. Available online: https://www.cancer.gov/types/prostate/hp/prostate-treatment-pdq (accessed on 14 May 2023).
  6. Mohan, R.; Schellhammer, P.F. Treatment options for localized prostate cancer. Am. Fam. Physician 2011, 84, 413–420. [Google Scholar]
  7. Sekhoacha, M.; Riet, K.; Motloung, P.; Gumenku, L.; Adegoke, A.; Mashele, S. Prostate Cancer Review: Genetics, Diagnosis, Treatment Options, and Alternative Approaches. Molecules 2022, 27, 5730. [Google Scholar] [CrossRef]
  8. Wallis, C.J.; Herschorn, S.; Saskin, R.; Su, J.; Klotz, L.H.; Chang, M.; Kulkarni, G.S.; Lee, Y.; Kodama, R.T.; Narod, S.A.; et al. Complications after radical prostatectomy or radiotherapy for prostate cancer: Results of a population-based, propensity score-matched analysis. Urology 2015, 85, 621–627. [Google Scholar] [CrossRef]
  9. Michaelson, M.D.; Cotter, S.E.; Gargollo, P.C.; Zietman, A.L.; Dahl, D.M.; Smith, M.R. Management of Complications of Prostate Cancer Treatment. CA Cancer J. Clin. 2008, 58, 196–213. [Google Scholar] [CrossRef]
  10. Garcia, J.A. Sipuleucel-T in patients with metastatic castration-resistant prostate cancer: An insight for oncologists. Ther. Adv. Med. Oncol. 2011, 3, 101–108. [Google Scholar] [CrossRef] [Green Version]
  11. Fitzgerald, F. Photodynamic Therapy (PDT); Nova Science Publishers, Incorporated: Hauppauge, NY, USA, 2017. [Google Scholar]
  12. Correia, J.H.; Rodrigues, J.A.; Pimenta, S.; Dong, T.; Yang, Z. Photodynamic Therapy Review: Principles, Photosensitizers, Applications, and Future Directions. Pharmaceutics 2021, 13, 1332. [Google Scholar] [CrossRef] [PubMed]
  13. Mishchenko, T.; Balalaeva, I.; Gorokhova, A.; Vedunova, M.; Krysko, D.V. Which cell death modality wins the contest for photodynamic therapy of cancer? Cell Death Dis. 2022, 13, 455. [Google Scholar] [CrossRef]
  14. Hamblin, M.R. Photodynamic Therapy for Cancer: What’s Past is Prologue. Photochem. Photobiol. 2020, 96, 506–516. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Lee, C.N.; Hsu, R.; Chen, H.; Wong, T.W. Daylight Photodynamic Therapy: An Update. Molecules 2020, 25, 5195. [Google Scholar] [CrossRef]
  16. Rodrigues, M.C.; de Sousa Junior, W.T.; Mundim, T.; Vale, C.L.C.; de Oliveira, J.V.; Ganassin, R.; Pacheco, T.J.A.; Vasconcelos Morais, J.A.; Longo, J.P.F.; Azevedo, R.B.; et al. Induction of Immunogenic Cell Death by Photodynamic Therapy Mediated by Aluminum-Phthalocyanine in Nanoemulsion. Pharmaceutics 2022, 14, 196. [Google Scholar] [CrossRef] [PubMed]
  17. Rocha, L.G.B. Development of a Novel Photosensitizer for Photodynamic Therapy of Cancer. Ph.D. Thesis, Universidade de Coimbra, Coimbra, Portugal, 2016. [Google Scholar]
  18. Kwiatkowski, S.; Knap, B.; Przystupski, D.; Saczko, J.; Kedzierska, E.; Knap-Czop, K.; Kotlinska, J.; Michel, O.; Kotowski, K.; Kulbacka, J. Photodynamic therapy—Mechanisms, photosensitizers and combinations. Biomed. Pharmacother. 2018, 106, 1098–1107. [Google Scholar] [CrossRef]
  19. Mroz, P.; Yaroslavsky, A.; Kharkwal, G.B.; Hamblin, M.R. Cell death pathways in photodynamic therapy of cancer. Cancers 2011, 3, 2516–2539. [Google Scholar] [CrossRef] [Green Version]
  20. Kubrak, T.P.; Kołodziej, P.; Sawicki, J.; Mazur, A.; Koziorowska, K.; Aebisher, D. Some Natural Photosensitizers and Their Medicinal Properties for Use in Photodynamic Therapy. Molecules 2022, 27, 1192. [Google Scholar] [CrossRef] [PubMed]
  21. Zhang, J.; Jiang, C.; Figueiró Longo, J.P.; Azevedo, R.B.; Zhang, H.; Muehlmann, L.A. An updated overview on the development of new photosensitizers for anticancer photodynamic therapy. Acta Pharm. Sin. B 2018, 8, 137–146. [Google Scholar] [CrossRef]
  22. Oleinick, N.L.; Morris, R.L.; Belichenko, I. The role of apoptosis in response to photodynamic therapy: What, where, why, and how. Photochem. Photobiol. Sci. 2002, 1, 1–21. [Google Scholar] [CrossRef]
  23. Tomasz, K.; Beata, C.-G.; Katarzyna, K.; Magdalena, S.; Daria, W.; Sebastian, L.; Tomasz, K.; Tomasz, G. Nurses and Pharmacists in Interdisciplinary Team of Health Care Providers in Photodynamic Therapy. In Photomedicine; Yohei, T., Ed.; IntechOpen: Rijeka, Croatia, 2017; Chapter 7. [Google Scholar] [CrossRef] [Green Version]
  24. O’Connor, A.E.; Gallagher, W.M.; Byrne, A.T. Porphyrin and nonporphyrin photosensitizers in oncology: Preclinical and clinical advances in photodynamic therapy. Photochem. Photobiol. 2009, 85, 1053–1074. [Google Scholar] [CrossRef] [PubMed]
  25. Nayak, C.S. Photodynamic therapy in dermatology. Indian J. Dermatol. Venereol. Leprol. 2005, 71, 155–160. [Google Scholar] [CrossRef] [PubMed]
  26. Zeng, J.Y.; Zou, M.Z.; Zhang, M.; Wang, X.S.; Zeng, X.; Cong, H.; Zhang, X.Z. π-Extended Benzoporphyrin-Based Metal—Organic Framework for Inhibition of Tumor Metastasis. ACS Nano 2018, 12, 4630–4640. [Google Scholar] [CrossRef]
  27. Dai, L.; Shen, G.; Wang, Y.; Yang, P.; Wang, H.; Liu, Z. PSMA-targeted melanin-like nanoparticles as a multifunctional nanoplatform for prostate cancer theranostics. J. Mater. Chem. B 2021, 9, 1151–1161. [Google Scholar] [CrossRef]
  28. Stallivieri, A.; Colombeau, L.; Jetpisbayeva, G.; Moussaron, A.; Myrzakhmetov, B.; Arnoux, P.; Acherar, S.; Vanderesse, R.; Frochot, C. Folic acid conjugates with photosensitizers for cancer targeting in photodynamic therapy: Synthesis and photophysical properties. Bioorganic Med. Chem. 2017, 25, 1–10. [Google Scholar] [CrossRef]
  29. Stallivieri, A.; Baros, F.; Jetpisbayeva, G.; Myrzakhmetov, B.; Frochot, C. The Interest of Folic Acid in Targeted Photodynamic Therapy. Curr. Med. Chem. 2015, 22, 3185–3207. [Google Scholar] [CrossRef]
  30. Singh, S.; Aggarwal, A.; Bhupathiraju, N.V.S.D.K.; Arianna, G.; Tiwari, K.; Drain, C.M. Glycosylated Porphyrins, Phthalocyanines, and Other Porphyrinoids for Diagnostics and Therapeutics. Chem. Rev. 2015, 115, 10261–10306. [Google Scholar] [CrossRef]
  31. Laville, I.; Figueiredo, T.; Loock, B.; Pigaglio, S.; Maillard, P.; Grierson, D.S.; Carrez, D.; Croisy, A.; Blais, J. Synthesis, cellular internalization and photodynamic activity of glucoconjugated derivatives of tri and tetra(meta-hydroxyphenyl)chlorins. Bioorganic Med. Chem. 2003, 11, 1643–1652. [Google Scholar] [CrossRef] [PubMed]
  32. Kamarulzaman, E.E.; Gazzali, A.M.; Acherar, S.; Frochot, C.; Barberi-Heyob, M.; Boura, C.; Chaimbault, P.; Sibille, E.; Wahab, H.A.; Vanderesse, R. New Peptide-Conjugated Chlorin-Type Photosensitizer Targeting Neuropilin-1 for Anti-Vascular Targeted Photodynamic Therapy. Int. J. Mol. Sci. 2015, 16, 24059–24080. [Google Scholar] [CrossRef] [Green Version]
  33. Chaleix, V.; Sol, V.; Huang, Y.-M.; Guilloton, M.; Granet, R.; Blais, J.C.; Krausz, P. RGD-Porphyrin Conjugates: Synthesis and Potential Application in Photodynamic Therapy. Eur. J. Org. Chem. 2003, 2003, 1486–1493. [Google Scholar] [CrossRef]
  34. Sol, V.; Lamarche, F.; Enache, M.; Garcia, G.; Granet, R.; Guilloton, M.; Blais, J.C.; Krausz, P. Polyamine conjugates of meso-tritolylporphyrin and protoporphyrin IX: Potential agents for photodynamic therapy of cancers. Bioorganic Med. Chem. 2006, 14, 1364–1377. [Google Scholar] [CrossRef]
  35. Garcia, G.; Sarrazy, V.; Sol, V.; Morvan, C.L.; Granet, R.; Alves, S.; Krausz, P. DNA photocleavage by porphyrin–polyamine conjugates. Bioorganic Med. Chem. 2009, 17, 767–776. [Google Scholar] [CrossRef]
  36. Bechet, D.; Couleaud, P.; Frochot, C.; Viriot, M.L.; Guillemin, F.; Barberi-Heyob, M. Nanoparticles as vehicles for delivery of photodynamic therapy agents. Trends Biotechnol. 2008, 26, 612–621. [Google Scholar] [CrossRef]
  37. Lismont, M.; Dreesen, L.; Wuttke, S. Metal-Organic Framework Nanoparticles in Photodynamic Therapy: Current Status and Perspectives. Adv. Funct. Mater. 2017, 27, 1606314. [Google Scholar] [CrossRef]
  38. Foglietta, F.; Pinnelli, V.; Giuntini, F.; Barbero, N.; Panzanelli, P.; Durando, G.; Terreno, E.; Serpe, L.; Canaparo, R. Sonodynamic Treatment Induces Selective Killing of Cancer Cells in an In Vitro Co-Culture Model. Cancers 2021, 13, 3852. [Google Scholar] [CrossRef]
  39. Borah, B.M.; Cacaccio, J.; Durrani, F.A.; Bshara, W.; Turowski, S.G.; Spernyak, J.A.; Pandey, R.K. Sonodynamic therapy in combination with photodynamic therapy shows enhanced long-term cure of brain tumor. Sci. Rep. 2020, 10, 21791. [Google Scholar] [CrossRef]
  40. Bulin, A.-L.; Truillet, C.; Chouikrat, R.; Lux, F.; Frochot, C.; Amans, D.; Ledoux, G.; Tillement, O.; Perriat, P.; Barberi-Heyob, M.; et al. X-ray-Induced Singlet Oxygen Activation with Nanoscintillator-Coupled Porphyrins. J. Phys. Chem. C 2013, 117, 21583–21589. [Google Scholar] [CrossRef]
  41. Newman, D.J.; Cragg, G.M. Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019. J. Nat. Prod. 2020, 83, 770–803. [Google Scholar] [CrossRef] [Green Version]
  42. Zhang, Y.; Huang, L.; Shi, H.; Chen, H.; Tao, J.; Shen, R.; Wang, T. Ursolic acid enhances the therapeutic effects of oxaliplatin in colorectal cancer by inhibition of drug resistance. Cancer Sci. 2018, 109, 94–102. [Google Scholar] [CrossRef] [Green Version]
  43. Muniyandi, K.; George, B.; Parimelazhagan, T.; Abrahamse, H. Role of Photoactive Phytocompounds in Photodynamic Therapy of Cancer. Molecules 2020, 25, 4102. [Google Scholar] [CrossRef]
  44. Mansoori, B.; Mohammadi, A.; Doustvandi, M.A.; Mohammadnejad, F.; Kamari, F.; Gjerstorff, M.F.; Baradaran, B.; Hamblin, M.R. Photodynamic therapy for cancer: Role of natural products. Photodiagnosis Photodyn. Ther. 2019, 26, 395–404. [Google Scholar] [CrossRef]
  45. Samat, N.; Tan, P.J.; Shaari, K.; Abas, F.; Lee, H.B. Prioritization of natural extracts by LC-MS-PCA for the identification of new photosensitizers for photodynamic therapy. Anal. Chem. 2014, 86, 1324–1331. [Google Scholar] [CrossRef] [PubMed]
  46. Arambula, J.F.; Preihs, C.; Borthwick, D.; Magda, D.; Sessler, J.L. Texaphyrins: Tumor localizing redox active expanded porphyrins. Anticancer Agents Med. Chem. 2011, 11, 222–232. [Google Scholar] [CrossRef]
  47. Panno, M.L.; Giordano, F.; Rizza, P.; Pellegrino, M.; Zito, D.; Giordano, C.; Mauro, L.; Catalano, S.; Aquila, S.; Sisci, D.; et al. Bergapten induces ER depletion in breast cancer cells through SMAD4-mediated ubiquitination. Breast Cancer Res. Treat. 2012, 136, 443–455. [Google Scholar] [CrossRef]
  48. Van Aelst, B.; Devloo, R.; Zachee, P.; t’Kindt, R.; Sandra, K.; Vandekerckhove, P.; Compernolle, V.; Feys, H.B. Psoralen and Ultraviolet A Light Treatment Directly Affects Phosphatidylinositol 3-Kinase Signal Transduction by Altering Plasma Membrane Packing. J. Biol. Chem. 2016, 291, 24364–24376. [Google Scholar] [CrossRef] [Green Version]
  49. Mastrangelopoulou, M.; Grigalavicius, M.; Berg, K.; Menard, M.; Theodossiou, T.A. Cytotoxic and Photocytotoxic Effects of Cercosporin on Human Tumor Cell Lines. Photochem. Photobiol. 2019, 95, 387–396. [Google Scholar] [CrossRef] [Green Version]
  50. Ge, Z.-C.; Qu, X.; Yu, H.-F.; Zhang, H.-M.; Wang, Z.-H.; Zhang, Z.-T. Antitumor and apoptotic effects of bergaptol are mediated via mitochondrial death pathway and cell cycle arrest in human breast carcinoma cells. Bangladesh J. Pharmacol. 2016, 11, 489–494. [Google Scholar] [CrossRef] [Green Version]
  51. Liszewski, W.; Naym, D.G.; Biskup, E.; Gniadecki, R. Psoralen with ultraviolet A-induced apoptosis of cutaneous lymphoma cell lines is augmented by type I interferons via the JAK1-STAT1 pathway. Photodermatol. Photoimmunol. Photomed. 2017, 33, 164–171. [Google Scholar] [CrossRef] [PubMed]
  52. Simpson, D.; Amos, S. Other plant metabolites. In Pharmacognosy; Elsevier: Cham, Switzerland, 2017; pp. 267–280. [Google Scholar]
  53. Priyadarsini, K.I. Photophysics, photochemistry and photobiology of curcumin: Studies from organic solutions, bio-mimetics and living cells. J. Photochem. Photobiol. C Photochem. Rev. 2009, 10, 81–95. [Google Scholar] [CrossRef]
  54. Abrahamse, H.; Hamblin, M.R. New photosensitizers for photodynamic therapy. Biochem. J. 2016, 473, 347–364. [Google Scholar] [CrossRef] [Green Version]
  55. Aziz, B.; Aziz, I.; Khurshid, A.; Raoufi, E.; Esfahani, F.N.; Jalilian, Z.; Mozafari, M.R.; Taghavi, E.; Ikram, M. An Overview of Potential Natural Photosensitizers in Cancer Photodynamic Therapy. Biomedicines 2023, 11, 224. [Google Scholar] [CrossRef]
  56. Park, K.; Lee, J.-H. Photosensitizer effect of curcumin on UVB-irradiated HaCaT cells through activation of caspase pathways. Oncol. Rep. 2007, 17, 537–540. [Google Scholar] [CrossRef]
  57. Mbese, Z.; Khwaza, V.; Aderibigbe, B.A. Curcumin and Its Derivatives as Potential Therapeutic Agents in Prostate, Colon and Breast Cancers. Molecules 2019, 24, 4386. [Google Scholar] [CrossRef] [Green Version]
  58. Zhang, S.-J.; Sun, D.; Hao, J.-B.; Wei, Y.-F.; Yin, L.-F.; Liu, X. The effect of dietary soyabean isoflavones on photodynamic therapy in K562 leukemia cells. J. Photochem. Photobiol. B Biol. 2012, 110, 28–33. [Google Scholar] [CrossRef] [PubMed]
  59. de Paula Rodrigues, R.; Tini, I.R.; Soares, C.P.; da Silva, N.S. Effect of photodynamic therapy supplemented with quercetin in HEp-2 cells. Cell Biol. Int. 2014, 38, 716–722. [Google Scholar] [CrossRef]
  60. Núñez Montoya, S.C.; Comini, L.R.; Rumie Vittar, B.; Fernández, I.M.; Rivarola, V.A.; Cabrera, J.L. Phototoxic effects of Heterophyllaea pustulata (Rubiaceae). Toxicon 2008, 51, 1409–1415. [Google Scholar] [CrossRef] [PubMed]
  61. Vittar, N.B.R.; Awruch, J.; Azizuddin, K.; Rivarola, V. Caspase-independent apoptosis, in human MCF-7c3 breast cancer cells, following photodynamic therapy, with a novel water-soluble phthalocyanine. Int. J. Biochem. Cell Biol. 2010, 42, 1123–1131. [Google Scholar] [CrossRef] [PubMed]
  62. Perez Martin, J.M.; Labrador, V.; Fernandez Freire, P.; Molero, M.L.; Hazen, M.J. Ultrastructural changes induced in HeLa cells after phototoxic treatment with harmine. J. Appl. Toxicol. 2004, 24, 197–201. [Google Scholar] [CrossRef]
  63. Burgeiro, A.; Gajate, C.; Dakir, E.L.H.; Villa-Pulgarín, J.A.; Oliveira, P.J.; Mollinedo, F. Involvement of mitochondrial and B-RAF/ERK signaling pathways in berberine-induced apoptosis in human melanoma cells. Anti-Cancer Drugs 2011, 22, 507–518. [Google Scholar] [CrossRef]
  64. Youn, M.-J.; So, H.-S.; Cho, H.-J.; Kim, H.-J.; Kim, Y.; Lee, J.-H.; Sohn, J.S.; Kim, Y.K.; Chung, S.-Y.; Park, R. Berberine, a Natural Product, Combined with Cisplatin Enhanced Apoptosis through a Mitochondria/Caspase-Mediated Pathway in HeLa Cells. Biol. Pharm. Bull. 2008, 31, 789–795. [Google Scholar] [CrossRef] [Green Version]
  65. Lan, G.; Ni, K.; Xu, Z.; Veroneau, S.S.; Song, Y.; Lin, W. Nanoscale Metal-Organic Framework Overcomes Hypoxia for Photodynamic Therapy Primed Cancer Immunotherapy. J. Am. Chem. Soc. 2018, 140, 5670–5673. [Google Scholar] [CrossRef]
  66. Wondrak, G.T. Redox-directed cancer therapeutics: Molecular mechanisms and opportunities. Antioxid. Redox Signal. 2009, 11, 3013–3069. [Google Scholar] [CrossRef] [Green Version]
  67. Pavlickova, V.; Rimpelova, S.; Jurasek, M.; Zaruba, K.; Fahnrich, J.; Krizova, I.; Bejcek, J.; Rottnerova, Z.; Spiwok, V.; Drasar, P.; et al. PEGylated Purpurin 18 with Improved Solubility: Potent Compounds for Photodynamic Therapy of Cancer. Molecules 2019, 24, 4477. [Google Scholar] [CrossRef] [Green Version]
  68. Huang, P.; Zhang, B.; Yuan, Q.; Zhang, X.; Leung, W.; Xu, C. Photodynamic treatment with purpurin 18 effectively inhibits triple negative breast cancer by inducing cell apoptosis. Lasers Med. Sci. 2021, 36, 339–347. [Google Scholar] [CrossRef]
  69. Yu, T.T.; Hu, J.; Li, Q.R.; Peng, X.C.; Xu, H.Z.; Han, N.; Li, L.G.; Yang, X.X.; Xu, X.; Yang, Z.Y.; et al. Chlorin e6-induced photodynamic effect facilitates immunogenic cell death of lung cancer as a result of oxidative endoplasmic reticulum stress and DNA damage. Int. Immunopharmacol. 2023, 115, 109661. [Google Scholar] [CrossRef]
  70. Azzouzi, A.R.; Lebdai, S.; Benzaghou, F.; Stief, C. Vascular-targeted photodynamic therapy with TOOKAD® Soluble in localized prostate cancer: Standardization of the procedure. World J. Urol. 2015, 33, 937–944. [Google Scholar] [CrossRef] [Green Version]
  71. Harmatys, K.M.; Overchuk, M.; Chen, J.; Ding, L.; Chen, Y.; Pomper, M.G.; Zheng, G. Tuning Pharmacokinetics to Improve Tumor Accumulation of a Prostate-Specific Membrane Antigen-Targeted Phototheranostic Agent. Bioconjugate Chem. 2018, 29, 3746–3756. [Google Scholar] [CrossRef]
  72. Matroule, J.-Y.; Carthy, C.M.; Granville, D.J.; Jolois, O.; Hunt, D.W.C.; Piette, J. Mechanism of colon cancer cell apoptosis mediated by pyropheophorbide-a methylester photosensitization. Oncogene 2001, 20, 4070–4084. [Google Scholar] [CrossRef] [Green Version]
  73. Nyman, E.S.; Hynninen, P.H. Research advances in the use of tetrapyrrolic photosensitizers for photodynamic therapy. J. Photochem. Photobiol. B 2004, 73, 1–28. [Google Scholar] [CrossRef]
  74. van Straten, D.; Mashayekhi, V.; de Bruijn, H.S.; Oliveira, S.; Robinson, D.J. Oncologic Photodynamic Therapy: Basic Principles, Current Clinical Status and Future Directions. Cancers 2017, 9, 19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Moore, C.M.; Pendse, D.; Emberton, M. Photodynamic therapy for prostate cancer—A review of current status and future promise. Nat. Clin. Pract. Urol. 2009, 6, 18–30. [Google Scholar] [CrossRef]
  76. Available online: https://clinicaltrials.gov/ (accessed on 14 May 2023).
  77. Taneja, S.S.; Bennett, J.; Coleman, J.; Grubb, R.; Andriole, G.; Reiter, R.E.; Marks, L.; Azzouzi, A.R.; Emberton, M. Final Results of a Phase I/II Multicenter Trial of WST11 Vascular Targeted Photodynamic Therapy for Hemi-Ablation of the Prostate in Men with Unilateral Low Risk Prostate Cancer Performed in the United States. J. Urol. 2016, 196, 1096–1104. [Google Scholar] [CrossRef]
  78. Ito, Y.; Udo, K.; Vertosick, E.A.; Sjoberg, D.D.; Vickers, A.J.; Al-Ahmadie, H.A.; Chen, Y.B.; Gopalan, A.; Sirintrapun, S.J.; Tickoo, S.K.; et al. Clinical Usefulness of Prostate and Tumor Volume Related Parameters following Radical Prostatectomy for Localized Prostate Cancer. J. Urol. 2019, 201, 535–540. [Google Scholar] [CrossRef]
  79. Osuchowski, M.; Aebisher, D.; Bartusik-Aebisher, D.; Krupka-Olek, M.; Dynarowicz, K.; Przygoda, M.; Kawczyk-Krupka, A. Photodynamic Therapy-Adjunctive Therapy in the Treatment of Prostate Cancer. Diagnostics 2022, 12, 1113. [Google Scholar] [CrossRef]
  80. Borgia, F.; Giuffrida, R.; Caradonna, E.; Vaccaro, M.; Guarneri, F.; Cannavo, S.P. Early and Late Onset Side Effects of Photodynamic Therapy. Biomedicines 2018, 6, 12. [Google Scholar] [CrossRef] [Green Version]
  81. Sarbadhikary, P.; George, B.P.; Abrahamse, H. Recent Advances in Photosensitizers as Multifunctional Theranostic Agents for Imaging-Guided Photodynamic Therapy of Cancer. Theranostics 2021, 11, 9054–9088. [Google Scholar] [CrossRef]
  82. Pierrard, V.; Lebdai, S.; Kleinclauss, F.; Azzouzi, A.-R.; Terrier, J.-E.; Fortier, E.; Joniau, S.; Van Der Poel, H.; Salomon, G.; Casanova, J.; et al. Radical Prostatectomy after Vascular Targeted Photodynamic Therapy with Padeliporfin: Feasibility, and Early and Intermediate Results. J. Urol. 2019, 201, 315–321. [Google Scholar] [CrossRef]
  83. Lebdai, S.; Villers, A.; Barret, E.; Nedelcu, C.; Bigot, P.; Azzouzi, A.R. Feasibility, safety, and efficacy of salvage radical prostatectomy after Tookad® Soluble focal treatment for localized prostate cancer. World J. Urol. 2015, 33, 965–971. [Google Scholar] [CrossRef]
  84. Hu, X.; Zhang, Y.-S.; Liu, Y.-C.; Wang, N.; Zeng, X.-T.; Zhang, L.-L. Emerging photodynamic/sonodynamic therapies for urological cancers: Progress and challenges. J. Nanobiotechnol. 2022, 20, 437. [Google Scholar] [CrossRef]
  85. Mohiuddin, T.M.; Zhang, C.; Sheng, W.; Al-Rawe, M.; Zeppernick, F.; Meinhold-Heerlein, I.; Hussain, A.F. Near Infrared Photoimmunotherapy: A Review of Recent Progress and Their Target Molecules for Cancer Therapy. Int. J. Mol. Sci. 2023, 24, 2655. [Google Scholar] [CrossRef]
  86. Nagaya, T.; Nakamura, Y.; Okuyama, S.; Ogata, F.; Maruoka, Y.; Choyke, P.L.; Kobayashi, H. Near-Infrared Photoimmunotherapy Targeting Prostate Cancer with Prostate-Specific Membrane Antigen (PSMA) AntibodyNear-Infrared Photoimmunotherapy Targeting PSMA. Mol. Cancer Res. 2017, 15, 1153–1162. [Google Scholar] [CrossRef] [Green Version]
  87. Poudel, B.K.; Soe, Z.C.; Ruttala, H.B.; Gupta, B.; Ramasamy, T.; Thapa, R.K.; Gautam, M.; Ou, W.; Nguyen, H.T.; Jeong, J.-H.; et al. In situ fabrication of mesoporous silica-coated silver-gold hollow nanoshell for remotely controllable chemo-photothermal therapy via phase-change molecule as gatekeepers. Int. J. Pharm. 2018, 548, 92–103. [Google Scholar] [CrossRef]
  88. Wang, X.; Tong, J.; He, Z.; Yang, X.; Meng, F.; Liang, H.; Zhang, X.; Luo, L. Paclitaxel-Potentiated Photodynamic Theranostics for Synergistic Tumor Ablation and Precise Anticancer Efficacy Monitoring. ACS Appl. Mater. Interfaces 2020, 12, 5476–5487. [Google Scholar] [CrossRef]
  89. Tan, H.; Hou, N.; Liu, Y.; Liu, B.; Cao, W.; Zheng, D.; Li, W.; Liu, Y.; Xu, B.; Wang, Z.; et al. CD133 antibody targeted delivery of gold nanostars loading IR820 and docetaxel for multimodal imaging and near-infrared photodynamic/photothermal/chemotherapy against castration resistant prostate cancer. Nanomed. Nanotechnol. Biol. Med. 2020, 27, 102192. [Google Scholar] [CrossRef]
  90. Huang, L.; Xu, C.; Xu, P.; Qin, Y.; Chen, M.; Feng, Q.; Pan, J.; Cheng, Q.; Liang, F.; Wen, X.; et al. Intelligent Photosensitive Mesenchymal Stem Cells and Cell-Derived Microvesicles for Photothermal Therapy of Prostate Cancer. Nanotheranostics 2019, 3, 41–53. [Google Scholar] [CrossRef]
  91. Pham, T.C.; Nguyen, V.-N.; Choi, Y.; Lee, S.; Yoon, J. Recent Strategies to Develop Innovative Photosensitizers for Enhanced Photodynamic Therapy. Chem. Rev. 2021, 121, 13454–13619. [Google Scholar] [CrossRef]
  92. Gallardo-Villagrán, M.; Paulus, L.; Charissoux, J.L.; Sutour, S.; Vergne-Salle, P.; Leger, D.Y.; Liagre, B.; Therrien, B. Evaluation of Ruthenium-Based Assemblies as Carriers of Photosensitizers to Treat Rheumatoid Arthritis by Photodynamic Therapy. Pharmaceutics 2021, 13, 2104. [Google Scholar] [CrossRef]
  93. Nkune, N.W.; Matlou, G.G.; Abrahamse, H. Photodynamic Therapy Efficacy of Novel Zinc Phthalocyanine Tetra Sodium 2-Mercaptoacetate Combined with Cannabidiol on Metastatic Melanoma. Pharmaceutics 2022, 14, 2418. [Google Scholar] [CrossRef]
  94. Mkhobongo, B.; Chandran, R.; Abrahamse, H. In Vitro Photodynamic Treatment Modality for A375 Melanoma Cell Line Using a Sulphonated Aluminum Phthalocyanine Chloride-Photosensitizer-Gold Nanoparticle Conjugate. Pharmaceutics 2022, 14, 2474. [Google Scholar] [CrossRef]
  95. Dandash, F.; Leger, D.Y.; Diab-Assaf, M.; Sol, V.; Liagre, B. Porphyrin/Chlorin Derivatives as Promising Molecules for Therapy of Colorectal Cancer. Molecules 2021, 26, 7268. [Google Scholar] [CrossRef]
  96. Cramer, S.W.; Chen, C.C. Photodynamic Therapy for the Treatment of Glioblastoma. Front. Surg. 2019, 6, 81. [Google Scholar] [CrossRef] [Green Version]
  97. Gallardo-Villagrán, M.; Leger, D.Y.; Liagre, B.; Therrien, B. Photosensitizers Used in the Photodynamic Therapy of Rheumatoid Arthritis. Int. J. Mol. Sci. 2019, 20, 3339. [Google Scholar] [CrossRef] [Green Version]
Pharmaceutics 15 01767 g002 550
Figure 2. Absorption wavelengths of non-tetrapyrrolic PS derivatives (furanocoumarins (Fu), thiophenes (Th), curcumins (Cu), flavonoids (Fl), anthraquinones (An), alkaloids (Al)) and tetrapyrrolic PS derivatives (benzoporphyrin (Be), texaphyrins (Te), purpurin (Pu), chlorin e6 (C6), bacteriochlorin (Ba), pyropheophorbide (Py)).
Figure 2. Absorption wavelengths of non-tetrapyrrolic PS derivatives (furanocoumarins (Fu), thiophenes (Th), curcumins (Cu), flavonoids (Fl), anthraquinones (An), alkaloids (Al)) and tetrapyrrolic PS derivatives (benzoporphyrin (Be), texaphyrins (Te), purpurin (Pu), chlorin e6 (C6), bacteriochlorin (Ba), pyropheophorbide (Py)).
Pharmaceutics 15 01767 g002
Pharmaceutics 15 01767 g003 550
Figure 3. Possible mechanisms of action to induce prostate cancer eradication by targeting several pathways involving oxidative stress, cell death and cell cycle arrest.
Figure 3. Possible mechanisms of action to induce prostate cancer eradication by targeting several pathways involving oxidative stress, cell death and cell cycle arrest.
Pharmaceutics 15 01767 g003
Table
Table 1. Natural and Synthetic PSs and their potential mechanism of action in PDT of prostate cancer (adapted from Muniyandi K et al. [43]).
Table 1. Natural and Synthetic PSs and their potential mechanism of action in PDT of prostate cancer (adapted from Muniyandi K et al. [43]).
Natural PSs
NameNatural SourcesType of PDT *Mechanism of Action
Furanocoumarins
(Fu)		Ruta graveolens, Angelicae dahuricae, Glehnia littoralis, Syzygium Sps Tetradium daniellii, and Ficus sps.Type II
-
Inhibition of STAT-3 pathway and PI3K/AKT pathway [47,48],
-
Activation of p53 [49],
-
Forming adducts with DNA and cell cycle arrest [50],
-
Upregulation of the mitochondrial genes BAK, BAX, and PUMA [49,51].
Thiophenes
(Th)		Echinops, Eclipta, Pluchea, Artemisia, Atractylodes, Tagetes, Porophyllum, and Xanthium.Type I and II
-
Accumulation in fatty acid-rich regions and by producing single oxygen leading to cell membrane destruction [52].
Curcumins
(Cu)		Curcuma longa (family Zingiberaceae, species Curcuma)Type I
-
Reduction of matrix metalloproteases’ (MMPs) enzyme production [53],
-
Downregulation of inflammatory pathways molecules (e.g., tumor necrosis factor (TNF)-α, lipoxygenase (LOX), and cyclooxygenase (COX)-2) transcription factors (e.g., AP-1, nuclear factor (NF)-κB) and growth factors (e.g., epidermal growth factor (EGFR) and HER-2) [54,55],
-
Activation of caspase-3, -8, and -9 and cytochrome c release [56],
-
Angiogenesis inhibition [44,54,55,57].
Flavonoids
(Fl)		Herbs, Vegetables, Seeds, Cereals, Fruits, Flowers, and NutsType II
-
ROS generation, DNA damage [58],
-
Upregulate the expression of apoptosis-related proteins [58,59],
-
Increase the expression and release of cytochrome c [59].
Anthraquinones
(An)		Polygonum cuspidatum, H. lycioides, Aloe vera, Rheum palmatu, Polyathia suberosa, Xanthoria parietina, Ramularia collo-cygni. and H. perforatumType I and II
-
ROS generation [60],
-
Induction of apoptosis, necrosis, or autophagy [60,61].
Alkaloids
(Al)		Guatteria blepharophylla, Berberis vulgaris, Sanguinaria Canadensis, Peganum harmala, and Indigofera tinctoria.Type I
-
ROS generation [62],
-
Promotion of apoptosis and autophagy by regulating several genes (Bax, Bcl-2, Bcl-xL, NF-κB) and various caspase proteins [62,63,64].
Synthetic PSs
NameCommercial Name/Excitation WavelengthPS Class/SourceType of PDT *Mechanism of Action
Benzoporphyrin
(Be)		Visudyne
λ = 689 ± 3 nm		Porphyrin-based PS
(Derived from benzoporphyrin)		Type II
-
Lymphocyte infiltration and inhibition of tumor metastasis [26,65],
-
Once excited, it enhances the formation of ·OH from intracellular H2O2 via a Fenton-like reaction by a catalyzer [26].
Texaphyrins
(Te)		Lutrin, Antrin, Optrin, Xcytrin
λ = 732 nm		Texaphyrin-based PS
(Derived from expanded porphyrins)		Type I
-
Weakens the cellular antioxidant system by inhibiting thioredoxin reductase and by oxidizing reducing species (e.g., ascorbate), leading to a buildup of damaging ROS (e.g., peroxide) [46,66].
Purpurin
(Pu)		Purlytin
λ = 664 nm		Porphyrin-based PS
(Derived from chlorophyll)		Type II
-
Production of singlet oxygen and other ROS that can cause oxidative damage to cellular structures such as lipids, proteins, and DNA and induce apoptosis [67,68].
Chlorin e6
(C6)		MACEDACEPhotoditazine
λ = 660 nm		Chlorin-based PS
(Derived from chlorophyll)		Type I and II
-
Induce oxidative endoplasmic reticulum stress and DNA damage [69].
Bacteriochlorin
(Ba)		TOOKAD
λ = 753 or 762 nm		Chlorin-based PS
(Derived from bacteriochlorophyll)		Type I and II
-
ROS generation.
-
Blocks blood and nutriment supply to the vascular damage and tumor accumulation [70].
Pyropheophorbide
(Py)		Pyropheophorbide-a methylester
λ = 675 nm		Chlorin-based PS
(Derived from chlorophyll)		Type II
-
Targeting prostate-specific membrane antigen (PSMA) [71],
-
ROS generation and apoptosis induction via cytochrome c release, caspase 3 and caspase 9 activation [72].
* Depending on the solvent used for the measurement [73].
Table
Table 2. An update of clinical studies conducted around the world to treat prostate cancer using PDT and combination approaches.
Table 2. An update of clinical studies conducted around the world to treat prostate cancer using PDT and combination approaches.
Intervention/
Treatment		PhaseActual
Enrollment		IdentifierResponsible PartyResults
Drug: 1 -mediated -VTP WST 1Phase 1
Phase 2
Terminated		30NCT00946881UCLA—Jonsson Comprehensive Cancer Center Los Angeles, California, United States
Midtown Urology & Midtown Urology Surgical Center Atlanta, Georgia, United States
Washington University School of Medicine- Barnes-Jewish Hospital Saint Louis, Missouri, United States
NYU Urology Associates, New York, New York, United States
Memorial Sloan-Kettering Cancer Center, New York, New York, United States		The study showed that hemi-ablation of the prostate with WST11 vascular targeted PDT could be an effective treatment for prostate cancer. Optimal dosing parameters and light dose index were found to play important roles in the tissue response, as determined by MRI and biopsy [77].
Drug: WST09Phase 2
Completed		28NCT00308919Princess Margaret Hospital Toronto, Ontario, CanadaNo Results Posted
Drug: WST09 Vascular Photodynamic therapyPhase 2
Phase 3
Terminated		16NCT00312442Abramson Cancer Center of The University of Pennsylvania Philadelphia, Pennsylvania, United StatesNo Results Posted
Drug: WST11Phase 2
Completed		86NCT00975429Centre Hospitalier Universitaire (CHU) Angers, France Hôpital Claude Huriez Lille, France
Institut Mutualiste Montsouris (IMM) Paris, France
University College London Hospital (UCLH)
Kings College Hospital (KCH)
Frimley Park Hospital NHS Trust
Catharina Ziekenhuis		No Results Posted
Drug: Motexafin lutetiumPhase 1
Terminated		24NCT00005067Abramson Cancer Center of The University of Pennsylvania Philadelphia, Pennsylvania, United StatesNo Results Posted
Drug: TOOKAD® Soluble 4 mg/kgPhase 2
Active		50NCT03315754Memorial Sloan-Kettering Cancer Center New York, New York, United StatesNo Results Posted
Focal therapies including PDT
(PS undetermined)		Recruiting200NCT03492424Weill Cornell Medicine
New York, New York, United States		No Results Posted
Drug: WST11Phase 2
Completed		42NCT00707356University Health Network-Princess Margaret Hospital Toronto, Canada
Centre Hospitalier Universitaire Angers, France
Hôpital Bocage-CHU Dijon, France
Hôpital Claude Huriez, Lille, France
Institut Mutualiste Montsouris (IMM), Paris, France
Frimley Park Hospital NHS Trust, Frimley, United Kingdom		No Results Posted
Drug: TOOKAD® SolublePhase 2
Completed		8NCT00305929The Prostate Centre Princess Margaret Hospital Toronto, Ontario, CanadaNo Results Posted
Drug: TOOKAD® SolublePhase 3
Completed		81NCT01875393Hospital General Tlahuac Mexico DF, Mexico
Pan-American Medical Research Institute (PAMRI) then moved to Consultario del Dr Rodriguez Panama city, Panama
Hospital Nacional Cayetano Heredia San Martin de Porres, Peru		No Results Posted
Drug: TOOKAD® SolublePhase 3
Withdrawn		0NCT04225299Memorial Sloan-Kettering Cancer Center New York, New York, United StatesNo Results Posted
Drug: TOOKAD® SolublePhase 4
Terminated		23NCT03849365Centre Hospitalier Universitaire Angers, FranceNo Results Posted
Drug: Visudyne®
Device: SpectraCure P18 System		Phase 1
Phase 2
Recruiting		66NCT03067051Memorial Sloan Kettering Cancer Center New York, New York, United States
Keith Cengel Philadelphia, Pennsylvania, United States
Princess Margaret Cancer Centre Toronto, Ontario, Canada		No Results Posted
Drug: TOOKAD® SolublePhase 3
Completed		413NCT01310894Dept. of Urology-University Hospitals Leuven Leuven, Belgium
Department of Urology-Tampere University Hospital- Tampere, Finland
Service d’Urologie—Centre Hospitalier Universitaire Angers, France		No Results Posted
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Wahnou, H.; Youlyouz-Marfak, I.; Liagre, B.; Sol, V.; Oudghiri, M.; Duval, R.E.; Limami, Y. Shining a Light on Prostate Cancer: Photodynamic Therapy and Combination Approaches. Pharmaceutics 2023, 15, 1767. https://doi.org/10.3390/pharmaceutics15061767

AMA Style

Wahnou H, Youlyouz-Marfak I, Liagre B, Sol V, Oudghiri M, Duval RE, Limami Y. Shining a Light on Prostate Cancer: Photodynamic Therapy and Combination Approaches. Pharmaceutics. 2023; 15(6):1767. https://doi.org/10.3390/pharmaceutics15061767

Chicago/Turabian Style

Wahnou, Hicham, Ibtissam Youlyouz-Marfak, Bertrand Liagre, Vincent Sol, Mounia Oudghiri, Raphaël Emmanuel Duval, and Youness Limami. 2023. "Shining a Light on Prostate Cancer: Photodynamic Therapy and Combination Approaches" Pharmaceutics 15, no. 6: 1767. https://doi.org/10.3390/pharmaceutics15061767

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop