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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 July 2016) | Viewed by 105359

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Special Issue Editor

Dr. Michael R. Hamblin

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Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA
Interests: photodynamic therapy (PDT); low-level light therapy (LLLT); wound healing and infectious disease; atherosclerotic vulnerable plaque; anti-tumor immunity; photochemical mechanisms
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Photodynamic therapy (PDT) for cancer came to prominence in 1978, in a landmark publication by Tom Dougherty regarding the use of Photofrin. Since then, hundreds of papers have presented the structures of different novel photosensitizers that could be used for anti-cancer PDT. Many investigators have dissected the signaling pathways and gene expression patterns that lead to cell death or cell survival after PDT. Nanotechnology is playing an increasingly major role in modern PDT research. Animal models allow testing of new PDT protocols, and, in the case of immunocompetent animals, also allow investigation of the anti-tumor immune response that often occurs after PDT. Clinical trials of PDT for cancer continue to be conducted and new regulatory approvals are eagerly awaited.

Prof. Dr. Michael R. Hamblin
Guest Editor

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Published Papers (13 papers)

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Research

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2070 KiB

Open AccessArticle

Combination of Near Infrared Light-Activated Photodynamic Therapy Mediated by Indocyanine Green with Etoposide to Treat Non-Small-Cell Lung Cancer

by Ting Luo, Qinrong Zhang and Qing-Bin Lu

Cancers 2017, 9(6), 63; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9060063 - 05 Jun 2017

Cited by 15 | Viewed by 6262

Abstract

Indocyanine green (ICG) has been reported as a potential near-infrared (NIR) photosensitizer for photodynamic therapy (PDT) of cancer. However the application of ICG-mediated PDT is both intrinsically and physiologically limited. Here we report a combination of ICG-PDT with a chemotherapy drug etoposide (VP-16), aiming to enhance the anticancer efficacy, to circumvent limitations of PDT using ICG, and to reduce side effects of VP-16. We found in controlled in vitro cell-based assays that this combination is effective in killing non-small-cell lung cancer cells (NSCLC, A549 cell line). We also found that the combination of ICG-PDT and VP-16 exhibits strong synergy in killing non-small-cell lung cancer cells partially through inducing more DNA double-strand breaks (DSBs), while it has a much weaker synergy in killing human normal cells (GM05757). Furthermore, by studying the treatment sequence dependence and the cytotoxicity of laser-irradiated mixtures of ICG and VP-16, we found that the observed synergy involves direct/indirect reactions between ICG and VP-16. We further propose that there exists an electron transfer reaction between ICG and VP-16 under irradiation. This study therefore shows the anticancer efficacy of ICG-PDT combined with VP-16. These findings suggest that ICG-mediated PDT may be applied in combination with the chemotherapy drug VP-16 to treat some cancers, especially the non-small-cell lung cancer. Full article

(This article belongs to the Special Issue Photodynamic Cancer Therapy)

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Open AccessArticle

Photodynamic Synergistic Effect of Pheophorbide a and Doxorubicin in Combined Treatment against Tumoral Cells

by Rubén Ruiz-González, Paula Milán, Roger Bresolí-Obach, Juan Carlos Stockert, Angeles Villanueva, Magdalena Cañete and Santi Nonell

Cancers 2017, 9(2), 18; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9020018 - 17 Feb 2017

Cited by 37 | Viewed by 7793

Abstract

A combination of therapies to treat cancer malignancies is at the forefront of research with the aim to reduce drug doses (ultimately side effects) and diminish the possibility of resistance emergence given the multitarget strategy. With this goal in mind, in the present study, we report the combination between the chemotherapeutic drug doxorubicin (DOXO) and the photosensitizing agent pheophorbide a (PhA) to inactivate HeLa cells. Photophysical studies revealed that DOXO can quench the excited states of PhA, detracting from its photosensitizing ability. DOXO can itself photosensitize the production of singlet oxygen; however, this is largely suppressed when bound to DNA. Photodynamic treatments of cells incubated with DOXO and PhA led to different outcomes depending on the concentrations and administration protocols, ranging from antagonistic to synergic for the same concentrations. Taken together, the results indicate that an appropriate combination of DOXO with PhA and red light may produce improved cytotoxicity with a smaller dose of the chemotherapeutic drug, as a result of the different subcellular localization, targets and mode of action of the two agents. Full article

(This article belongs to the Special Issue Photodynamic Cancer Therapy)

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Open AccessArticle

A Comparison of Singlet Oxygen Explicit Dosimetry (SOED) and Singlet Oxygen Luminescence Dosimetry (SOLD) for Photofrin-Mediated Photodynamic Therapy

by Michele M. Kim, Rozhin Penjweini, Nathan R. Gemmell, Israel Veilleux, Aongus McCarthy, Gerald S. Buller, Robert H. Hadfield, Brian C. Wilson and Timothy C. Zhu

Cancers 2016, 8(12), 109; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers8120109 - 06 Dec 2016

Cited by 24 | Viewed by 5922

Abstract

Accurate photodynamic therapy (PDT) dosimetry is critical for the use of PDT in the treatment of malignant and nonmalignant localized diseases. A singlet oxygen explicit dosimetry (SOED) model has been developed for in vivo purposes. It involves the measurement of the key components in PDT—light fluence (rate), photosensitizer concentration, and ground-state oxygen concentration ([³O₂])—to calculate the amount of reacted singlet oxygen ([¹O₂]_rx), the main cytotoxic component in type II PDT. Experiments were performed in phantoms with the photosensitizer Photofrin and in solution using phosphorescence-based singlet oxygen luminescence dosimetry (SOLD) to validate the SOED model. Oxygen concentration and photosensitizer photobleaching versus time were measured during PDT, along with direct SOLD measurements of singlet oxygen and triplet state lifetime (τ_Δ and τ_t), for various photosensitizer concentrations to determine necessary photophysical parameters. SOLD-determined cumulative [¹O₂]_rx was compared to SOED-calculated [¹O₂]_rx for various photosensitizer concentrations to show a clear correlation between the two methods. This illustrates that explicit dosimetry can be used when phosphorescence-based dosimetry is not feasible. Using SOED modeling, we have also shown evidence that SOLD-measured [¹O₂]_rx using a 523 nm pulsed laser can be used to correlate to singlet oxygen generated by a 630 nm laser during a clinical malignant pleural mesothelioma (MPM) PDT protocol by using a conversion formula. Full article

(This article belongs to the Special Issue Photodynamic Cancer Therapy)

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Open AccessArticle

Mreg Activity in Tumor Response to Photodynamic Therapy and Photodynamic Therapy-Generated Cancer Vaccines

by Mladen Korbelik, Judith Banáth and Wei Zhang

Cancers 2016, 8(10), 94; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers8100094 - 15 Oct 2016

Cited by 17 | Viewed by 4760

Abstract

Myeloid regulatory cells (Mregs) are, together with regulatory T cells (Tregs), a dominant effector population responsible for restriction of the duration and strength of antitumor immune response. Photodynamic therapy (PDT) and cancer vaccines generated by PDT are modalities whose effectiveness in tumor destruction is closely dependent on the associated antitumor immune response. The present study investigated whether the immunodepletion of granulocytic Mregs in host mice by anti-GR1 antibody would improve the response of tumors to PDT or PDT vaccines in these animals. Anti-GR1 administration immediately after Temoporfin-PDT of mouse SCCVII tumors abrogated curative effect of PDT. The opposite effect, increasing PDT-mediated tumor cure-rates was attained by delaying anti-GR1 treatment to 1 h post PDT. With PDT vaccines, multiple anti-GR1 administrations (days 0, 4, and 8 post vaccination) improved the therapy response with SCCVII tumors. The results with PDT suggest that neutrophils (boosting antitumor effect of this therapy) that are engaged immediately after photodynamic light treatment are within one hour replaced with a different myeloid population, presumably Mregs that hampers the therapy-mediated antitumor effect. Anti-GR1 antibody, when used with optimal timing, can improve the efficacy of both PDT of tumors in situ and PDT-generated cancer vaccines. Full article

(This article belongs to the Special Issue Photodynamic Cancer Therapy)

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Review

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Open AccessReview

Oncologic Photodynamic Therapy: Basic Principles, Current Clinical Status and Future Directions

by Demian Van Straten, Vida Mashayekhi, Henriette S. De Bruijn, Sabrina Oliveira and Dominic J. Robinson

Cancers 2017, 9(2), 19; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9020019 - 18 Feb 2017

Cited by 720 | Viewed by 22280

Abstract

Photodynamic therapy (PDT) is a clinically approved cancer therapy, based on a photochemical reaction between a light activatable molecule or photosensitizer, light, and molecular oxygen. When these three harmless components are present together, reactive oxygen species are formed. These can directly damage cells and/or vasculature, and induce inflammatory and immune responses. PDT is a two-stage procedure, which starts with photosensitizer administration followed by a locally directed light exposure, with the aim of confined tumor destruction. Since its regulatory approval, over 30 years ago, PDT has been the subject of numerous studies and has proven to be an effective form of cancer therapy. This review provides an overview of the clinical trials conducted over the last 10 years, illustrating how PDT is applied in the clinic today. Furthermore, examples from ongoing clinical trials and the most recent preclinical studies are presented, to show the directions, in which PDT is headed, in the near and distant future. Despite the clinical success reported, PDT is still currently underutilized in the clinic. We also discuss the factors that hamper the exploration of this effective therapy and what should be changed to render it a more effective and more widely available option for patients. Full article

(This article belongs to the Special Issue Photodynamic Cancer Therapy)

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Open AccessReview

Interstitial Photodynamic Therapy—A Focused Review

by Gal Shafirstein, David Bellnier, Emily Oakley, Sasheen Hamilton, Mary Potasek, Karl Beeson and Evgueni Parilov

Cancers 2017, 9(2), 12; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9020012 - 24 Jan 2017

Cited by 148 | Viewed by 9243

Abstract

Multiple clinical studies have shown that interstitial photodynamic therapy (I-PDT) is a promising modality in the treatment of locally-advanced cancerous tumors. However, the utilization of I-PDT has been limited to several centers. The objective of this focused review is to highlight the different approaches employed to administer I-PDT with photosensitizers that are either approved or in clinical studies for the treatment of prostate cancer, pancreatic cancer, head and neck cancer, and brain cancer. Our review suggests that I-PDT is a promising treatment in patients with large-volume or thick tumors. Image-based treatment planning and real-time dosimetry are required to optimize and further advance the utilization of I-PDT. In addition, pre- and post-imaging using computed tomography (CT) with contrast may be utilized to assess the response. Full article

(This article belongs to the Special Issue Photodynamic Cancer Therapy)

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Open AccessReview

Photodynamic Therapy and Non-Melanoma Skin Cancer

by Liezel L. Griffin and John T. Lear

Cancers 2016, 8(10), 98; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers8100098 - 22 Oct 2016

Cited by 58 | Viewed by 13517

Abstract

Non-melanoma skin cancer (NMSC) is the most common malignancy among the Caucasian population. Photodynamic therapy (PDT) is gaining popularity for the treatment of basal cell carcinoma (BCC), Bowen’s disease (BD) and actinic keratosis (AK). A topical or systemic exogenous photosensitiser, results in selective uptake by malignant cells. Protoporphyrin IX (PpIX) is produced then activated by the introduction of a light source. Daylight-mediated MAL (methyl aminolaevulinate) PDT for AKs has the advantage of decreased pain and better patient tolerance. PDT is an effective treatment for superficial BCC, BD and both individual and field treatment of AKs. Excellent cosmesis can be achieved with high patient satisfaction. Variable results have been reported for nodular BCC, with improved outcomes following pretreatment and repeated PDT cycles. The more aggressive basisquamous, morphoeic infiltrating subtypes of BCC and invasive squamous cell carcinoma (SCC) are not suitable for PDT. Prevention of “field cancerization” in organ transplant recipients on long-term immunosuppression and patients with Gorlin syndrome (naevoid basal cell carcinoma syndrome) is a promising development. The optimisation of PDT techniques with improved photosensitiser delivery to target tissues, new generation photosensitisers and novel light sources may expand the future role of PDT in NMSC management. Full article

(This article belongs to the Special Issue Photodynamic Cancer Therapy)

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Open AccessReview

Modulation of the Anti-Tumor Efficacy of Photodynamic Therapy by Nitric Oxide

by Albert W. Girotti

Cancers 2016, 8(10), 96; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers8100096 - 20 Oct 2016

Cited by 23 | Viewed by 5267

Abstract

Nitric oxide (NO) produced by nitric oxide synthase (NOS) enzymes is a free radical molecule involved in a wide variety of normophysiologic and pathophysiologic processes. Included in the latter category are cancer promotion, progression, and resistance to therapeutic intervention. Animal tumor photodynamic therapy (PDT) studies several years ago revealed that endogenous NO can reduce PDT efficacy and that NOS inhibitors can alleviate this. Until relatively recently, little else was known about this anti-PDT effect of NO, including: (a) the underlying mechanisms; (b) type(s) of NOS involved; and (c) whether active NO was generated in vascular cells, tumor cells, or both. In addressing these questions for various cancer cell lines exposed to PDT-like conditions, the author’s group has made several novel findings, including: (i) exogenous NO can scavenge lipid-derived free radicals arising from photostress, thereby protecting cells from membrane-damaging chain peroxidation; (ii) cancer cells can upregulate inducible NOS (iNOS) after a PDT-like challenge and the resulting NO can signal for resistance to photokilling; (iii) photostress-surviving cells with elevated iNOS/NO proliferate and migrate/invade more aggressively; and (iv) NO produced by photostress-targeted cells can induce greater aggressiveness in non-targeted bystander cells. In this article, the author briefly discusses these various means by which NO can interfere with PDT and how this may be mitigated by use of NOS inhibitors as PDT adjuvants. Full article

(This article belongs to the Special Issue Photodynamic Cancer Therapy)

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Open AccessReview

Hypericin in the Dark: Foe or Ally in Photodynamic Therapy?

by Veronika Huntosova and Katarina Stroffekova

Cancers 2016, 8(10), 93; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers8100093 - 14 Oct 2016

Cited by 18 | Viewed by 4961

Abstract

Photosensitizers (PSs) in photodynamic therapy (PDT) are, in most cases, administered systemically with preferential accumulation in malignant tissues; however, exposure of non-malignant tissues to PS may also be clinically relevant, when PS molecules affect the pro-apoptotic cascade without illumination. Hypericin (Hyp) as PS and its derivatives have long been studied, regarding their photodynamic and photocytotoxic characteristics. Hyp and its derivatives have displayed light-activated antiproliferative and cytotoxic effects in many tumor cell lines without cytotoxicity in the dark. However, light-independent effects of Hyp have emerged. Contrary to the acclaimed Hyp minimal dark cytotoxicity and preferential accumulation in tumor cells, it was recently been shown that non-malignant and malignant cells uptake Hyp at a similar level. In addition, Hyp has displayed light-independent toxicity and anti-proliferative effects in a wide range of concentrations. There are multiple mechanisms underlying Hyp light-independent effects, and we are still missing many details about them. In this paper, we focus on Hyp light-independent effects at several sub-cellular levels—protein distribution and synthesis, organelle ultrastructure and function, and Hyp light-independent effects regarding reactive oxygen species (ROS). We summarize work from our laboratories and that of others to reveal an intricate network of the Hyp light-independent effects. We propose a schematic model of pro- and anti-apoptotic protein dynamics between cell organelles due to Hyp presence without illumination. Based on our model, Hyp can be explored as an adjuvant therapeutic drug in combination with chemo- or radiation cancer therapy. Full article

(This article belongs to the Special Issue Photodynamic Cancer Therapy)

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Open AccessReview

Boosting Tumor-Specific Immunity Using PDT

by Nicole Maeding, Thomas Verwanger and Barbara Krammer

Cancers 2016, 8(10), 91; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers8100091 - 06 Oct 2016

Cited by 72 | Viewed by 5725

Abstract

Photodynamic therapy (PDT) is a cancer treatment with a long-standing history. It employs the application of nontoxic components, namely a light-sensitive photosensitizer and visible light, to generate reactive oxygen species (ROS). These ROS lead to tumor cell destruction, which is accompanied by the induction of an acute inflammatory response. This inflammatory process sends a danger signal to the innate immune system, which results in activation of specific cell types and release of additional inflammatory mediators. Activation of the innate immune response is necessary for subsequent induction of the adaptive arm of the immune system. This includes the priming of tumor-specific cytotoxic T lymphocytes (CTL) that have the capability to directly recognize and kill cells which display an altered self. The past decades have brought increasing appreciation for the importance of the generation of an adaptive immune response for long-term tumor control and induction of immune memory to combat recurrent disease. This has led to considerable effort to elucidate the immune effects PDT treatment elicits. In this review we deal with the progress which has been made during the past 20 years in uncovering the role of PDT in the induction of the tumor-specific immune response, with special emphasis on adaptive immunity. Full article

(This article belongs to the Special Issue Photodynamic Cancer Therapy)

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Open AccessReview

Photodynamic Therapy for Non-Melanoma Skin Cancers

by Diana K. Cohen and Peter K. Lee

Cancers 2016, 8(10), 90; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers8100090 - 04 Oct 2016

Cited by 96 | Viewed by 6517

Abstract

Non‐melanoma skin cancer (NMSC) is traditionally treated with surgical excision. Nonsurgical methods such as cryotherapy and topical chemotherapeutics, amongst other treatments, are other options. Actinic keratosis (AKs) are considered precancerous lesions that eventually may progress to squamous cell carcinoma (SCC). Photodynamic therapy (PDT) offers an effective treatment for AKs, and is also effective for superficial basal cell carcinoma (BCC). Nodular BCC and Bowen’s disease (SCC in situ) have shown acceptable response rates with PDT, although recurrence rates are higher for these two NMSC subtypes. Methylaminolevulinate (MAL) PDT is a more effective treatment option than 5‐aminolevulinic acid (ALA) PDT for nodular BCC. Several studies have shown that PDT results in superior cosmetic outcomes compared to surgical treatment. PDT is overall well‐tolerated, with pain being the most common side effect. Full article

(This article belongs to the Special Issue Photodynamic Cancer Therapy)

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Open AccessReview

Photodynamic Therapy in Gynecologic Malignancies: A Review of the Roswell Park Cancer Institute Experience

by Paul C. Mayor and Shashikant Lele

Cancers 2016, 8(10), 88; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers8100088 - 23 Sep 2016

Cited by 14 | Viewed by 4205

Abstract

Photodynamic therapy (PDT) is a treatment modality used in the management of solid tumor malignancies that employs the use of a photosensitizing agent, a light source and oxygen in order to illicit a direct cytotoxic effect. Its use in gynecologic malignancies is somewhat novel and has been used for palliative and curative intent. At the Roswell Park Cancer Institute, the use of PDT in the management of gynecologic cancers began in the mid 1980s and since that time 35 patients have received PDT as a treatment for recurrent or metastatic cutaneous and vulvar, vaginal, anal, and cervical recurrences. In our experience, 85% patients with metastatic cutaneous lesions had a complete response. Twenty-seven percent of patients with metastatic vaginal, cervical or anal recurrences had a complete response to therapy with a median response time of 28 months. Side effects from the treatment included moderate to severe burning sensation, pain and edema at the treatment site requiring narcotic pain medication for symptom management in patients who underwent treatment to cutaneous lesions as well as lower genital tract recurrences. PDT should be considered an option in patients who are too frail to undergo the standard of care or decline the standard of care in lieu of a less invasive treatment modality. Full article

(This article belongs to the Special Issue Photodynamic Cancer Therapy)

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Open AccessReview

Prospects in the Application of Photodynamic Therapy in Oral Cancer and Premalignant Lesions

by Rajan Saini, Nathan V. Lee, Kelly Y. P. Liu and Catherine F. Poh

Cancers 2016, 8(9), 83; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers8090083 - 02 Sep 2016

Cited by 97 | Viewed by 7830

Abstract

Oral cancer is a global health burden with significantly poor survival, especially when the diagnosis is at its late stage. Despite advances in current treatment modalities, there has been minimal improvement in survival rates over the last five decades. The development of local recurrence, regional failure, and the formation of second primary tumors accounts for this poor outcome. For survivors, cosmetic and functional compromises resulting from treatment are often devastating. These statistics underscore the need for novel approaches in the management of this deadly disease. Photodynamic therapy (PDT) is a treatment modality that involves administration of a light-sensitive drug, known as a photosensitizer, followed by light irradiation of an appropriate wavelength that corresponds to an absorbance band of the sensitizer. In the presence of tissue oxygen, cytotoxic free radicals that are produced cause direct tumor cell death, damage to the microvasculature, and induction of inflammatory reactions at the target sites. PDT offers a prospective new approach in controlling this disease at its various stages either as a stand-alone therapy for early lesions or as an adjuvant therapy for advanced cases. In this review, we aim to explore the applications of PDT in oral cancer therapy and to present an overview of the recent advances in PDT that can potentially reposition its utility for oral cancer treatment. Full article

(This article belongs to the Special Issue Photodynamic Cancer Therapy)

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