Cancer remains a worldwide health problem, being the disease with the highest impact on global health. Even with all the recent technological improvements, recurrence and metastasis still are the main cause of death. Since photodynamic therapy (PDT) does not compromise other treatment options and presents reduced long-term morbidity when compared with chemotherapy or radiotherapy, it appears as a promising alternative treatment for controlling malignant diseases. In this review, we set out to perform a broad up-date on PDT in cancer research and treatment, discussing how this approach has been applied and what it could add to breast cancer therapy. We covered topics going from the photochemical mechanisms involved, the different cell death mechanisms being triggered by a myriad of photosensitizers up to the more recent-on-going clinical trials.
Cancer remains a worldwide health problem. In particular, breast cancer is the disease with the highest impact on global health. Even with all the recent technological improvements, recurrence and metastasis still are the main causes of death. In fact, the high mortality as a consequence of distant metastasis in patients remains a bottleneck for an effective treatment in clinic[
Light has been known to provide a therapeutic potential for several thousands of years. Over 3000 years ago, since the Ancient, Indian and Chinese civilizations it has been used for the treatment of various diseases[
Photodynamic therapy (PDT) is currently being used as an alternative treatment for the control of malignant diseases[
As previously stated, PDT involves the photosensitized oxidation of biomolecules which can be separated in two mechanisms. In Type I, light energy passes from excited molecules to biomolecules through electron/hydrogen transfer (radical mechanism) in direct-contact reactions
Mechanisms of photosensitization. The photosensitizer (PS), is a molecule capable to absorb energy from light in a specific wavelength. Once excited, the PS transits from its ground state PS(S0), to its singlet excited PS(S1) and triplet excited PS(T1) states. At this point PS(T1) can react directly with biomolecules, like proteins or lipids (targets), via Type I photochemical reaction, resulting in formation of radicals, like PS•, capable to initiate radical chain reactions. Otherwise, PS (T1) can react with molecular oxygen 3O2, via the Type II photochemical reaction. Both generates diffusive oxidant species like radical superoxide, O2.-, and singlet oxygen, 1O2, via type I and II respectively, capable to extend the damage
Damages to proteins and membranes are of particular importance for PDT in order to optimize the cytotoxic efficiency to the process. Indeed, PSs displaying a higher degree of accumulation in cell and/or organelles membranes are usually more cytotoxic[
Mechanisms of photo-induced membrane damage. This graphical sketch represents how Type I and Type II photochemical reactions contribute to membrane leakage through lipid damage. Type I reactions lead to changes in membrane fluidity which occur as a result of direct-contact reactions between the PS triplet [PS (T1)] and either the lipid double bond of LH or the LOOH. Type II reactions [PS (T1) and molecular oxygen (3O2)] generates singlet oxygen (1O2) which leads to the formation of hydroperoxide (LOOH) as primary product. Modified from[
The PS is one of the three crucial elements of PDT, apart from light and oxygen. Due to their photochemistry properties and uptake efficiency currently only a few PSs have official approval worldwide and are being used clinically. Related to cancer treatment, PS approved or in clinical trial are listed on
Photosensitizers investigated in clinical trial for cancer treatment[
Photosensitizer | Chemical family | Treatment Wavelength (nm) | Cancer type | Characteristics |
---|---|---|---|---|
Porfirmer sodium, HPD: hematoporphyrin derivative (Photofrin) | Porphyrin | 630 | Lung, esophagus, bile duct, bladder, brain, ovarian, breast skin metastases | 1st generation PS
|
5-ALA: 5-aminolevulinic acid (Levulan) | Porphyrin precursor | 630 | Skin, bladder, brain, esophagus | 2nd generation PS
|
MAL: methyl-aminolevulinate (Metvix) | Porphyrin precursor | 630 | Skin | 2nd generation PS
|
h-ALA: hexylaminolevulinate (Hexvix) | Porphyrin precursor | White light | Basal cell | 2nd generation PS
|
Veteporfin, BDP: benzoporphyrin derivative (Visudyne) | Porphyrin | 690 | Pancreas, breast | 2nd generation PS
|
Palladium bactereopheophorbide, padeliporfin, WST-11 (Tookad) | Porphyrin | 762 | Esophagus, prostate | 2nd generation PS
|
Temoporfin, mTHPC: meso-tetrahydroxyphenylchlorine (Foscan) | Chlorin | 652 | Head and neck, lung, brain, bile duct, pancreas skin, breast | 2nd generation PS
|
Talaporfin, mono-L-aspartyl chlorin e6, NPe6, LS11 (Laserphyrin) | Chlorin | 660 | Liver, colon, brain, lung, breast skin metastases | 2nd generation PS
|
HPPH: 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (Photochlor) | Chlorin | 665 | Head and neck, esophagus, lung | 2nd generation PS
|
Rostaporfin, SnEt2: tin ethyl etiopurpurin I, or (Purlytin) | Chlorin | 660 | Skin, breast | 2nd generation PS
|
Fimaporfin, disulfonated tetraphenyl chlorin, TPCS2a (Amphinex) | Chlorin | 633 | Superficial cancers, Cholon | 2nd generation PS
|
Motexafin lutetium (Lutex) | Texaphyrin | 732 | Breast | 2nd generation PS
|
TBD: to be determined
Several studies have been performed over the last decades in order to better characterize PS efficacy and selectivity. Some of them have focused on the development of agents with higher absorption wavelengths, allowing deeper penetration of illuminating sources and thus the depths at which tumor cells can be targeted, the so-called second-generation PSs. Third-generation PSs have recently emerged aiming mainly at targeting strategies, such as antibody-directed PS and PS-loaded nanocarriers. These approaches were developed in order to increase the power and efficiency of PDT and have allowed the broadening of the types of diseased tissues that could be treated[
Besides the PSs photoactive capacity, which enables it as a therapeutic agent upon light activation, their autofluorescence is also an important characteristic. Indeed, PS’s fluorescence confers them imaging properties to be used for detection of pre-cancer lesions and early malignancies, as well as tumor margins. Furthermore, this property can be used for the identification of remaining dysplastic tissue upon surgical tumor resections, and to monitor the progress of the PDT treatment. Thus the combination of imaging, detection and therapeutic properties confers them the characteristics of theranostic agents[
PDT is considered to be involved in at least three main mechanisms of tissue destruction. The first one is the ability to directly kill cells through the action of damaging reactive chemical species generated by PS excitation. Direct phototoxic effect of PDT involves irreversible photodamage to specific targets, such as membranes and organelles[
Cell death subroutines are strongly connected with successful therapy outcome. Even when a detailed explanation of cell death mechanisms is not the scope of this review (updated and deeper information can be assessed in[
At the cellular level, PDT has been shown to induce multiple cell death subroutines, that can be accidental or not
Overview of cell death subroutines that can be elicited by Photodynamic therapy. The most described locations of different photosensitizers (PS) are the plasma membrane (PM), endoplasmic reticulum (ER), mitochondria (M) or the lysosome (L). Depending on its localization, after activation by light (red lightinhbolt) it can directly damage the PM causing unregulated necrosis or culminate in one or more regulated cell death (RCD) mechanisms. UPR: unfolded protein response; LMP: lysosome membrane permeabilization; Fe: iron; ROS: reactive oxygen species; -P: phosphate group presented in the active forms of RIPK3 and MLKL on necroptosis pathway; LDCD: lysosomal dependent cell death
PS localization within or on the cell surface is critical to determining the mode of cell death induction and thus the cellular response to photodamage[
Porphyrins can present a variable localization pattern, mostly associated with plasma membranes and mitochondria. PSs that are located in the mitochondria can cause mitochondrial inner membrane permeabilization and selectively damage antiapoptotic proteins of the BCL-2 family, localized at the outer mitochondrial membrane while the proapoptotic proteins are left intact, resulting in an unbalance of pro- and anti-apoptotic players that results in caspase activation[
The major challenge in the fight against cancer includes treatment toxicity and drug-resistance associated with incompletely tumor removal by surgical resection. In order to extend patient survival, systemic chemotherapy has become an essential part of treatment after surgery. However, therapies effective in both reducing the high mortality rate associated with the disease as well as improving patient quality of life still need to be developed[
Examples of immunotherapy include the use of monoclonal antibodies to block immune checkpoint activity of cancer cells, enabling anti-cancer T cell responses, or adoptive cellular therapy to prime patient’s own lymphocytes to attack cancer cells. The goal of immunotherapy is to generate a robust immune response, stimulating the endogenous cytotoxic lymphocytes to eradicate tumor cells and ultimately achieve long-term anticancer immunity[
The best way to reestablish an immune system response against tumors is by eliciting, therapeutically, a cancer cell death pathway that is accompanied by high immunogenicity and is possibly able to inhibit or reduce the influence of the pro-tumorigenic cytokine signaling. Over the last years, several studies demonstrated that few selected anti-cancer therapeutic approaches are able to induce a promising kind of cancer cell demise called immunogenic cell death (ICD)[
Preclinical studies have shown that in contrast to the effects of traditional therapies, low-dose PDT regimens can induce anti-tumor immunity, and these can be combined with high-dose PDT to achieve local tumor control with the immune suppression of distant disease[
Overall, accumulating evidence indicates that the therapeutic efficacy of several antineoplastic agents, including PDT, relies on their capacity to influence the tumor-host interaction, tipping the balance toward the activation of an immune response specific for malignant cells, especially for metastasize cancer.
PDT has been shown to be effective in treating different types of cancers, especially the ones with superficial localizations, as this intervention provides a significant improvement in both the patient’s quality of life[
The most common concern about the clinical use of PDT constitutes the limited penetration of light. However, nowadays this old idea that PDT is as a surface treatment because the application of external light may only treat superficial lesions is no longer believed. This problem is actually in the way of being solved because of the possibility of using fibers which can be placed in determined locations within the tumor site. Due to advances in fiber optics and microendoscopic technology, PDT can be used in the clinic with interstitial, endoscopic, intraoperative or laparoscopic light delivery systems. In this scenario, the laser light can be adapted into thin optical fibers for delivery of light into deeper and more difficult to access treatment sites[
Regarding light source technology, researchers have been developing light delivery systems with uniform illumination, which is essential to improving light penetration and reproducibility. An example of this is the use of bulb-shaped isotropic emitters along with light detectors which have been used in hollow organs. Light dosimetry can also help to optimize the positioning of light diffusers. Furthermore, increasing the selectivity of PDT could be achieved by customizing the diffusers such as balloons and cylindrical applicators according to the form and dimensions of the target tissue[
Additionally, recent advances in LED and diode lasers have allowed to merge their ability of output potency, enhanced portability and precision optical fiber coupling. These, non-collimated and less expensive light sources will certainly ease the translation of PDT to clinical procedures. They are usually employed due to their robustness, short bandwidth, relatively low maintenance cost and ability to be configured to the wavelength required by the PS. Lamps such as Tungsten filament lamps, metal halide lamps, powerful Xenon arc lamps and pulsed lasers are also commonly used in the PDT field[
Besides the light source itself, defining the strategy of light application is of fundamental importance since different irradiation protocols using the same source can lead to different outcomes in PDT. Another drawback to be dealt with in PDT prescriptions is light dose regimens because they might also influence the host anti-tumor reactions and optimal strategies are likely case dependent[
In terms of adverse events associated with PDT, the most common is skin photosensitivity, especially when PSs of the first generation were systemically administered. In these cases, patients have to avoid sunlight and strong artificial light for weeks[
Most people diagnosed with cancer will require surgery as the main strategy for tumor removal with or without radiotherapy and systemic therapy. Tumor cells generally migrate from a primary tumor through the blood stream and lymphatic system and may be detected in one or more sentinel lymph nodes before spreading further to a secondary site. In the case of non-metastatic cancer, identifying cancer cells in the lymph nodes is one of the most important prognostic factors for determining the need for adjuvant radiation therapy and/or chemotherapy. Once cancer has spread to distant sites, the removal of tumor has not consistently shown a survival benefit. In these cases, surgery may help with palliative control of an ulcerated tumor on the chest wall and only unspecific broad-spectrum therapies are the currently treatment option available[
Several
The effect of PDT combined with traditional chemotherapy for the treatment of breast cancer has also been studied and there are many examples. The treatment with appropriately combined low doses of cisplatin and indocyanine green- based PDT
Further research and more effort are required in order to allow PDT to be accepted as a suitable treatment for breast cancer. Even though, there is lot of evidence pointing that this therapeutic approach should be considered as an antitumor treatment, the actual challenge for PDT is to translate the advances in understanding the effects in the cell-line-based and animal models studies into the clinical practice.
Despite the increasing number of studies with a growing number of chemical compounds and their generally increased number of favorable aspects as compared to more standard treatments, only a few PS have already been approved for clinical use and only for the treatment of a few diseases.
While the majority of PDT uses involve different types of cancer, ALA use with distinct formulations is already approved for several clinical applications, ranging from mild and moderate actinic keratosis to non-hyperkeratotic actinic keratosis. Some are also used to treat the Bowen’s disease and basal cell carcinoma[
Since PDT has the potential to present a local effect, it lacks systemic adverse effects seen in other therapies. Additionally, because of its mechanism, PDT can be used in the clinic in combination with other procedures, such as radiotherapy, chemotherapy or surgery. At the present time there are a number of on-going trials using PDT with distinct PS for different types of cancer. Among all the on-going trials registered at clinicaltrials.gov (not concluded), about 50% of them use PDT alone or in combination with other therapies for at least one condition
Number of on-going trials registered in clinicaltrials.gov using Photodynamic therapy for major conditions
Major condition | Number of trials |
---|---|
Cancer | 49 |
Dermatological diseases | 21 |
Mouth diseases | 17 |
Ocular diseases | 5 |
Cardiovascular diseases | 2 |
Others (only 1 trial each) | 6 |
Details of on-going clinical trials with the usage of PDT for handling neoplastic diseases
Indication | Photosensitizer | Study type | Estimated study completion date | Estimated enrollment (participants) | ClincalTrials.gov Identifier |
---|---|---|---|---|---|
Anal Cancer | Aminolevulinic acid | Interventional | Apr/21 | 12 | NCT02698293 |
Basal Cell Carcinoma | Aminolevulinic acid | Interventional | Nov/21 | 50 | NCT03467789 |
Basal Cell Carcinoma | Aminolevulinic acid | Interventional | 01/May/23 | 50 | NCT03483441 |
Basal Cell Carcinoma | Aminolevulinic acid
|
Interventional | Sep/20 | 281 | NCT02144077 |
Basal Cell Carcinoma | Methyl aminolevulinate | Interventional | 01/Jun/20 | 20 | NCT03167762 |
Basal Cell Carcinoma
|
Aminolevulinic acid
|
Interventional | Dec/22 | 117 | NCT02367547 |
Basal Cell Carcinoma, Superficial | Aminolevulinic acid | Interventional | Aug/24 | 186 | NCT03573401 |
Brain Tumor, Recurrent | Porfimer sodium | Interventional | Jun/31 | 30 | NCT01966809 |
Brain Tumor, Recurrent | Porfimer sodium | Interventional | Apr/24 | 24 | NCT01682746 |
Breast Cancer, Metastatic | Verteporfin | Interventional | Dec/19 | 15 | NCT02939274 |
Cervical Intraepithelial Neoplasia | Aminolevulinic acid | Interventional | Nov/18 | 60 | NCT02631863 |
Cholangiocarcinoma | Porfimer sodium | Interventional | 22/Mar/18 | 55 | NCT01755013 |
Cholangiocarcinoma | Porfimer sodium | Interventional | Jul/18 | 39 | NCT02585856 |
Cholangiocarcinoma | Temoporfin | Interventional | Aug/19 | 20 | NCT03003065 |
Cholangiocarcinoma | Fimaporfin | Interventional | Aug/19 | 55 | NCT01900158 |
Cholangiocarcinoma, Hilar | Deuteporfin | Interventional | May/19 | 50 | NCT02955771 |
Desmoid Tumors | Aminolevulinic acid | Interventional | Dec/26 | 140 | NCT01898416 |
Esophageal Adenocarcinoma, Stages I, II, III
|
Porfimer sodium | Interventional | Dec/19 | 40 | NCT02628665 |
Esophagogastric Cancer | Palladium bacteriopheophorbide | Interventional | Apr/19 | 36 | NCT03133650 |
Glioblastoma | Aminolevulinic acid | Interventional | Dec/19 | 10 | NCT03048240 |
Head and Neck Carcinoma, Recurrent
|
Porfimer sodium | Interventional | 01/Nov/22 | 82 | NCT03727061 |
Lung Cancer | Porfimer sodium | Interventional | 15/Sep/17 | 10 | NCT03211078 |
Lung Cancer
|
Porfimer sodium | Interventional | Mar/19 | 10 | NCT03344861 |
Lung Cancer, Non Small Cell | Porfimer sodium | Interventional | Sep/21 | 66 | NCT03564054 |
Lung Cancer, Non Small Cell
|
Porfimer sodium | Interventional | May/19 | 5 | NCT02916745 |
Lung Cancer, Non-Small Cell
|
Porfimer sodium | Interventional | 01/Aug/21 | 12 | NCT03678350 |
Lung Cancer, Squamous Cell | Chlorin e6-PVP | Interventional | Oct/24 | 111 | NCT03346304 |
Mesothelioma, Epitheliod Malignant Pleural | Porfimer sodium | Interventional | May/18 | 102 | NCT02153229 |
Neurofibromatosis | Aminolevulinic acid | Interventional | Nov/18 | 30 | NCT01682811 |
Neurofibromatosis | Aminolevulinic acid | Interventional | Aug/23 | 30 | NCT02728388 |
Oral cancer | Aminolevulinic acid | Interventional | 31/May/19 | 30 | NCT03638622 |
Oral Cavity Squamous Cell Carcinoma, Stage I
|
HPPH* | Interventional | 02/Nov/21 | 114 | NCT03090412 |
Pancreatic Cancer, Non-Resectable | Verteporfin | Interventional | Jan/22 | 15 | NCT03033225 |
Pancreatic Cancer, Stage III
|
Porfimer sodium | Interventional | 31/Jan/20 | 12 | NCT01770132 |
Peritoneal Carcinomatosis | Interventional | Jul/20 | 50 | NCT02840331 | |
Prostate Cancer, Localized | Palladium bacteriopheophorbide | Interventional | 01/Mar/24 | 50 | NCT03315754 |
Prostate Cancer, Recurrent | Verteporfin | Interventional | 31/Dec/20 | 36 | NCT03067051 |
Skin Cancer, Non-melanoma | Aminolevulinic acid | Interventional | Mar/21 | 20 | NCT02751151 |
Skin Cancer, Non-melanoma | Aminolevulinic acid | Interventional | Dec/22 | 40 | NCT02867722 |
Skin Cancer, Non-melanoma | Aminolevulinic acid | Interventional | 30/Apr/21 | 20 | NCT03110159 |
Squamous Cell Carcinoma | Aminolevulinic acid | Interventional | Jan/20 | 40 | NCT03025724 |
Urothelial Carcinoma, Upper Tract | Palladium bacteriopheophorbide | Interventional | Aug/20 | 18 | NCT03617003 |
Cholangiocarcinoma | Porfimer sodium | Observational | 30/Dec/18 | 200 | NCT01524146 |
Esophageal Adenocarcinoma, Early | any | Observational | Jan/22 | 400 | NCT00587314 |
Lung Cancer | Porfimer sodium | Observational | 30/Dec/24 | 1000 | NCT01842555 |
Lung Cancer | any | Observational | 15/Dec/23 | 1000 | NCT03589456 |
Neoplastic Disease | any | Observational | Jul/21 | 400 | NCT02159742 |
Prostate Cancer | any | Observational | 01/Mar/20 | 200 | NCT03492424 |
*HPPH stands for 2-1[Heyloxyethyl]-2-Devinylpyropheophorbide-a
The majority of approved PDT protocols are related to the treatment of superficial lesions of skin and luminal organs. However, due the enhancement of PS efficiency and light delivery, interstitial and intra-operative approaches have been investigated for the ablation of a broad range of solid tumors[
There are several other new approaches being tested in “
Although PDT is based on the preferential accumulation in the tumor tissue, this selectivity is not absolute and some damage can occur to the surrounding tissue. Thus, a deeper understanding of the molecular mechanisms involved in drug delivery and specific targeting of tumors should contribute to the development of more specific technologies to deliver light and/or drugs to the tumor site and also to minimize resistance to PDT. Accordingly, the development of new PS targeting specific tumor sites have led to the modality of targeted-PDT[
The challenges in fighting the disease rely on intrinsic tumor resistance properties, molecular heterogeneity, and metastasis. Considering all the information provided one can conclude that there are almost no doubts that one relevant advantage of PDT over other cancer treatments is the possibility of generating less side effects to the patients.
In summary, in this review we have explored and presented a broad up-date on the use of PDT as a therapeutic approach in the treatment of primary cancer as well as metastasis. We have covered several topics ranging from the photochemical mechanisms involved, the different cell death mechanisms being triggered by several photosensitizers up to the more recent-on-going clinical trials. Additionally, we have presented a significant amount of information underscoring the relevance of PDT as an alternative therapeutic approach capable of inducing several mechanisms of cell death, some of them simultaneously. This capacity could be an interesting way of overcoming the problem of death resistance displayed by many tumors since one of the characteristics that is important for an alternative therapy for cancer treatment is to broaden the spectrum of cell death mechanisms being gathered in order to by-pass the different resistance mechanisms displayed by malignant cells.
Finally, even if more research is still needed in the field including the development and optimization of PS synthesis in order to increase the efficiency on specific tumor cell damage, light sources and irradiation protocols, it is evident that in the majority of the cases, PDT represents a suitable therapeutic alternative presenting several advantages over the traditional clinical approaches for cancer treatments. It is clear that PDT deserves more opportunities and investment in clinical trials. By doing so, it could be expected that the increase in the number of clinical studies with metastatic or non-mestastatic cancer, in the near future, could allow the scientific and clinical community to make more robust conclusions about PDT’s real translational potential to become a standard first-line therapy, either alone or in combination with other treatments, for a wide variety of tumors.
Responsible for the paper: Baptista MS, Labriola L
Concept, design, definition of intellectual content: dos Santos AF, Baptista MS, Labriola L
Literature search, manuscript preparation and revision: dos Santos AF, de Almeida DRQ, Terra LF, Baptista MS, Labriola L
Manuscript editing: dos Santos AF, Labriola L
Not applicable.
This work was supported by CAPES, CNPq and FAPESP (2017/03618-6; 2016/04676-7 and 2013/07937-8).
All authors declared that there are no conflicts of interest.
Not applicable.
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© The Author(s) 2019.