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Cancers
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Advances in Cancer Photomedicine
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Advances in Cancer Photomedicine

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 25188

Special Issue Editors

Dr. Theodossis A. Theodossiou

E-Mail Website
Guest Editor
Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, 379 Oslo, Norway
Interests: photochemistry; photobiology; photomedicine; reactive oxygen species; free radicals; cell metabolism & bioenergetics; mitochondrial respiration and electron transport chain; nanomedicine; second harmonic generation from tissue; radiobiology; chemi/bio-luminescence in photomedicine
Dr. Mantas Grigalavicius

E-Mail Website
Guest Editor
Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, 379 Oslo, Norway
Interests: photochemistry; photobiology, photomedicine,radiobiology

Special Issue Information

Dear Colleagues,

According to the World Health Organization (WHO), cancer claimed an estimated 9.6 million lives in 2018 (about 1 in 6 deaths was related to cancer) and is the second leading cause of death globally. By 2040, the projected number of cancer related deaths is expected to climb up to 16.4 million.

The current standards of care for cancer treatment in general include surgery, radiotherapy, chemotherapy, and immunotherapies. However, these modalities are not sufficient to curb the grim cancer statistics summarized above.

Cancer photomedicine, with photodynamic therapy of cancer (PDT) and photochemical internalization (PCI) as its most prominent representatives in the clinic, is currently underrated and mainly limited by the poor penetration of light into tissue.

Photomedical cancer treatments are cross-disciplinary, spanning synthetic chemistry, photochemistry, photobiology, bio- and nano-engineering, chemi-/bio-luminescence, photogenerated reactive oxygen species and redox systems, and clinical research, among other disciplines. In addition, several hybrid/combinatorial treatment modalities are emerging as of late.

This Special Issue aims to provide an overview of the state of the art in cancer photomedicine across disciplines and also provide an outlook into future trends and prospective clinical applications.

Dr. Theodossis A. Theodossiou
Dr. Mantas Grigalavicius
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • photomedicine
  • photodynamic therapy
  • photochemical internalization
  • photogenerated ROS
  • photochemistry
  • chemistry
  • bio-engineering
  • nanoparticles
  • clinical photomedicine
  • chemi-/bio-luminescence

Published Papers (10 papers)

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Research

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13 pages, 2187 KiB  
Article
Eosin Y-Functionalized Upconverting Nanoparticles: Nanophotosensitizers and Deep Tissue Bioimaging Agents for Simultaneous Therapeutic and Diagnostic Applications
by Gabriel López-Peña, Silvia Simón-Fuente, Dirk H. Ortgies, María Ángeles Moliné, Emma Martín Rodríguez, Francisco Sanz-Rodríguez and María Ribagorda
Cancers 2023, 15(1), 102; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15010102 - 23 Dec 2022
Cited by 2 | Viewed by 1439
Abstract
Functionalized upconverting nanoparticles (UCNPs) are promising theragnostic nanomaterials for simultaneous therapeutic and diagnostic purposes. We present two types of non-toxic eosin Y (EY) nanoconjugates derived from UCNPs as novel nanophotosensitizers (nano-PS) and deep-tissue bioimaging agents employing light at 800 nm. This excitation wavelength [...] Read more.
Functionalized upconverting nanoparticles (UCNPs) are promising theragnostic nanomaterials for simultaneous therapeutic and diagnostic purposes. We present two types of non-toxic eosin Y (EY) nanoconjugates derived from UCNPs as novel nanophotosensitizers (nano-PS) and deep-tissue bioimaging agents employing light at 800 nm. This excitation wavelength ensures minimum cell damage, since the absorption of water is negligible, and increases tissue penetration, enhancing the specificity of the photodynamic treatment (PDT). These UCNPs are uniquely qualified to fulfil three important roles: as nanocarriers, as energy-transfer materials, and as contrast agents. First, the UCNPs enable the transport of EY across the cell membrane of living HeLa cells that would not be possible otherwise. This cellular internalization facilitates the use of such EY-functionalized UCNPs as nano-PS and allows the generation of reactive oxygen species (ROS) under 800 nm light inside the cell. This becomes possible due to the upconversion and energy transfer processes within the UCNPs, circumventing the excitation of EY by green light, which is incompatible with deep tissue applications. Moreover, the functionalized UCNPs present deep tissue NIR-II fluorescence under 808 nm excitation, thus demonstrating their potential as bioimaging agents in the NIR-II biological window. Full article
(This article belongs to the Special Issue Advances in Cancer Photomedicine)
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16 pages, 2779 KiB  
Article
A Non-Invasive Deep Photoablation Technique to Inhibit DCIS Progression and Induce Antitumor Immunity
by Kensuke Kaneko, Hiroshi Nagata, Xiao-Yi Yang, Joshua Ginzel, Zachary Hartman, Jeffrey Everitt, Philip Hughes, Timothy Haystead, Michael Morse, Herbert Kim Lyerly and Takuya Osada
Cancers 2022, 14(23), 5762; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14235762 - 23 Nov 2022
Viewed by 1327
Abstract
Ductal carcinoma in situ (DCIS) of the breast is often managed by lumpectomy and radiation or mastectomy, despite its indolent features. Effective non-invasive treatment strategies could reduce the morbidity of DCIS treatment. We have exploited the high heat shock protein 90 (HSP90) activity [...] Read more.
Ductal carcinoma in situ (DCIS) of the breast is often managed by lumpectomy and radiation or mastectomy, despite its indolent features. Effective non-invasive treatment strategies could reduce the morbidity of DCIS treatment. We have exploited the high heat shock protein 90 (HSP90) activity in premalignant and malignant breast disease to non-invasively detect and selectively ablate tumors using photodynamic therapy (PDT). PDT with the HSP90-targeting photosensitizer, HS201, can not only ablate invasive breast cancers (BCs) while sparing non-tumor tissue, but also induce antitumor immunity. We hypothesized that HS201-PDT would both non-invasively ablate DCIS and prevent progression to invasive BC. We tested in vitro selective uptake and photosensitivity of HS201 in DCIS cell lines compared to the non-selective parental verteporfin, and assessed in vivo antitumor efficacy in mammary fat pad and intraductal implantation models. Selective uptake of HS201 enabled treatment of intraductal lesions while minimizing toxicity to non-tumor tissue. The in vivo activity of HS201-PDT was also tested in female MMTV-neu mice prior to the development of spontaneous invasive BC. Mice aged 5 months were administered HS201, and their mammary glands were exposed to laser light. HS201-PDT delayed the emergence of invasive BC, significantly prolonged disease-free survival (DFS) (p = 0.0328) and tended to improve overall survival compared to the no-treatment control (p = 0.0872). Systemic administration of anti-PD-L1 was combined with HS201-PDT and was tested in a more aggressive spontaneous tumor model, HER2delta16 transgenic mice. A single PDT dose combined with anti-PD-L1 improved DFS compared to the no-treatment control, which was significantly improved with repetitive HS201-PDT given with anti-PD-L1 (p = 0.0319). In conclusion, a non-invasive, skin- and tissue-sparing PDT strategy in combination with anti-PD-L1 antibodies effectively prevented malignant progression of DCIS to invasive BC. This non-invasive treatment strategy of DCIS may be safe and effective, while providing an option to reduce the morbidity of current conventional treatment for patients with DCIS. Clinical testing of HS201 is currently underway. Full article
(This article belongs to the Special Issue Advances in Cancer Photomedicine)
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17 pages, 17242 KiB  
Article
Phototherapeutic Induction of Immunogenic Cell Death and CD8+ T Cell-Granzyme B Mediated Cytolysis in Human Lung Cancer Cells and Organoids
by Asta Valančiūtė, Layla Mathieson, Richard A. O’Connor, Jamie I. Scott, Marc Vendrell, David A. Dorward, Ahsan R. Akram and Kevin Dhaliwal
Cancers 2022, 14(17), 4119; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14174119 - 25 Aug 2022
Cited by 6 | Viewed by 2633
Abstract
Augmenting T cell mediated tumor killing via immunogenic cancer cell death (ICD) is the cornerstone of emerging immunotherapeutic approaches. We investigated the potential of methylene blue photodynamic therapy (MB-PDT) to induce ICD in human lung cancer. Non-Small Cell Lung Cancer (NSCLC) cell lines [...] Read more.
Augmenting T cell mediated tumor killing via immunogenic cancer cell death (ICD) is the cornerstone of emerging immunotherapeutic approaches. We investigated the potential of methylene blue photodynamic therapy (MB-PDT) to induce ICD in human lung cancer. Non-Small Cell Lung Cancer (NSCLC) cell lines and primary human lung cancer organoids were evaluated in co-culture killing assays with MB-PDT and light emitting diodes (LEDs). ICD was characterised using immunoblotting, immunofluorescence, flow cytometry and confocal microscopy. Phototherapy with MB treatment and low energy LEDs decreased the proliferation of NSCLC cell lines inducing early necrosis associated with reduced expression of the anti-apoptotic protein, Bcl2 and increased expression of ICD markers, calreticulin (CRT), intercellular cell-adhesion molecule-1 (ICAM-1) and major histocompatibility complex I (MHC-I) in NSCLC cells. MB-PDT also potentiated CD8+ T cell-mediated cytolysis of lung cancer via granzyme B in lung cancer cells and primary human lung cancer organoids. Full article
(This article belongs to the Special Issue Advances in Cancer Photomedicine)
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24 pages, 5812 KiB  
Article
5-ALA Is a Potent Lactate Dehydrogenase Inhibitor but Not a Substrate: Implications for Cell Glycolysis and New Avenues in 5-ALA-Mediated Anticancer Action
by Mantas Grigalavicius, Somayeh Ezzatpanah, Athanasios Papakyriakou, Tine Therese Henriksen Raabe, Konstantina Yannakopoulou and Theodossis A. Theodossiou
Cancers 2022, 14(16), 4003; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14164003 - 18 Aug 2022
Cited by 8 | Viewed by 3658
Abstract
In a course of metabolic experiments, we determined that the addition of δ-aminolevulinic acid (5-ALA) to a panel of glioblastoma multiforme (GBM) cells caused a steep reduction in their glycolytic activity. This reduction was accompanied by a decrease in adenosine triphosphate (ATP) production [...] Read more.
In a course of metabolic experiments, we determined that the addition of δ-aminolevulinic acid (5-ALA) to a panel of glioblastoma multiforme (GBM) cells caused a steep reduction in their glycolytic activity. This reduction was accompanied by a decrease in adenosine triphosphate (ATP) production from glycolysis. These results suggested that 5-ALA is an inhibitor of glycolysis; due to the structural similarity of 5-ALA to the established lactate dehydrogenase (LDH) inhibitors oxamate (OXM) and tartronate (TART), we initially investigated LDH inhibition by 5-ALA in silico. The modelling revealed that 5-ALA could indeed be a competitive inhibitor of LDH but not a substrate. These theoretical findings were corroborated by enzymatic and cell lysate assays in which 5-ALA was found to confer a potent LDH inhibition comparable to that of OXM and TART. We subsequently evaluated the effect of 5-ALA-induced glycolysis inhibition on the viability of GBM cells with diverse metabolic phenotypes. In the Warburg-type cell lines Ln18 and U87, incubation with 5-ALA elicited profound and irreversible cell death (90–98%) at 10 mM after merely 24 h. In T98G, however, which exhibited both high respiratory and glycolytic rates, LD95 was achieved after 72 h of incubation with 20 mM 5-ALA. We additionally examined the production of the 5-ALA photosensitive metadrug protoporphyrin IX (PpIX), with and without prior LDH inhibition by TART. These studies revealed that ~20% of the 5-ALA taken up by the cells was engaged in LDH inhibition. We subsequently performed 5-ALA photodynamic therapy (PDT) on Ln18 GBM cells, again with and without prior LDH inhibition with TART, and found a PDT outcome enhancement of ~15% upon LDH pre-inhibition. We expect our findings to have a profound impact on contemporary oncology, particularly for the treatment of otherwise incurable brain cancers such as GBM, where the specific accumulation of 5-ALA is very high compared to the surrounding normal tissue. Full article
(This article belongs to the Special Issue Advances in Cancer Photomedicine)
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26 pages, 48591 KiB  
Article
Connexin Hemichannel Activation by S-Nitrosoglutathione Synergizes Strongly with Photodynamic Therapy Potentiating Anti-Tumor Bystander Killing
by Chiara Nardin, Chiara Peres, Sabrina Putti, Tiziana Orsini, Claudia Colussi, Flavia Mazzarda, Marcello Raspa, Ferdinando Scavizzi, Anna Maria Salvatore, Francesco Chiani, Abraham Tettey-Matey, Yuanyuan Kuang, Guang Yang, Mauricio A. Retamal and Fabio Mammano
Cancers 2021, 13(20), 5062; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205062 - 10 Oct 2021
Cited by 7 | Viewed by 2608
Abstract
In this study, we used B16-F10 cells grown in the dorsal skinfold chamber (DSC) preparation that allowed us to gain optical access to the processes triggered by photodynamic therapy (PDT). Partial irradiation of a photosensitized melanoma triggered cell death in non-irradiated tumor cells. [...] Read more.
In this study, we used B16-F10 cells grown in the dorsal skinfold chamber (DSC) preparation that allowed us to gain optical access to the processes triggered by photodynamic therapy (PDT). Partial irradiation of a photosensitized melanoma triggered cell death in non-irradiated tumor cells. Multiphoton intravital microscopy with genetically encoded fluorescence indicators revealed that bystander cell death was mediated by paracrine signaling due to adenosine triphosphate (ATP) release from connexin (Cx) hemichannels (HCs). Intercellular calcium (Ca2+) waves propagated from irradiated to bystander cells promoting intracellular Ca2+ transfer from the endoplasmic reticulum (ER) to mitochondria and rapid activation of apoptotic pathways. Combination treatment with S-nitrosoglutathione (GSNO), an endogenous nitric oxide (NO) donor that biases HCs towards the open state, greatly potentiated anti-tumor bystander killing via enhanced Ca2+ signaling, leading to a significant reduction of post-irradiation tumor mass. Our results demonstrate that HCs can be exploited to dramatically increase cytotoxic bystander effects and reveal a previously unappreciated role for HCs in tumor eradication promoted by PDT. Full article
(This article belongs to the Special Issue Advances in Cancer Photomedicine)
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14 pages, 2522 KiB  
Article
Mechanism of Differential Susceptibility of Two (Canine Lung Adenocarcinoma) Cell Lines to 5-Aminolevulinic Acid-Mediated Photodynamic Therapy
by Tomohiro Osaki, Narumi Kunisue, Urara Ota, Hideo Imazato, Takuya Ishii, Kiwamu Takahashi, Masahiro Ishizuka, Tohru Tanaka and Yoshiharu Okamoto
Cancers 2021, 13(16), 4174; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164174 - 19 Aug 2021
Cited by 2 | Viewed by 1796
Abstract
Photodynamic therapy (PDT) is a clinically approved, minimally invasive treatment for malignant tumors. Protoporphyrin IX (PpIX), derived from 5-aminolevulinic acid (5-ALA) as the prodrug, is one of the photosensitizers used in PDT. Recently, we reported a significant difference in response to 5-ALA-mediated PDT [...] Read more.
Photodynamic therapy (PDT) is a clinically approved, minimally invasive treatment for malignant tumors. Protoporphyrin IX (PpIX), derived from 5-aminolevulinic acid (5-ALA) as the prodrug, is one of the photosensitizers used in PDT. Recently, we reported a significant difference in response to 5-ALA-mediated PDT treatment in two canine primary lung adenocarcinoma cell lines (sensitive to PDT: HDC cells, resistant to PDT: LuBi cells). This study aimed to examine the difference in cytotoxicity of 5-ALA-mediated PDT in these cells. Although intracellular PpIX levels before irradiation were similar between HDC and LuBi cells, the percentage of ROS-positive cells and apoptotic cells in LuBi cells treated with 5-ALA-mediated PDT was significantly lower than that in HDC cells treated with 5-ALA-mediated PDT. A high dosage of the NO donor, DETA NONOate, significantly increased the cytotoxicity of 5-ALA-mediated PDT against LuBi cells. These results suggest that the sensitivity of 5-ALA-mediated PDT might be correlated with NO. Full article
(This article belongs to the Special Issue Advances in Cancer Photomedicine)
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18 pages, 3196 KiB  
Article
Sonodynamic Treatment Induces Selective Killing of Cancer Cells in an In Vitro Co-Culture Model
by Federica Foglietta, Vanessa Pinnelli, Francesca Giuntini, Nadia Barbero, Patrizia Panzanelli, Gianni Durando, Enzo Terreno, Loredana Serpe and Roberto Canaparo
Cancers 2021, 13(15), 3852; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153852 - 30 Jul 2021
Cited by 10 | Viewed by 2733
Abstract
Sonodynamic Therapy (SDT) is a new anticancer strategy based on ultrasound (US) technique and is derived from photodynamic therapy (PDT); SDT is still, however, far from clinical application. In order to move this therapy forward from bench to bedside, investigations have been focused [...] Read more.
Sonodynamic Therapy (SDT) is a new anticancer strategy based on ultrasound (US) technique and is derived from photodynamic therapy (PDT); SDT is still, however, far from clinical application. In order to move this therapy forward from bench to bedside, investigations have been focused on treatment selectivity between cancer cells and normal cells. As a result, the effects of the porphyrin activation by SDT on cancer (HT-29) and normal (HDF 106-05) cells were studied in a co-culture evaluating cell cytotoxicity, reactive oxygen species (ROS) production, mitochondrial function and plasma membrane fluidity according to the bilayer sonophore (BLS) theory. While PDT induced similar effects on both HT-29 and HDF 106-05 cells in co-culture, SDT elicited significant cytotoxicity, ROS production and mitochondrial impairment on HT-29 cells only, whereas HDF 106-05 cells were unaffected. Notably, HT-29 and HDF 106-05 showed different cell membrane fluidity during US exposure. In conclusion, our data demonstrate a marked difference between cancer cells and normal cells in co-culture in term of responsiveness to SDT, suggesting that this different behavior can be ascribed to diversity in plasma membrane properties, such as membrane fluidity, according to the BLS theory. Full article
(This article belongs to the Special Issue Advances in Cancer Photomedicine)
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Review

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32 pages, 1260 KiB  
Review
Photodynamic Therapy Combined with Ferroptosis Is a Synergistic Antitumor Therapy Strategy
by Yunpeng Huang, Xiaoyu Li, Zijian Zhang, Li Xiong, Yongxiang Wang and Yu Wen
Cancers 2023, 15(20), 5043; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15205043 - 19 Oct 2023
Cited by 5 | Viewed by 1750
Abstract
Ferroptosis is a programmed death mode that regulates redox homeostasis in cells, and recent studies suggest that it is a promising mode of tumor cell death. Ferroptosis is regulated by iron metabolism, lipid metabolism, and intracellular reducing substances, which is the mechanism basis [...] Read more.
Ferroptosis is a programmed death mode that regulates redox homeostasis in cells, and recent studies suggest that it is a promising mode of tumor cell death. Ferroptosis is regulated by iron metabolism, lipid metabolism, and intracellular reducing substances, which is the mechanism basis of its combination with photodynamic therapy (PDT). PDT generates reactive oxygen species (ROS) and 1O2 through type I and type II photochemical reactions, and subsequently induces ferroptosis through the Fenton reaction and the peroxidation of cell membrane lipids. PDT kills tumor cells by generating excessive cytotoxic ROS. Due to the limited laser depth and photosensitizer enrichment, the systemic treatment effect of PDT is not good. Combining PDT with ferroptosis can compensate for these shortcomings. Nanoparticles constructed by photosensitizers and ferroptosis agonists are widely used in the field of combination therapy, and their targeting and biological safety can be improved through modification. These nanoparticles not only directly kill tumor cells but also further exert the synergistic effect of PDT and ferroptosis by activating antitumor immunity, improving the hypoxia microenvironment, and inhibiting the tumor angiogenesis. Ferroptosis-agonist-induced chemotherapy and PDT-induced ablation also have good clinical application prospects. In this review, we summarize the current research progress on PDT and ferroptosis and how PDT and ferroptosis promote each other. Full article
(This article belongs to the Special Issue Advances in Cancer Photomedicine)
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22 pages, 878 KiB  
Review
A Gold Nanoparticle Bioconjugate Delivery System for Active Targeted Photodynamic Therapy of Cancer and Cancer Stem Cells
by Onyisi Christiana Didamson, Rahul Chandran and Heidi Abrahamse
Cancers 2022, 14(19), 4558; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194558 - 20 Sep 2022
Cited by 9 | Viewed by 2235
Abstract
Cancer stem cells (CSCs), also called tumor-initiating cells, are a subpopulation of cancer cells believed to be the leading cause of cancer initiation, growth, metastasis, and recurrence. Presently there are no effective treatments targeted at eliminating CSCs. Hence, an urgent need to develop [...] Read more.
Cancer stem cells (CSCs), also called tumor-initiating cells, are a subpopulation of cancer cells believed to be the leading cause of cancer initiation, growth, metastasis, and recurrence. Presently there are no effective treatments targeted at eliminating CSCs. Hence, an urgent need to develop measures to target CSCs to eliminate potential recurrence and metastasis associated with CSCs. Cancer stem cells have inherent and unique features that differ from other cancer cells, which they leverage to resist conventional therapies. Targeting such features with photodynamic therapy (PDT) could be a promising treatment for drug-resistant cancer stem cells. Photodynamic therapy is a light-mediated non-invasive treatment modality. However, PDT alone is unable to eliminate cancer stem cells effectively, hence the need for a targeted approach. Gold nanoparticle bioconjugates with PDT could be a potential approach for targeted photodynamic therapy of cancer and CSCs. This approach has the potential for enhanced drug delivery, selective and specific attachment to target tumor cells/CSCs, as well as the ability to efficiently generate ROS. This review examines the impact of a smart gold nanoparticle bioconjugate coupled with a photosensitizer (PS) in promoting targeted PDT of cancer and CSC. Full article
(This article belongs to the Special Issue Advances in Cancer Photomedicine)
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33 pages, 5184 KiB  
Review
Deep-Tissue Activation of Photonanomedicines: An Update and Clinical Perspectives
by Nimit Shah, John Squire, Mina Guirguis, Debabrata Saha, Kenneth Hoyt, Ken Kang-Hsin Wang, Vijay Agarwal and Girgis Obaid
Cancers 2022, 14(8), 2004; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14082004 - 15 Apr 2022
Cited by 6 | Viewed by 3286
Abstract
With the continued development of nanomaterials over the past two decades, specialized photonanomedicines (light-activable nanomedicines, PNMs) have evolved to become excitable by alternative energy sources that typically penetrate tissue deeper than visible light. These sources include electromagnetic radiation lying outside the visible near-infrared [...] Read more.
With the continued development of nanomaterials over the past two decades, specialized photonanomedicines (light-activable nanomedicines, PNMs) have evolved to become excitable by alternative energy sources that typically penetrate tissue deeper than visible light. These sources include electromagnetic radiation lying outside the visible near-infrared spectrum, high energy particles, and acoustic waves, amongst others. Various direct activation mechanisms have leveraged unique facets of specialized nanomaterials, such as upconversion, scintillation, and radiosensitization, as well as several others, in order to activate PNMs. Other indirect activation mechanisms have leveraged the effect of the interaction of deeply penetrating energy sources with tissue in order to activate proximal PNMs. These indirect mechanisms include sonoluminescence and Cerenkov radiation. Such direct and indirect deep-tissue activation has been explored extensively in the preclinical setting to facilitate deep-tissue anticancer photodynamic therapy (PDT); however, clinical translation of these approaches is yet to be explored. This review provides a summary of the state of the art in deep-tissue excitation of PNMs and explores the translatability of such excitation mechanisms towards their clinical adoption. A special emphasis is placed on how current clinical instrumentation can be repurposed to achieve deep-tissue PDT with the mechanisms discussed in this review, thereby further expediting the translation of these highly promising strategies. Full article
(This article belongs to the Special Issue Advances in Cancer Photomedicine)
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