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Obaid G, Celli JP, Broekgaarden M, Bulin AL, Uusimaa P, Pogue B, Hasan T, Huang HC. Engineering photodynamics for treatment, priming and imaging. NATURE REVIEWS BIOENGINEERING 2024; 2:752-769. [PMID: 39927170 PMCID: PMC11801064 DOI: 10.1038/s44222-024-00196-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 05/07/2024] [Indexed: 02/11/2025]
Abstract
Photodynamic therapy (PDT) is a photochemistry-based treatment approach that relies on the activation of photosensitizers by light to locally generate reactive oxygen species that induce cellular cytotoxicity, in particular for the treatment of tumours. The cytotoxic effects of PDT are depth-limited owing to light penetration limits in tissue. However, photodynamic priming (PDP), which inherently occurs during PDT, can prime the tissue microenvironment to adjuvant therapies beyond the direct PDT ablative zone. In this Review, we discuss the underlying mechanisms of PDT and PDP, and their application to the treatment of cancer, outlining how PDP can permeabilize the tumour vasculature, overcome biological barriers, modulate multidrug resistance, enhance immune responses, increase tumour permeability and enable the photochemical release of drugs. We further examine the molecular engineering of photosensitizers to improve their pharmacodynamic and pharmacokinetic properties, increase their molecular specificity and allow image guidance of PDT, and investigate engineered cellular models for the design and optimization of PDT and PDP. Finally, we discuss alternative activation sources, including ultrasound, X-rays and self-illuminating compounds, and outline key barriers to the clinical translation of PDT and PDP.
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Affiliation(s)
- Girgis Obaid
- Department of Bioengineering, University of Texas at Dallas, Richardson, TX, USA
| | - Jonathan P. Celli
- Department of Physics, University of Massachusetts Boston, Boston, MA, USA
| | - Mans Broekgaarden
- Grenoble Alpes University, INSERM U1209, CNRS UMR5309, Institute for Advanced Biosciences, Grenoble, France
| | - Anne-Laure Bulin
- Grenoble Alpes University, INSERM U1209, CNRS UMR5309, Institute for Advanced Biosciences, Grenoble, France
| | | | - Brian Pogue
- Department of Medical Physics, University of Wisconsin School of Medicine, Madison, WI, USA
| | - Tayyaba Hasan
- Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Huang-Chiao Huang
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
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Xu C, Law SK, Leung AWN. Comparison of the Differences between Two-Photon Excitation, Upconversion, and Conventional Photodynamic Therapy on Cancers in In Vitro and In Vivo Studies. Pharmaceuticals (Basel) 2024; 17:663. [PMID: 38931331 PMCID: PMC11206628 DOI: 10.3390/ph17060663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/14/2024] [Accepted: 05/17/2024] [Indexed: 06/28/2024] Open
Abstract
Photodynamic therapy (PDT) is a minimally invasive treatment for several diseases. It combines light energy with a photosensitizer (PS) to destroy the targeted cells or tissues. A PS itself is a non-toxic substance, but it becomes toxic to the target cells through the activation of light at a specific wavelength. There are some limitations of PDT, although it has been used in clinical studies for a long time. Two-photon excitation (TPE) and upconversion (UC) for PDT have been recently developed. A TPE nanoparticle-based PS combines the advantages of TPE and nanotechnology that has emerged as an attractive therapeutic agent for near-infrared red (NIR) light-excited PDT, whilst UC is also used for the NIR light-triggered drug release, activation of 'caged' imaging, or therapeutic molecules during PDT process for the diagnosis, imaging, and treatment of cancers. METHODS Nine electronic databases were searched, including WanFang Data, PubMed, Science Direct, Scopus, Web of Science, Springer Link, SciFinder, and China National Knowledge Infrastructure (CNKI), without any language constraints. TPE and UCNP were evaluated to determine if they had different effects from PDT on cancers. All eligible studies were analyzed and summarized in this review. RESULTS TPE-PDT and UCNP-PDT have a high cell or tissue penetration ability through the excitation of NIR light to activate PS molecules. This is much better than the conventional PDT induced by visible or ultraviolet (UV) light. These studies showed a greater PDT efficacy, which was determined by enhanced generation of reactive oxygen species (ROS) and reduced cell viability, as well as inhibited abnormal cell growth for the treatment of cancers. CONCLUSIONS Conventional PDT involves Type I and Type II reactions for the generation of ROS in the treatment of cancer cells, but there are some limitations. Recently, TPE-PDT and UCNP-PDT have been developed to overcome these problems with the help of nanotechnology in in vitro and in vivo studies.
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Affiliation(s)
- Chuanshan Xu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Siu Kan Law
- Department of Food and Health Sciences, The Technological and Higher Education Institute of Hong Kong, Tsing Yi, New Territories, Hong Kong;
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Sun H, Yang W, Ong Y, Busch TM, Zhu TC. Fractionated Photofrin-Mediated Photodynamic Therapy Significantly Improves Long-Term Survival. Cancers (Basel) 2023; 15:5682. [PMID: 38067385 PMCID: PMC10705090 DOI: 10.3390/cancers15235682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/23/2023] [Accepted: 11/28/2023] [Indexed: 02/12/2024] Open
Abstract
This study investigates the effect of fractionated (two-part) PDT on the long-term local control rate (LCR) using the concentration of reactive oxygen species ([ROS]rx) as a dosimetry quantity. Groups with different fractionation schemes are examined, including a 2 h interval between light delivery sessions to cumulative fluences of 135, 180, and 225 J/cm2. While the total treatment time remains constant within each group, the division of treatment time between the first and second fractionations are explored to assess the impact on long-term survival at 90 days. In all preclinical studies, Photofrin is intravenously administered to mice at a concentration of 5 mg/kg, with an incubation period between 18 and 24 h before the first light delivery session. Fluence rate is fixed at 75 mW/cm2. Treatment ensues via a collimated laser beam, 1 cm in diameter, emitting light at 630 nm. Dosimetric quantities are assessed for all groups along with long-term (90 days) treatment outcomes. This study demonstrated a significant improvement in long-term survival after fractionated treatment schemes compared to single-fraction treatment, with the optimal 90-day survival increasing to 63%, 86%, and 100% vs. 20%, 25%, and 50%, respectively, for the three cumulative fluences. The threshold [ROS]rx for the optimal scheme of fractionated Photofrin-mediated PDT, set at 0.78 mM, is significantly lower than that for the single-fraction PDT, at 1.08 mM.
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Affiliation(s)
- Hongjing Sun
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA; (H.S.); (W.Y.); (T.M.B.)
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Weibing Yang
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA; (H.S.); (W.Y.); (T.M.B.)
| | - Yihong Ong
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA; (H.S.); (W.Y.); (T.M.B.)
| | - Theresa M. Busch
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA; (H.S.); (W.Y.); (T.M.B.)
| | - Timothy C. Zhu
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA; (H.S.); (W.Y.); (T.M.B.)
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Bian S, Zheng X, Liu W, Li J, Gao Z, Ren H, Zhang W, Lee CS, Wang P. Pyrrolopyrrole aza-BODIPY-based NIR-II fluorophores for in vivo dynamic vascular dysfunction visualization of vascular-targeted photodynamic therapy. Biomaterials 2023; 298:122130. [PMID: 37146363 DOI: 10.1016/j.biomaterials.2023.122130] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 04/17/2023] [Accepted: 04/20/2023] [Indexed: 05/07/2023]
Abstract
Real-time monitoring vascular responses is crucial for evaluating the therapeutic effects of vascular-targeted photodynamic therapy (V-PDT). Herein, we developed a highly-stable and bright aggregation induced emission (AIE) fluorophore (PTPE3 NP) for dynamic fluorescence (FL) imaging of vascular dysfunction beyond 1300 nm window during V-PDT. The superior brightness (ϵmaxΦf>1000 nm ≈ 180.05 M-1 cm-1) and high resolution of PTPE3 NP affords not only high-clarity images of whole-body and local vasculature (hindlimbs, mesentery, and tumor) but also high-speed video imaging for tracking blood circulation process. By virtue of the NPs' prolonged blood circulation time (t1/2 ≈ 86.5 min) and excellent photo/chemical (pH, RONS) stability, mesenteric and tumor vascular dysfunction (thrombosis formation, vessel occlusion, and hemorrhage) can be successfully visualized during V-PDT by FL imaging for the first time. Furthermore, the reduction of blood flow velocity (BFV) can be monitored in real time for precisely evaluating efficacy of V-PDT. These provide a powerful approach for assessing vascular responses during V-PDT and promote the development of advanced fluorophores for biological imaging.
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Affiliation(s)
- Shuaishuai Bian
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials and CityU-CAS Joint Laboratory of Functional Materials and Devices, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, 100190, China; School of Future Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiuli Zheng
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials and CityU-CAS Joint Laboratory of Functional Materials and Devices, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.
| | - Weimin Liu
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials and CityU-CAS Joint Laboratory of Functional Materials and Devices, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, 100190, China; School of Future Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jihao Li
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials and CityU-CAS Joint Laboratory of Functional Materials and Devices, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, 100190, China; School of Future Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zekun Gao
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials and CityU-CAS Joint Laboratory of Functional Materials and Devices, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, 100190, China; School of Future Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Haohui Ren
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials and CityU-CAS Joint Laboratory of Functional Materials and Devices, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, 100190, China
| | - Wenjun Zhang
- Center of Super-Diamond and Advanced Films (COSDAF) & Department of Materials Science and Engineering, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Chun-Sing Lee
- Center of Super-Diamond and Advanced Films (COSDAF) & Department of Materials Science and Engineering, City University of Hong Kong, Hong Kong SAR, 999077, China.
| | - Pengfei Wang
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials and CityU-CAS Joint Laboratory of Functional Materials and Devices, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, 100190, China; School of Future Technology, University of Chinese Academy of Sciences, Beijing, 100049, China.
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Turchin I, Bano S, Kirillin M, Orlova A, Perekatova V, Plekhanov V, Sergeeva E, Kurakina D, Khilov A, Kurnikov A, Subochev P, Shirmanova M, Komarova A, Yuzhakova D, Gavrina A, Mallidi S, Hasan T. Combined Fluorescence and Optoacoustic Imaging for Monitoring Treatments against CT26 Tumors with Photoactivatable Liposomes. Cancers (Basel) 2021; 14:197. [PMID: 35008362 PMCID: PMC8750546 DOI: 10.3390/cancers14010197] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/22/2021] [Accepted: 12/29/2021] [Indexed: 12/12/2022] Open
Abstract
The newly developed multimodal imaging system combining raster-scan optoacoustic (OA) microscopy and fluorescence (FL) wide-field imaging was used for characterizing the tumor vascular structure with 38/50 μm axial/transverse resolution and assessment of photosensitizer fluorescence kinetics during treatment with novel theranostic agents. A multifunctional photoactivatable multi-inhibitor liposomal (PMILs) nano platform was engineered here, containing a clinically approved photosensitizer, Benzoporphyrin derivative (BPD) in the bilayer, and topoisomerase I inhibitor, Irinotecan (IRI) in its inner core, for a synergetic therapeutic impact. The optimized PMIL was anionic, with the hydrodynamic diameter of 131.6 ± 2.1 nm and polydispersity index (PDI) of 0.05 ± 0.01, and the zeta potential between -14.9 ± 1.04 to -16.9 ± 0.92 mV. In the in vivo studies on BALB/c mice with CT26 tumors were performed to evaluate PMILs' therapeutic efficacy. PMILs demonstrated the best inhibitory effect of 97% on tumor growth compared to the treatment with BPD-PC containing liposomes (PALs), 81%, or IRI containing liposomes (L-[IRI]) alone, 50%. This confirms the release of IRI within the tumor cells upon PMILs triggering by NIR light, which is additionally illustrated by FL monitoring demonstrating enhancement of drug accumulation in tumor initiated by PDT in 24 h after the treatment. OA monitoring revealed the largest alterations of the tumor vascular structure in the PMILs treated mice as compared to BPD-PC or IRI treated mice. The results were further corroborated with histological data that also showed a 5-fold higher percentage of hemorrhages in PMIL treated mice compared to the control groups. Overall, these results suggest that multifunctional PMILs simultaneously delivering PDT and chemotherapy agents along with OA and FL multi-modal imaging offers an efficient and personalized image-guided platform to improve cancer treatment outcomes.
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Affiliation(s)
- Ilya Turchin
- Institute of Applied Physics RAS, 46 Ulyanov St., 603950 Nizhny Novgorod, Russia; (M.K.); (A.O.); (V.P.); (V.P.); (E.S.); (D.K.); (A.K.); (A.K.); (P.S.)
| | - Shazia Bano
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; (S.B.); (S.M.); (T.H.)
| | - Mikhail Kirillin
- Institute of Applied Physics RAS, 46 Ulyanov St., 603950 Nizhny Novgorod, Russia; (M.K.); (A.O.); (V.P.); (V.P.); (E.S.); (D.K.); (A.K.); (A.K.); (P.S.)
| | - Anna Orlova
- Institute of Applied Physics RAS, 46 Ulyanov St., 603950 Nizhny Novgorod, Russia; (M.K.); (A.O.); (V.P.); (V.P.); (E.S.); (D.K.); (A.K.); (A.K.); (P.S.)
| | - Valeriya Perekatova
- Institute of Applied Physics RAS, 46 Ulyanov St., 603950 Nizhny Novgorod, Russia; (M.K.); (A.O.); (V.P.); (V.P.); (E.S.); (D.K.); (A.K.); (A.K.); (P.S.)
| | - Vladimir Plekhanov
- Institute of Applied Physics RAS, 46 Ulyanov St., 603950 Nizhny Novgorod, Russia; (M.K.); (A.O.); (V.P.); (V.P.); (E.S.); (D.K.); (A.K.); (A.K.); (P.S.)
| | - Ekaterina Sergeeva
- Institute of Applied Physics RAS, 46 Ulyanov St., 603950 Nizhny Novgorod, Russia; (M.K.); (A.O.); (V.P.); (V.P.); (E.S.); (D.K.); (A.K.); (A.K.); (P.S.)
| | - Daria Kurakina
- Institute of Applied Physics RAS, 46 Ulyanov St., 603950 Nizhny Novgorod, Russia; (M.K.); (A.O.); (V.P.); (V.P.); (E.S.); (D.K.); (A.K.); (A.K.); (P.S.)
| | - Aleksandr Khilov
- Institute of Applied Physics RAS, 46 Ulyanov St., 603950 Nizhny Novgorod, Russia; (M.K.); (A.O.); (V.P.); (V.P.); (E.S.); (D.K.); (A.K.); (A.K.); (P.S.)
| | - Alexey Kurnikov
- Institute of Applied Physics RAS, 46 Ulyanov St., 603950 Nizhny Novgorod, Russia; (M.K.); (A.O.); (V.P.); (V.P.); (E.S.); (D.K.); (A.K.); (A.K.); (P.S.)
| | - Pavel Subochev
- Institute of Applied Physics RAS, 46 Ulyanov St., 603950 Nizhny Novgorod, Russia; (M.K.); (A.O.); (V.P.); (V.P.); (E.S.); (D.K.); (A.K.); (A.K.); (P.S.)
| | - Marina Shirmanova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603005 Nizhny Novgorod, Russia; (M.S.); (A.K.); (D.Y.); (A.G.)
| | - Anastasiya Komarova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603005 Nizhny Novgorod, Russia; (M.S.); (A.K.); (D.Y.); (A.G.)
| | - Diana Yuzhakova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603005 Nizhny Novgorod, Russia; (M.S.); (A.K.); (D.Y.); (A.G.)
| | - Alena Gavrina
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603005 Nizhny Novgorod, Russia; (M.S.); (A.K.); (D.Y.); (A.G.)
| | - Srivalleesha Mallidi
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; (S.B.); (S.M.); (T.H.)
- Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA
| | - Tayyaba Hasan
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; (S.B.); (S.M.); (T.H.)
- Division of Health Sciences and Technology, Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Implantable optical fibers for immunotherapeutics delivery and tumor impedance measurement. Nat Commun 2021; 12:5138. [PMID: 34446702 PMCID: PMC8390758 DOI: 10.1038/s41467-021-25391-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/05/2021] [Indexed: 12/13/2022] Open
Abstract
Immune checkpoint blockade antibodies have promising clinical applications but suffer from disadvantages such as severe toxicities and moderate patient-response rates. None of the current delivery strategies, including local administration aiming to avoid systemic toxicities, can sustainably supply drugs over the course of weeks; adjustment of drug dose, either to lower systemic toxicities or to augment therapeutic response, is not possible. Herein, we develop an implantable miniaturized device using electrode-embedded optical fibers with both local delivery and measurement capabilities over the course of a few weeks. The combination of local immune checkpoint blockade antibodies delivery via this device with photodynamic therapy elicits a sustained anti-tumor immunity in multiple tumor models. Our device uses tumor impedance measurement for timely presentation of treatment outcomes, and allows modifications to the delivered drugs and their concentrations, rendering this device potentially useful for on-demand delivery of potent immunotherapeutics without exacerbating toxicities.
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De Silva P, Saad MA, Thomsen HC, Bano S, Ashraf S, Hasan T. Photodynamic therapy, priming and optical imaging: Potential co-conspirators in treatment design and optimization - a Thomas Dougherty Award for Excellence in PDT paper. J PORPHYR PHTHALOCYA 2020; 24:1320-1360. [PMID: 37425217 PMCID: PMC10327884 DOI: 10.1142/s1088424620300098] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/25/2023]
Abstract
Photodynamic therapy is a photochemistry-based approach, approved for the treatment of several malignant and non-malignant pathologies. It relies on the use of a non-toxic, light activatable chemical, photosensitizer, which preferentially accumulates in tissues/cells and, upon irradiation with the appropriate wavelength of light, confers cytotoxicity by generation of reactive molecular species. The preferential accumulation however is not universal and, depending on the anatomical site, the ratio of tumor to normal tissue may be reversed in favor of normal tissue. Under such circumstances, control of the volume of light illumination provides a second handle of selectivity. Singlet oxygen is the putative favorite reactive molecular species although other entities such as nitric oxide have been credibly implicated. Typically, most photosensitizers in current clinical use have a finite quantum yield of fluorescence which is exploited for surgery guidance and can also be incorporated for monitoring and treatment design. In addition, the photodynamic process alters the cellular, stromal, and/or vascular microenvironment transiently in a process termed photodynamic priming, making it more receptive to subsequent additional therapies including chemo- and immunotherapy. Thus, photodynamic priming may be considered as an enabling technology for the more commonly used frontline treatments. Recently, there has been an increase in the exploitation of the theranostic potential of photodynamic therapy in different preclinical and clinical settings with the use of new photosensitizer formulations and combinatorial therapeutic options. The emergence of nanomedicine has further added to the repertoire of photodynamic therapy's potential and the convergence and co-evolution of these two exciting tools is expected to push the barriers of smart therapies, where such optical approaches might have a special niche. This review provides a perspective on current status of photodynamic therapy in anti-cancer and anti-microbial therapies and it suggests how evolving technologies combined with photochemically-initiated molecular processes may be exploited to become co-conspirators in optimization of treatment outcomes. We also project, at least for the short term, the direction that this modality may be taking in the near future.
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Affiliation(s)
- Pushpamali De Silva
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Mohammad A. Saad
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Hanna C. Thomsen
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Shazia Bano
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Shoaib Ashraf
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Tayyaba Hasan
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Division of Health Sciences and Technology, Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Sirotkina MA, Gubarkova EV, Plekhanov AA, Sovetsky AA, Elagin VV, Matveyev AL, Matveev LA, Kuznetsov SS, Zagaynova EV, Gladkova ND, Zaitsev VY. In vivo assessment of functional and morphological alterations in tumors under treatment using OCT-angiography combined with OCT-elastography. BIOMEDICAL OPTICS EXPRESS 2020; 11:1365-1382. [PMID: 32206416 PMCID: PMC7075625 DOI: 10.1364/boe.386419] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 02/08/2020] [Accepted: 02/09/2020] [Indexed: 05/13/2023]
Abstract
Emerging methods of anti-tumor therapies require new approaches to tumor response evaluation, especially enabling label-free diagnostics and in vivo utilization. Here, to assess the tumor early reaction and predict its long-term response, for the first time we apply in combination the recently developed OCT extensions - optical coherence angiography (OCA) and compressional optical coherence elastography (OCE), thus enabling complementary functional/microstructural tumor characterization. We study two vascular-targeted therapies of different types, (1) anti-angiogenic chemotherapy (ChT) and (2) photodynamic therapy (PDT), aimed to indirectly kill tumor cells through blood supply injury. Despite different mechanisms of anti-angiogenic action for ChT and PDT, in both cases OCA demonstrated high sensitivity to blood perfusion cessation. The new method of OCE-based morphological segmentation revealed very similar histological structure alterations. The OCE results showed high correlation with conventional histology in evaluating percentages of necrotic and viable tumor zones. Such possibilities make OCE an attractive tool enabling previously inaccessible in vivo monitoring of individual tumor response to therapies without taking multiple biopsies.
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Affiliation(s)
| | | | | | | | - Vadim V. Elagin
- Privolzhsky Research Medical University, Nizhny Novgorod, Russia
| | | | - Lev A. Matveev
- Institute of Applied Physics RAS, Nizhny Novgorod, Russia
| | - Sergey S. Kuznetsov
- N.A. Semashko Nizhny Novgorod Regional Clinical Hospital, Nizhny Novgorod, Russia
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Shi L, Liu P, Wu J, Ma L, Zheng H, Antosh MP, Zhang H, Wang B, Chen W, Wang X. The effectiveness and safety of X-PDT for cutaneous squamous cell carcinoma and melanoma. Nanomedicine (Lond) 2019; 14:2027-2043. [PMID: 31165659 DOI: 10.2217/nnm-2019-0094] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Aim: To clarify the effectiveness and safety of x-ray-activated photodynamic therapy (X-PDT) for cutaneous squamous cell carcinoma (SCC) and melanoma. Materials & methods: Copper-cysteamine nanoparticles were used as a photosensitizer of X-PDT. The dark toxicity and cytotoxicity were studied in vitro. Tumor volume, microvessel density and acute toxicity of mice were evaluated in vivo. Results: Without x-ray irradiation, copper-cysteamine nanoparticles were nontoxic for keratinocyte cells. XL50 cells (SCC) were more sensitive to X-PDT than B16F10 cells (melanoma). X-PDT successfully inhibited the growth of SCC in vivo (p < 0.05), while the B16F10 melanoma was resistant. Microvessel density in SCC tissue was remarkably reduced (p < 0.05). No obvious acute toxicity reaction was observed. Conclusion: X-PDT is a safe and effective treatment for SCC.
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Affiliation(s)
- Lei Shi
- Institute of Photomedicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, 200443, PR China
| | - Pei Liu
- Institute of Photomedicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, 200443, PR China
| | - Jing Wu
- Department of Computer Science & Statistics, University of Rhode Island, 9 Greenhouse Rd, Kingston, RI 02881, USA
| | - Lun Ma
- Department of Physics, the University of Texas at Arlington, Arlington, TX 76019-0059, USA
| | - Han Zheng
- Department of Physics, the University of Texas at Arlington, Arlington, TX 76019-0059, USA
| | - Michael P Antosh
- Physics Department, University of Rhode Island, 2 Lippitt Rd, Kingston, RI 02881, USA.,Institute for Brain & Neural Systems, Brown University, 184 Hope St, Providence, RI 02912, USA
| | - Haiyan Zhang
- Institute of Photomedicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, 200443, PR China
| | - Bo Wang
- Institute of Photomedicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, 200443, PR China
| | - Wei Chen
- Department of Physics, the University of Texas at Arlington, Arlington, TX 76019-0059, USA
| | - Xiuli Wang
- Institute of Photomedicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, 200443, PR China
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Wang H, Mislati R, Ahmed R, Vincent P, Nwabunwanne SF, Gunn JR, Pogue BW, Doyley MM. Elastography Can Map the Local Inverse Relationship between Shear Modulus and Drug Delivery within the Pancreatic Ductal Adenocarcinoma Microenvironment. Clin Cancer Res 2018; 25:2136-2143. [PMID: 30352906 DOI: 10.1158/1078-0432.ccr-18-2684] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 10/05/2018] [Accepted: 10/19/2018] [Indexed: 12/18/2022]
Abstract
PURPOSE High tissue pressure prevents chemotherapeutics from reaching the core of pancreatic tumors. Therefore, targeted therapies have been developed to reduce this pressure. While point probes have shown the effectiveness of these pressure-reducing therapies via single-location estimates, ultrasound elastography is now widely available as an imaging technique to provide real-time spatial maps of shear modulus (tissue stiffness). However, the relationship between shear modulus and the underlying tumor microenvironmental causes of high tissue pressure has not been investigated. In this work, elastography was used to investigate how shear modulus influences drug delivery in situ, and how it correlates with collagen density, hyaluronic acid content, and patent vessel density-features of the tumor microenvironment known to influence tissue pressure. EXPERIMENTAL DESIGN Intravenous injection of verteporfin, an approved human fluorescent drug, was used in two pancreatic cancer xenograft models [AsPC-1 (n = 25) and BxPC-3 (n = 25)]. RESULTS Fluorescence intensity was higher in AsPC-1 tumors than in BxPC-3 tumors (P < 0.0001). Comparing drug uptake images and shear wave elastographic images with histologic images revealed that: (i) drug delivery and shear modulus were inversely related, (ii) shear modulus increased linearly with increasing collagen density, and (iii) shear modulus was marginally correlated with the local assessment of hyaluronic acid content. CONCLUSIONS These results demonstrate that elastography could guide targeted therapy and/or identify patients with highly elevated tissue pressure.See related commentary by Nia et al., p. 2024.
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Affiliation(s)
- Hexuan Wang
- Department of Electrical and Computer Engineering, University of Rochester, Rochester, New York
| | - Reem Mislati
- Department of Electrical and Computer Engineering, University of Rochester, Rochester, New York
| | - Rifat Ahmed
- Department of Electrical and Computer Engineering, University of Rochester, Rochester, New York
| | - Phuong Vincent
- Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire
| | | | - Jason R Gunn
- Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire
| | - Brian W Pogue
- Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire
| | - Marvin M Doyley
- Department of Electrical and Computer Engineering, University of Rochester, Rochester, New York.
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11
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Liu M, Zhang Y, Sun S, Khan AR, Ji J, Yang M, Zhai G. Recent advances in electrospun for drug delivery purpose. J Drug Target 2018; 27:270-282. [PMID: 29798692 DOI: 10.1080/1061186x.2018.1481413] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Electrospun, an advanced technology, has been successfully employed for fibre production and offers many merits in novel drug delivery systems (DDSs). In recent years, electrospun has gained significant attention and attraction of the scientists in soaring numbers. This technology is superior to other technologies in fabricating the fibres which range from micrometers to manometers scale. The selection of appropriate polymers, electrospun processes and electrospun parameters play important roles in controlling the drug release while, treating serious illness. Besides, electrospraying process has similar characteristics to the electrospun and is presented briefly here. Further, in vivo and in vitro evaluations of the electrospun nanofibers are comprehensively discussed. In addition, the electrospun nanotechnology has been exploited to design drug release systems, investigate drug's pharmacokinetics and further develop DDS. The electrospun nanofibers improve bioactivity of various types of drugs including water-insoluble, soluble, anticancer and antibacterial drugs and genetic materials. In the end, the prospects and challenges in the process of designing drug-loaded electrospun nanofibers are discussed in detail.
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Affiliation(s)
- Mengyao Liu
- a Department of Pharmaceutics, College of Pharmacy , Shandong University , Jinan , China
| | - Yanan Zhang
- a Department of Pharmaceutics, College of Pharmacy , Shandong University , Jinan , China
| | - Siyu Sun
- a Department of Pharmaceutics, College of Pharmacy , Shandong University , Jinan , China
| | - Abdur Rauf Khan
- a Department of Pharmaceutics, College of Pharmacy , Shandong University , Jinan , China
| | - Jianbo Ji
- a Department of Pharmaceutics, College of Pharmacy , Shandong University , Jinan , China
| | - Mingshi Yang
- b Department of Pharmacy, Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark
| | - Guangxi Zhai
- a Department of Pharmaceutics, College of Pharmacy , Shandong University , Jinan , China
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12
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Dobson J, de Queiroz GF, Golding JP. Photodynamic therapy and diagnosis: Principles and comparative aspects. Vet J 2018; 233:8-18. [DOI: 10.1016/j.tvjl.2017.11.012] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 08/22/2017] [Accepted: 11/21/2017] [Indexed: 12/16/2022]
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13
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Thong PSP, Lee K, Toh HJ, Dong J, Tee CS, Low KP, Chang PH, Bhuvaneswari R, Tan NC, Soo KC. Early assessment of tumor response to photodynamic therapy using combined diffuse optical and diffuse correlation spectroscopy to predict treatment outcome. Oncotarget 2017; 8:19902-19913. [PMID: 28423634 PMCID: PMC5386732 DOI: 10.18632/oncotarget.15720] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 01/16/2017] [Indexed: 12/30/2022] Open
Abstract
Photodynamic therapy (PDT) of cancer involves the use of a photosensitizer that can be light-activated to eradicate tumors via direct cytotoxicity, damage to tumor vasculature and stimulating the body's immune system. Treatment outcome may vary between individuals even under the same regime; therefore a non-invasive tumor response monitoring system will be useful for personalization of the treatment protocol. We present the combined use of diffuse optical spectroscopy (DOS) and diffuse correlation spectroscopy (DCS) to provide early assessment of tumor response. The relative tissue oxygen saturation (rStO2) and relative blood flow (rBF) in tumors were measured using DOS and DCS respectively before and after PDT with reference to baseline values in a mouse model. In complete responders, PDT-induced decreases in both rStO2 and rBF levels were observed at 3 h post-PDT and the rBF remained low until 48 h post-PDT. Recovery of these parameters to baseline values was observed around 2 weeks after PDT. In partial responders, the rStO2 and rBF levels also decreased at 3 h post PDT, however the rBF values returned toward baseline values earlier at 24 h post-PDT. In contrast, the rStO2 and rBF readings in control tumors showed fluctuations above the baseline values within the first 48 h. Therefore tumor response can be predicted at 3 to 48 h post-PDT. Recovery or sustained decreases in the rBF at 48 h post-PDT corresponded to long-term tumor control. Diffuse optical measurements can thus facilitate early assessment of tumor response. This approach can enable physicians to personalize PDT treatment regimens for best outcomes.
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Affiliation(s)
| | - Kijoon Lee
- Division of Bioengineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore.,Nanyang Technological University, Singapore.,Current address: Daegu Gyeongbuk Institute of Science and Technology, Korea
| | - Hui-Jin Toh
- Division of Medical Sciences, National Cancer Centre, Singapore
| | - Jing Dong
- Division of Bioengineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore.,Nanyang Technological University, Singapore.,Current address: Harvard Medical School and Wellman Center for Photomedicine, Massachusetts General Hospital, USA
| | - Chuan-Sia Tee
- Division of Medical Sciences, National Cancer Centre, Singapore
| | - Kar-Perng Low
- Division of Medical Sciences, National Cancer Centre, Singapore
| | - Pui-Haan Chang
- Division of Medical Sciences, National Cancer Centre, Singapore
| | | | - Ngian-Chye Tan
- Division of Surgical Oncology, National Cancer Centre, Singapore
| | - Khee-Chee Soo
- Division of Medical Sciences, National Cancer Centre, Singapore
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14
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Kraus D, Palasuberniam P, Chen B. Targeting Phosphatidylinositol 3-Kinase Signaling Pathway for Therapeutic Enhancement of Vascular-Targeted Photodynamic Therapy. Mol Cancer Ther 2017; 16:2422-2431. [PMID: 28835385 DOI: 10.1158/1535-7163.mct-17-0326] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 07/10/2017] [Accepted: 08/07/2017] [Indexed: 11/16/2022]
Abstract
Vascular-targeted photodynamic therapy (PDT) selectively disrupts vascular function by inducing oxidative damages to the vasculature, particularly endothelial cells. Although effective tumor eradication and excellent safety profile are well demonstrated in both preclinical and clinical studies, incomplete vascular shutdown and angiogenesis are known to cause tumor recurrence after vascular-targeted PDT. We have explored therapeutic enhancement of vascular-targeted PDT with PI3K signaling pathway inhibitors because the activation of PI3K pathway was involved in promoting endothelial cell survival and proliferation after PDT. Here, three clinically relevant small-molecule inhibitors (BYL719, BKM120, and BEZ235) of the PI3K pathway were evaluated in combination with verteporfin-PDT. Although all three inhibitors were able to synergistically enhance PDT response in endothelial cells, PDT combined with dual PI3K/mTOR inhibitor BEZ235 exhibited the strongest synergism, followed in order by combinations with pan-PI3K inhibitor BKM120 and p110α isoform-selective inhibitor BYL719. Combination treatments of PDT and BEZ235 exhibited a cooperative inhibition of antiapoptotic Bcl-2 family protein Mcl-1 and induced more cell apoptosis than each treatment alone. In addition to increasing treatment lethality, BEZ235 combined with PDT effectively inhibited PI3K pathway activation and consequent endothelial cell proliferation after PDT alone, leading to a sustained growth inhibition. In the PC-3 prostate tumor model, combination treatments improved treatment outcomes by turning a temporary tumor regrowth delay induced by PDT alone to a more long-lasting treatment response. Our study strongly supports the combination of vascular-targeted PDT and PI3K pathway inhibitors, particularly mTOR inhibitors, for therapeutic enhancement. Mol Cancer Ther; 16(11); 2422-31. ©2017 AACR.
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Affiliation(s)
- Daniel Kraus
- Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, Pennsylvania
| | - Pratheeba Palasuberniam
- Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, Pennsylvania
| | - Bin Chen
- Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, Pennsylvania. .,Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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15
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Moret F, Reddi E. Strategies for optimizing the delivery to tumors of macrocyclic photosensitizers used in photodynamic therapy (PDT). J PORPHYR PHTHALOCYA 2017. [DOI: 10.1142/s1088424617300014] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
This review briefly summaries the principles and mechanisms of action of photodynamic therapy (PDT) as concerns its application in the oncological field, highlighting its drawbacks and some of the strategies that have been or are being explored to overcome them. The major aim is to increase the efficiency and selectivity of the photosensitizer (PS) uptake in the cancer cells for optimizing the PDT effects on tumors while sparing normal cells. Some attempts to achieve this are based on the conjugation of the PS to biomolecules (small ligands, peptides) functioning as carriers with the ability to efficiently penetrate cells and/or specifically recognize and bind proteins/receptors overexpressed on the surface of cancer cells. Alternatively, the PS can be entrapped in nanocarriers derived from various types of materials that can target the tumor by exploiting the enhanced permeability and retention (EPR) effects. The use of nanocarriers is particularly attractive because it allows the simultaneous delivery of more than one drug with the possibility of combining PDT with other therapeutic modalities.
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Affiliation(s)
- Francesca Moret
- Department of Biology, University of Padova, via U. Bassi 58/B 35121 Padova, Italy
| | - Elena Reddi
- Department of Biology, University of Padova, via U. Bassi 58/B 35121 Padova, Italy
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16
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Schaberle FA, Abreu AR, Gonçalves NPF, Sá GFF, Pereira MM, Arnaut LG. Ultrafast Dynamics of Manganese(III), Manganese(II), and Free-Base Bacteriochlorin: Is There Time for Photochemistry? Inorg Chem 2017; 56:2677-2689. [PMID: 28206747 DOI: 10.1021/acs.inorgchem.6b02871] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Manganese(III) and manganese(II) complexes of halogenated sulfonamide tetraphenylbacteriochlorins were prepared for the first time via a transmetalation reaction and shown to be stable at room temperature. The behavior of the electronic states of the paramagnetic complexes is remarkably different from those of the metal-free bacteriochlorins or diamagnetic metallobacteriochlorins. The Mn3+ complex exhibits eight electronic transitions between different states from 300 to 1100 nm, with a very prominent band (molar absorption coefficient of ca. 50000 M-1 cm-1) at 829 nm. Ultrafast transient absorption showed the formation of an excited singquintet state that decays to a tripquintet state with a femtosecond lifetime. The tripquintet state decays in 5 ps, yielding a tripseptet state with a 570 ps lifetime. The electronic absorption of the Mn2+ complex more closely resembles those of diamagnetic metallobacteriochlorins, but the longest decay lifetime is only ca. 8 ps. The intense photoacoustic waves generated with near-infrared excitation suggest the use of these complexes in photoacoustic tomography.
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Affiliation(s)
- Fabio A Schaberle
- Luzitin SA, Ed. Bluepharma , S. Martinho do Bispo, 3045-016 Coimbra, Portugal.,Chemistry Department, University of Coimbra , 3004-535 Coimbra, Portugal
| | - Artur R Abreu
- Luzitin SA, Ed. Bluepharma , S. Martinho do Bispo, 3045-016 Coimbra, Portugal
| | - Nuno P F Gonçalves
- Luzitin SA, Ed. Bluepharma , S. Martinho do Bispo, 3045-016 Coimbra, Portugal
| | - Gonçalo F F Sá
- LaserLeap SA, IPN , R. Pedro Nunes, 3030-199 Coimbra, Portugal
| | - Mariette M Pereira
- Chemistry Department, University of Coimbra , 3004-535 Coimbra, Portugal
| | - Luís G Arnaut
- Chemistry Department, University of Coimbra , 3004-535 Coimbra, Portugal
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17
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Chen B. 14 Vascular imaging in photodynamic therapy. IMAGING IN PHOTODYNAMIC THERAPY 2017:275-292. [DOI: 10.1201/9781315278179-15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
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18
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Tylcz JB, Bastogne T, Bourguignon A, Frochot C, Barberi-Heyob M. Realtime Tracking of the Photobleaching Trajectory During Photodynamic Therapy. IEEE Trans Biomed Eng 2017; 64:1742-1749. [PMID: 28113251 DOI: 10.1109/tbme.2016.2620239] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
OBJECTIVE Photodynamic therapy (PDT) is an alternative treatment for cancer, which involves the administration of a photosensitizing agent that is activated by light at a specific wavelength. This illumination causes after a sequence of photoreactions, the production of reactive oxygen species responsible for the death of the tumor cells but also the degradation of the photosensitizing agent, which then loose the fluorescence properties. The phenomenon is commonly known as the photobleaching process and can be considered as a therapy efficiency indicator. METHODS This paper presents the design and validation of a real-time controller able to track a preset photobleaching trajectory by modulating the light impulses width during the treatment sessions. RESULTS This innovative solution was validated by in vivo experiments that have shown a significantly improvement of reproducibility of the interindividual photobleaching kinetic. CONCLUSION We believe that this approach could lead to personalized PDT modalities. SIGNIFICANCE This work may open new perspectives in the control and optimization of photodynamic treatments.
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19
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Qiu H, Mao Y, Zeng J, Wang Y, Zhang J, Huang N, Liu Q, Yang Y, Linghu E, Gu Y. Vascular-targeted photodynamic therapy of gastric antral vascular ectasia (GAVE). JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY 2017; 166:58-62. [PMID: 27871022 DOI: 10.1016/j.jphotobiol.2016.10.033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 10/25/2016] [Accepted: 10/27/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND STUDY AIM Vascular-targeted photodynamic therapy (V-PDT) has been used for several benign vascular diseases. The aim of this pilot study was to demonstrate the potential benefits of VPDT in the treatment of gastric antral vascular ectasia (GAVE). PATIENTS AND METHODS Data from patients with GAVE (n=5) who underwent endoscopic V-PDT were analyzed retrospectively. Pre- and post-V-PDT clinical and endoscopic features, hemoglobin levels, and transfusion requirement were compared. RESULTS The five GAVE patients received one to four sessions of V-PDT. The hemoglobin levels of all five patients increased steadily following V-PDT. Within 6-48months of follow-up, gastrointestinal bleeding and melena disappeared in all five patients and none of the patients needed a transfusion. Endoscopy examinations showed that the dilated vessels had disappeared without scar formation. No significant side effects or adverse reactions were reported. CONCLUSION This preliminary study indicates the good selectivity, safety, and efficacy of V-PDT in the treatment of patients with GAVE. Larger prospective studies are needed to further confirm the feasibility of using V-PDT to treat patients with GAVE.
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Affiliation(s)
- Haixia Qiu
- Department of Laser Medicine, Chinese PLA General Hospital, China
| | - Yongping Mao
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, China.
| | - Jing Zeng
- Department of Laser Medicine, Chinese PLA General Hospital, China
| | - Ying Wang
- Department of Laser Medicine, Chinese PLA General Hospital, China
| | - Jiaying Zhang
- Department of Laser Medicine, Chinese PLA General Hospital, China
| | - Naiyang Huang
- Department of Laser Medicine, Chinese PLA General Hospital, China
| | - Qingsen Liu
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, China
| | - Yunsheng Yang
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, China
| | - Enqiang Linghu
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, China
| | - Ying Gu
- Department of Laser Medicine, Chinese PLA General Hospital, China.
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20
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Photodynamic Therapy-Induced Microvascular Changes in a Nonmelanoma Skin Cancer Model Assessed by Photoacoustic Microscopy and Diffuse Correlation Spectroscopy. PHOTONICS 2016. [DOI: 10.3390/photonics3030048] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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21
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Obaid G, Broekgaarden M, Bulin AL, Huang HC, Kuriakose J, Liu J, Hasan T. Photonanomedicine: a convergence of photodynamic therapy and nanotechnology. NANOSCALE 2016; 8:12471-503. [PMID: 27328309 PMCID: PMC4956486 DOI: 10.1039/c5nr08691d] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
As clinical nanomedicine has emerged over the past two decades, phototherapeutic advancements using nanotechnology have also evolved and impacted disease management. Because of unique features attributable to the light activation process of molecules, photonanomedicine (PNM) holds significant promise as a personalized, image-guided therapeutic approach for cancer and non-cancer pathologies. The convergence of advanced photochemical therapies such as photodynamic therapy (PDT) and imaging modalities with sophisticated nanotechnologies is enabling the ongoing evolution of fundamental PNM formulations, such as Visudyne®, into progressive forward-looking platforms that integrate theranostics (therapeutics and diagnostics), molecular selectivity, the spatiotemporally controlled release of synergistic therapeutics, along with regulated, sustained drug dosing. Considering that the envisioned goal of these integrated platforms is proving to be realistic, this review will discuss how PNM has evolved over the years as a preclinical and clinical amalgamation of nanotechnology with PDT. The encouraging investigations that emphasize the potent synergy between photochemistry and nanotherapeutics, in addition to the growing realization of the value of these multi-faceted theranostic nanoplatforms, will assist in driving PNM formulations into mainstream oncological clinical practice as a necessary tool in the medical armamentarium.
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Affiliation(s)
| | | | | | | | | | | | - Tayyaba Hasan
- Harvard Medical School, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard-MIT Division of Health Science and Technology, Boston, Massachusetts, USA
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22
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Pogue BW, Elliott JT, Kanick SC, Davis SC, Samkoe KS, Maytin EV, Pereira SP, Hasan T. Revisiting photodynamic therapy dosimetry: reductionist & surrogate approaches to facilitate clinical success. Phys Med Biol 2016; 61:R57-89. [PMID: 26961864 DOI: 10.1088/0031-9155/61/7/r57] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Photodynamic therapy (PDT) can be a highly complex treatment, with many parameters influencing treatment efficacy. The extent to which dosimetry is used to monitor and standardize treatment delivery varies widely, ranging from measurement of a single surrogate marker to comprehensive approaches that aim to measure or estimate as many relevant parameters as possible. Today, most clinical PDT treatments are still administered with little more than application of a prescribed drug dose and timed light delivery, and thus the role of patient-specific dosimetry has not reached widespread clinical adoption. This disconnect is at least partly due to the inherent conflict between the need to measure and understand multiple parameters in vivo in order to optimize treatment, and the need for expedience in the clinic and in the regulatory and commercialization process. Thus, a methodical approach to selecting primary dosimetry metrics is required at each stage of translation of a treatment procedure, moving from complex measurements to understand PDT mechanisms in pre-clinical and early phase I trials, towards the identification and application of essential dose-limiting and/or surrogate measurements in phase II/III trials. If successful, identifying the essential and/or reliable surrogate dosimetry measurements should help facilitate increased adoption of clinical PDT. In this paper, examples of essential dosimetry points and surrogate dosimetry tools that may be implemented in phase II/III trials are discussed. For example, the treatment efficacy as limited by light penetration in interstitial PDT may be predicted by the amount of contrast uptake in CT, and so this could be utilized as a surrogate dosimetry measurement to prescribe light doses based upon pre-treatment contrast. Success of clinical ALA-based skin lesion treatment is predicted almost uniquely by the explicit or implicit measurements of photosensitizer and photobleaching, yet the individualization of treatment based upon each patients measured bleaching needs to be attempted. In the case of ALA, lack of PpIX is more likely an indicator that alternative PpIX production methods must be implemented. Parsimonious dosimetry, using surrogate measurements that are clinically acceptable, might strategically help to advance PDT in a medical world that is increasingly cost and time sensitive. Careful attention to methodologies that can identify and advance the most critical dosimetric measurements, either direct or surrogate, are needed to ensure successful incorporation of PDT into niche clinical procedures.
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Affiliation(s)
- Brian W Pogue
- Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA. Department of Surgery, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
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23
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Tang W, Zhen Z, Wang M, Wang H, Chuang YJ, Zhang W, Wang GD, Todd T, Cowger T, Chen H, Liu L, Li Z, Xie J. Red Blood Cell-Facilitated Photodynamic Therapy for Cancer Treatment. ADVANCED FUNCTIONAL MATERIALS 2016; 26:1757-1768. [PMID: 31749670 PMCID: PMC6867707 DOI: 10.1002/adfm.201504803] [Citation(s) in RCA: 155] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Photodynamic therapy (PDT) is a promising treatment modality for cancer management. So far, most PDT studies have focused on delivery of photosensitizers to tumors. O2, another essential component of PDT, is not artificially delivered but taken from the biological milieu. However, cancer cells demand a large amount of O2 to sustain their growth and that often leads to low O2 levels in tumors. The PDT process may further potentiate the oxygen deficiency, and in turn, adversely affect the PDT efficiency. In the present study, a new technology called red blood cell (RBC)-facilitated PDT, or RBC-PDT, is introduced that can potentially solve the issue. As the name tells, RBC-PDT harnesses erythrocytes, an O2 transporter, as a carrier for photosensitizers. Because photosensitizers are adjacent to a carry-on O2 source, RBC-PDT can efficiently produce 1O2 even under low oxygen conditions. The treatment also benefits from the long circulation of RBCs, which ensures a high intraluminal concentration of photosensitizers during PDT and hence maximizes damage to tumor blood vessels. When tested in U87MG subcutaneous tumor models, RBC-PDT shows impressive tumor suppression (76.7%) that is attributable to the codelivery of O2 and photosensitizers. Overall, RBC-PDT is expected to find wide applications in modern oncology.
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Affiliation(s)
- Wei Tang
- Department of Chemistry, University of Georgia, Athens, GA 30602, USA,
| | - Zipeng Zhen
- Department of Chemistry, University of Georgia, Athens, GA 30602, USA,
| | - Mengzhe Wang
- Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA,
| | - Hui Wang
- Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA,
| | - Yen-Jun Chuang
- College of Engineering, University of Georgia, Athens, GA 30602, USA
| | - Weizhong Zhang
- Department of Chemistry, University of Georgia, Athens, GA 30602, USA,
| | - Geoffrey D Wang
- Department of Chemistry, University of Georgia, Athens, GA 30602, USA,
| | - Trever Todd
- Department of Chemistry, University of Georgia, Athens, GA 30602, USA,
| | - Taku Cowger
- Department of Chemistry, University of Georgia, Athens, GA 30602, USA,
| | - Hongmin Chen
- Department of Chemistry, University of Georgia, Athens, GA 30602, USA,
| | - Lin Liu
- Department of Radiology, China-Japan Union Hospital, Jilin University, Changchun, Jilin 130033, China
| | - Zibo Li
- Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA,
| | - Jin Xie
- Department of Chemistry, University of Georgia, Athens, GA 30602, USA,
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24
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Rohrbach DJ, Rigual N, Arshad H, Tracy EC, Cooper MT, Shafirstein G, Wilding G, Merzianu M, Baumann H, Henderson BW, Sunar U. Intraoperative optical assessment of photodynamic therapy response of superficial oral squamous cell carcinoma. JOURNAL OF BIOMEDICAL OPTICS 2016; 21:18002. [PMID: 26780226 PMCID: PMC5996863 DOI: 10.1117/1.jbo.21.1.018002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 12/11/2015] [Indexed: 06/05/2023]
Abstract
This study investigated whether diffuse optical spectroscopy (DOS) measurements could assess clinical response to photodynamic therapy (PDT) in patients with head and neck squamous cell carcinoma (HNSCC). In addition, the correlation between parameters measured with DOS and the crosslinking of signal transducer and activator of transcription 3 (STAT3), a molecular marker for PDT-induced photoreaction, was investigated. Thirteen patients with early stage HNSCC received the photosensitizer 2-[1-hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH) and DOS measurements were performed before and after PDT in the operating room (OR). In addition, biopsies were acquired after PDT to assess the STAT3 crosslinking. Parameters measured with DOS, including blood volume fraction, blood oxygen saturation (StO2), HPPH concentration (cHPPH), HPPH fluorescence, and blood flow index (BFI), were compared to the pathologic response and the STAT3 crosslinking. The best individual predictor of pathological response was a change in cHPPH (sensitivity=60%, specificity=100%), while discrimination analysis using a two-parameter classifier (change in cHPPH and change in StO2) classified pathological response with 100% sensitivity and 100% specificity. BFI showed the best correlation with the crosslinking of STAT3. These results indicate that DOS-derived parameters can assess the clinical response in the OR, allowing for earlier reintervention if needed.
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Affiliation(s)
- Daniel J. Rohrbach
- Roswell Park Cancer Institute, Department of Cell Stress Biology, Elm and Carlton Streets, Buffalo, New York 14263, United States
- Wright State University, Department of Biomedical, Industrial and Human Factors Engineering, 207 Russ Center, Dayton, Ohio 45435, United States
| | - Nestor Rigual
- Roswell Park Cancer Institute, Department of Head and Neck Surgery, Elm and Carlton Streets, Buffalo, New York 14263, United States
| | - Hassan Arshad
- Roswell Park Cancer Institute, Department of Head and Neck Surgery, Elm and Carlton Streets, Buffalo, New York 14263, United States
| | - Erin C. Tracy
- Roswell Park Cancer Institute, Department of Cellular and Molecular Biology, Elm and Carlton Streets, Buffalo, New York 14263, United States
| | - Michelle T. Cooper
- Roswell Park Cancer Institute, Department of Cell Stress Biology, Elm and Carlton Streets, Buffalo, New York 14263, United States
| | - Gal Shafirstein
- Roswell Park Cancer Institute, Department of Cell Stress Biology, Elm and Carlton Streets, Buffalo, New York 14263, United States
| | - Gregory Wilding
- Roswell Park Cancer Institute, Department of Biostatistics and Bioinformatics, Elm and Carlton Streets, Buffalo, New York 14263, United States
| | - Mihai Merzianu
- Roswell Park Cancer Institute, Department of Pathology and Laboratory Medicine, Elm and Carlton Streets, Buffalo, New York 14263, United States
| | - Heinz Baumann
- Roswell Park Cancer Institute, Department of Cellular and Molecular Biology, Elm and Carlton Streets, Buffalo, New York 14263, United States
| | - Barbara W. Henderson
- Roswell Park Cancer Institute, Department of Cell Stress Biology, Elm and Carlton Streets, Buffalo, New York 14263, United States
| | - Ulas Sunar
- Roswell Park Cancer Institute, Department of Cell Stress Biology, Elm and Carlton Streets, Buffalo, New York 14263, United States
- Wright State University, Department of Biomedical, Industrial and Human Factors Engineering, 207 Russ Center, Dayton, Ohio 45435, United States
- State University of New York at Buffalo, Department of Biomedical Engineering, 332 Bonner Hall, Buffalo, New York 14228, United States
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25
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Doxorubicin encapsulated in stealth liposomes conferred with light-triggered drug release. Biomaterials 2015; 75:193-202. [PMID: 26513413 DOI: 10.1016/j.biomaterials.2015.10.027] [Citation(s) in RCA: 168] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 10/08/2015] [Accepted: 10/13/2015] [Indexed: 01/01/2023]
Abstract
Stealth liposomes can be used to extend the blood circulation time of encapsulated therapeutics. Inclusion of 2 molar % porphyrin-phospholipid (PoP) imparted optimal near infrared (NIR) light-triggered release of doxorubicin (Dox) from conventional sterically stabilized stealth liposomes. The type and amount of PoP affected drug loading, serum stability and drug release induced by NIR light. Cholesterol and PEGylation were required for Dox loading, but slowed light-triggered release. Dox in stealth PoP liposomes had a long circulation half-life in mice of 21.9 h and was stable in storage for months. Following intravenous injection and NIR irradiation, Dox deposition increased ∼ 7 fold in treated subcutaneous human pancreatic xenografts. Phototreatment induced mild tumor heating and complex tumor hemodynamics. A single chemophototherapy treatment with Dox-loaded stealth PoP liposomes (at 5-7 mg/kg Dox) eradicated tumors while corresponding chemo- or photodynamic therapies were ineffective. A low dose 3 mg/kg Dox phototreatment with stealth PoP liposomes was more effective than a maximum tolerated dose of free (7 mg/kg) or conventional long-circulating liposomal Dox (21 mg/kg). To our knowledge, Dox-loaded stealth PoP liposomes represent the first reported long-circulating nanoparticle capable of light-triggered drug release.
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Yeung HY, Lo PC, Ng DKP, Fong WP. Anti-tumor immunity of BAM-SiPc-mediated vascular photodynamic therapy in a BALB/c mouse model. Cell Mol Immunol 2015; 14:223-234. [PMID: 26388236 DOI: 10.1038/cmi.2015.84] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Revised: 07/15/2015] [Accepted: 08/10/2015] [Indexed: 12/22/2022] Open
Abstract
In recent decades, accumulating evidence from both animal and clinical studies has suggested that a sufficiently activated immune system may strongly augment various types of cancer treatment, including photodynamic therapy (PDT). Through the generation of reactive oxygen species, PDT eradicates tumors by triggering localized tumor damage and inducing anti-tumor immunity. As the major component of anti-tumor immunity, the involvement of a cell-mediated immune response in PDT has been well investigated in the past decade, whereas the role of humoral immunity has remained relatively unexplored. In the present investigation, using the photosensitizer BAM-SiPc and the CT26 tumor-bearing BALB/c mouse model, it was demonstrated that both cell-mediated and humoral adaptive immune components could be involved in PDT. With a vascular PDT (VPDT) regimen, BAM-SiPc could eradicate the tumors of ∼70% of tumor-bearing mice and trigger an anti-tumor immune response that could last for more than 1 year. An elevation of Th2 cytokines was detected ex vivo after VPDT, indicating the potential involvement of a humoral response. An analysis of serum from the VPDT-cured mice also revealed elevated levels of tumor-specific antibodies. Moreover, this serum could effectively hinder tumor growth and protect the mice against further re-challenge in a T-cell-dependent manner. Taken together, these results show that the humoral components induced after BAM-SiPc-VPDT could assist the development of anti-tumor immunity.
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Affiliation(s)
- Hing-Yuen Yeung
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
| | - Pui-Chi Lo
- Department of Biomedical Sciences, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China
| | - Dennis K P Ng
- Department of Chemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
| | - Wing-Ping Fong
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
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Roussakis E, Li Z, Nichols AJ, Evans CL. Sauerstoffmessung in der Biomedizin - von der Makro- zur Mikroebene. Angew Chem Int Ed Engl 2015. [DOI: 10.1002/ange.201410646] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Roussakis E, Li Z, Nichols AJ, Evans CL. Oxygen-Sensing Methods in Biomedicine from the Macroscale to the Microscale. Angew Chem Int Ed Engl 2015; 54:8340-62. [DOI: 10.1002/anie.201410646] [Citation(s) in RCA: 114] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Revised: 01/05/2015] [Indexed: 12/15/2022]
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Gallagher-Colombo SM, Miller J, Cengel KA, Putt ME, Vinogradov SA, Busch TM. Erlotinib Pretreatment Improves Photodynamic Therapy of Non-Small Cell Lung Carcinoma Xenografts via Multiple Mechanisms. Cancer Res 2015; 75:3118-26. [PMID: 26054596 DOI: 10.1158/0008-5472.can-14-3304] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 05/11/2015] [Indexed: 01/08/2023]
Abstract
Aberrant expression of the epidermal growth factor receptor (EGFR) is a common characteristic of many cancers, including non-small cell lung carcinoma (NSCLC), head and neck squamous cell carcinoma, and ovarian cancer. Although EGFR is currently a favorite molecular target for the treatment of these cancers, inhibition of the receptor with small-molecule inhibitors (i.e., erlotinib) or monoclonal antibodies (i.e., cetuximab) does not provide long-term therapeutic benefit as standalone treatment. Interestingly, we have found that addition of erlotinib to photodynamic therapy (PDT) can improve treatment response in typically erlotinib-resistant NSCLC tumor xenografts. Ninety-day complete response rates of 63% are achieved when erlotinib is administered in three doses before PDT of H460 human tumor xenografts, compared with 16% after PDT-alone. Similar benefit is found when erlotinib is added to PDT of A549 NCSLC xenografts. Improved response is accompanied by increased vascular shutdown, and erlotinib increases the in vitro cytotoxicity of PDT to endothelial cells. Tumor uptake of the photosensitizer (benzoporphyrin derivative monoacid ring A; BPD) is increased by the in vivo administration of erlotinib; nevertheless, this elevation of BPD levels only partially accounts for the benefit of erlotinib to PDT. Thus, pretreatment with erlotinib augments multiple mechanisms of PDT effect that collectively lead to large improvements in therapeutic efficacy. These data demonstrate that short-duration administration of erlotinib before PDT can greatly improve the responsiveness of even erlotinib-resistant tumors to treatment. Results will inform clinical investigation of EGFR-targeting therapeutics in conjunction with PDT.
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Affiliation(s)
- Shannon M Gallagher-Colombo
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Joann Miller
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Keith A Cengel
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Mary E Putt
- Department of Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sergei A Vinogradov
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Theresa M Busch
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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Srivatsan A, Missert JR, Upadhyay SK, Pandey RK. Porphyrin-based photosensitizers and the corresponding multifunctional nanoplatforms for cancer-imaging and phototherapy. J PORPHYR PHTHALOCYA 2015. [DOI: 10.1142/s1088424615300037] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
This review article briefly describes: (a) the advantages in developing multifunctional nanoparticles for cancer-imaging and therapy, (b) the advantages and limitations of most of the porphyrin-based compounds in fluorescence imaging and photodynamic therapy (PDT), (c) problems associated with current Food and Drug Administration (FDA) approved photosensitizers, (d) challenges in developing in vivo target-specific PDT agents, (e) development of porphyrin-based nuclear-imaging agents (PET, SPECT) with an option of PDT, (f) the importance of light dosimetry in PDT, (g) the role of whole body or local hyperthermia in enhancing tumor-uptake, tumor-imaging and phototherapy and finally, (h) the advantages of photosensitizer-gold nanocages (Ps- Au NC) in photoacoustic and PDT.
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Affiliation(s)
- Avinash Srivatsan
- Department of Molecular Pharmacology and Cancer Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Joseph R. Missert
- PDT Center, Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | | | - Ravindra K. Pandey
- Department of Molecular Pharmacology and Cancer Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
- PDT Center, Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
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Phase I/II study of verteporfin photodynamic therapy in locally advanced pancreatic cancer. Br J Cancer 2014; 110:1698-704. [PMID: 24569464 PMCID: PMC3974098 DOI: 10.1038/bjc.2014.95] [Citation(s) in RCA: 287] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/05/2014] [Accepted: 01/29/2014] [Indexed: 02/06/2023] Open
Abstract
Background: Patients with pancreatic cancer have a poor prognosis apart from the few suitable for surgery. Photodynamic therapy (PDT) produces localised tissue necrosis but previous studies using the photosensitiser meso-tetrahydroxyphenylchlorin (mTHPC) caused prolonged skin photosensitivity. This study assessed a shorter acting photosensitiser, verteporfin. Methods: Fifteen inoperable patients with locally advanced cancers were sensitised with 0.4 mg kg−1 verteporfin. After 60–90 min, laser light (690 nm) was delivered via single (13 patients) or multiple (2 patients) fibres positioned percutaneously under computed tomography (CT) guidance, the light dose escalating (initially 5 J, doubling after each three patients) until 12 mm of necrosis was achieved consistently. Results: In all, 12 mm lesions were seen consistently at 40 J, but with considerable variation in necrosis volume (mean volume 3.5 cm3 at 40 J). Minor, self-limiting extrapancreatic effects were seen in multifibre patients. No adverse interactions were seen in patients given chemotherapy or radiotherapy before or after PDT. After PDT, one patient underwent an R0 Whipple's pancreaticoduodenectomy. Conclusions: Verteporfin PDT-induced tumour necrosis in locally advanced pancreatic cancer is feasible and safe. It can be delivered with a much shorter drug light interval and with less photosensitivity than with older compounds.
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Sunar U. Monitoring photodynamic therapy of head and neck malignancies with optical spectroscopies. World J Clin Cases 2013; 1:96-105. [PMID: 24303476 PMCID: PMC3845916 DOI: 10.12998/wjcc.v1.i3.96] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Revised: 04/02/2013] [Accepted: 05/08/2013] [Indexed: 02/05/2023] Open
Abstract
In recent years there has been significant developments in photosensitizers (PSs), light sources and light delivery systems that have allowed decreasing the treatment time and skin phototoxicity resulting in more frequent use of photodynamic therapy (PDT) in the clinical settings. Compared to standard treatment approaches such as chemo-radiation and surgery, PDT has much reduced morbidity for head and neck malignancies and is becoming an alternative treatment option. It can be used as an adjunct therapy to other treatment modalities without any additive cumulative side effects. Surface illumination can be an option for pre-malignant and early-stage malignancies while interstitial treatment is for debulking of thick tumors in the head and neck region. PDT can achieve equivalent or greater efficacy in treating head and neck malignancies, suggesting that it may be considered as a first line therapy in the future. Despite progressive development, clinical PDT needs improvement in several topics for wider acceptance including standardization of protocols that involve the same administrated light and PS doses and establishing quantitative tools for PDT dosimetry planning and response monitoring. Quantitative measures such as optical parameters, PS concentration, tissue oxygenation and blood flow are essential for accurate PDT dosimetry as well as PDT response monitoring and assessing therapy outcome. Unlike conventional imaging modalities like magnetic resonance imaging, novel optical imaging techniques can quantify PDT-related parameters without any contrast agent administration and enable real-time assessment during PDT for providing fast feedback to clinicians. Ongoing developments in optical imaging offer the promise of optimization of PDT protocols with improved outcomes.
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Allison RR, Moghissi K. Photodynamic Therapy (PDT): PDT Mechanisms. Clin Endosc 2013; 46:24-9. [PMID: 23422955 PMCID: PMC3572346 DOI: 10.5946/ce.2013.46.1.24] [Citation(s) in RCA: 423] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Revised: 01/08/2013] [Accepted: 01/11/2013] [Indexed: 12/23/2022] Open
Abstract
Photodynamic therapy (PDT) is a light based therapy used to ablate tumors. As practiced in oncology a photosensitizing agent is applied and then activated by a specific wavelength and energy of light. This light energy in the presence of oxygen will lead to the creation of the photodynamic reaction which is cyto and vasculo toxic. This paper will review the mechanisms of action of PDT and how they may be manipulated to improve clinical outcome in cancer patients.
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Su GC, Wei YH, Wang HW. NADH fluorescence as a photobiological metric in 5-aminolevlinic acid (ALA)-photodynamic therapy. OPTICS EXPRESS 2011; 19:21145-21154. [PMID: 22108965 DOI: 10.1364/oe.19.021145] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Photodynamic therapy (PDT) dosimetry is complex as many factors are involved and varied interdependently. Monitoring the biological consequence of PDT such as cell death is the most direct approach to assess treatment efficacy. In this study, we performed 5-aminolevlinic acid (ALA)-PDT in vitro to induce different cell death modes (i.e., slight cell cytotoxicity, apoptosis, and necrosis) by a fixed fluence rate of 10 mW/cm(2) and varied fluences (1, 2, and 6 J/cm(2)). Time course measurements of cell viability, caspase-3 activity, and DNA fragmentation were conducted to determine the mode of cell death. We demonstrated that NADH fluorescence lifetime together with NADH fluorescence intensity permit us to detect apoptosis and differentiate it from necrosis. This feature will be unique in the use of optimizing apoptosis-favored treatments such as metronomic PDT.
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Affiliation(s)
- Guan-Chin Su
- Institute of Biophotonics, National Yang-Ming University, 155 Li-Nong St., Sec. 2, Taipei 112, Taiwan
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35
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Busch TM, Wang HW, Wileyto EP, Yu G, Bunte RM. Increasing damage to tumor blood vessels during motexafin lutetium-PDT through use of low fluence rate. Radiat Res 2010; 174:331-40. [PMID: 20726728 DOI: 10.1667/rr2075.1] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Photodynamic therapy (PDT) with low light fluence rate has rarely been studied in protocols that use short drug-light intervals and thus deliver illumination while plasma concentrations of photosensitizer are high, creating a prominent vascular response. In this study, the effects of light fluence rate on PDT response were investigated using motexafin lutetium (10 mg/kg) in combination with 730 nm light and a 180-min drug-light interval. At 180 min, the plasma level of photosensitizer was 5.7 ng/microl compared to 3.1 ng/mg in RIF tumor, and PDT-mediated vascular effects were confirmed by a spasmodic decrease in blood flow during illumination. Light delivery at 25 mW/cm(2) significantly improved long-term tumor responses over that at 75 mW/cm(2). This effect could not be attributed to oxygen conservation at low fluence rate, because 25 mW/cm(2) PDT provided little benefit to tumor hemoglobin oxygen saturation. However, 25 mW/cm(2) PDT did prolong the duration of ischemic insult during illumination and was correspondingly associated with greater decreases in perfusion immediately after PDT, followed by smaller increases in total hemoglobin concentration in the hours after PDT. Increases in blood volume suggest blood pooling from suboptimal vascular damage; thus the smaller increases after 25 mW/cm(2) PDT provide evidence of more widespread vascular damage, which was accompanied by greater decreases in clonogenic survival. Further study of low fluence rate as a means to improve responses to PDT under conditions designed to predominantly damage vasculature is warranted.
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Affiliation(s)
- Theresa M Busch
- Department of Radiation Oncology, School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania 19104, USA.
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Garrier J, Bressenot A, Gräfe S, Marchal S, Mitra S, Foster TH, Guillemin F, Bezdetnaya L. Compartmental targeting for mTHPC-based photodynamic treatment in vivo: Correlation of efficiency, pharmacokinetics, and regional distribution of apoptosis. Int J Radiat Oncol Biol Phys 2010; 78:563-71. [PMID: 20656417 DOI: 10.1016/j.ijrobp.2010.04.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2009] [Revised: 04/12/2010] [Accepted: 04/14/2010] [Indexed: 11/26/2022]
Abstract
PURPOSE The present study investigates the efficacy of compartmental targeting in xenografted tumors treated by meta-tetra(hydroxyphenyl)chlorin (mTHPC)-mediated photodynamic therapy (PDT). The therapeutic efficacy was, furthermore, related to a regional photoinduced distribution of apoptosis and an mTHPC biodistribution profile. METHODS AND MATERIALS Mice bearing EMT6 tumors were subjected to a single irradiation (10 J/cm(2)) of red laser light (652 nm) at different intervals after a single- (0.3 mg/kg or 0.15 mg/kg) or double-intravenous (2 × 0.15 mg/kg) injection(s) of mTHPC. Efficiency of the treatment was evaluated by monitoring tumor regrowth. mTHPC pharmacokinetics were assessed by high-performance liquid chromatography analysis of excised organs. The regional distribution of apoptosis in tumor sections was investigated with a newly developed colabelling immunohistochemistry technique. RESULTS A fractionated double-injection protocol of mTHPC with 24-h and 3-h drug-light intervals (DLI) yielded 100% tumor cure, with tumors presenting a massive apoptosis of neoplastic cells along with a distortion of vessels. The best efficiency for a single injection (0.3 mg/kg) was about 54% tumor cure and corresponded to a DLI of 3 h. At this DLI, tumors showed apoptosis of endothelial cells in residual vessels. Concentrations of mTHPC observed in plasma and tumor for the fractionated injection were not statistically different and were less than the total drug dose in each compartment. CONCLUSIONS The present work suggests that clinical PDT protocols with mTHPC could be greatly improved by fractionation of the drug administration. Time points should be chosen based on the intratumoral spatiotemporal drug distribution.
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Affiliation(s)
- Julie Garrier
- Centre de Recherche en Automatique de Nancy, CRAN-UMR, Nancy-University, CNRS, Centre Alexis Vautrin, Vandœuvre-lès-Nancy, France
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Samkoe KS, Chen A, Rizvi I, O'Hara JA, Hoopes PJ, Pereira SP, Hasan T, Pogue BW. Imaging tumor variation in response to photodynamic therapy in pancreatic cancer xenograft models. Int J Radiat Oncol Biol Phys 2010; 76:251-9. [PMID: 20005458 PMCID: PMC2902770 DOI: 10.1016/j.ijrobp.2009.08.041] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2009] [Revised: 07/20/2009] [Accepted: 08/06/2009] [Indexed: 01/06/2023]
Abstract
PURPOSE A treatment monitoring study investigated the differential effects of orthotopic pancreatic cancer models in response to interstitial photodynamic therapy (PDT), and the validity of using magnetic resonance imaging as a surrogate measure of response was assessed. METHODS AND MATERIALS Different orthotopic pancreatic cancer xenograft models (AsPC-1 and Panc-1) were used to represent the range of pathophysiology observed in human beings. Identical dose escalation studies (10, 20, and 40J/cm) using interstitial verteporfin PDT were performed, and magnetic resonance imaging with T2-weighted and T1-weighted contrast were used to monitor the total tumor volume and the vascular perfusion volume, respectively. RESULTS There was a significant amount of necrosis in the slower-growing Panc-1 tumor using high light dose, although complete necrosis was not observed. Lower doses were required for the same level of tumor kill in the faster-growing AsPC-1 cell line. CONCLUSIONS The tumor growth rate and vascular pattern of the tumor affect the optimal PDT treatment regimen, with faster-growing tumors being relatively easier to treat. This highlights the fact that therapy in human beings shows a heterogeneous range of outcomes, and suggests a need for careful individualized treatment outcomes assessment in clinical work.
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Choi H, Lim W, Kim JE, Kim I, Jeong J, Ko Y, Song J, You S, Kim D, Kim M, Kim BK, Kim O. Cell Death and Intracellular Distribution of Hematoporphyrin in a KB Cell Line. Photomed Laser Surg 2009; 27:453-60. [DOI: 10.1089/pho.2008.2334] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Hongran Choi
- Department of Oral Pathology, School of Dentistry, Dental Science Research Institute, Chonnam National University, Bug-Gu, Gwangju, Korea
| | - Wonbong Lim
- Department of Oral Pathology, School of Dentistry, Dental Science Research Institute, Chonnam National University, Bug-Gu, Gwangju, Korea
| | - Ji-Eun Kim
- K&C Welbeing Co. Dong-Gu, Chonnam National University, Gwangju, Korea
| | - Inae Kim
- Department of Oral Pathology, School of Dentistry, Dental Science Research Institute, Chonnam National University, Bug-Gu, Gwangju, Korea
| | - Jinan Jeong
- K&C Welbeing Co. Dong-Gu, Chonnam National University, Gwangju, Korea
| | - Youngjong Ko
- K&C Welbeing Co. Dong-Gu, Chonnam National University, Gwangju, Korea
| | - Jongwoon Song
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Dental Science Research Institute, Bug-Gu, Gwangju, Korea
| | - Sunyeol You
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Dental Science Research Institute, Bug-Gu, Gwangju, Korea
| | - Doman Kim
- School of Biological Sciences and Technology, Chonnam National University, Bug-Gu, Gwangju, Korea
| | - Misook Kim
- Jeonnam Institution of Health and Environment, NongSungDong, Seo-Gu, Gwangju, Korea
| | - Byung-Kuk Kim
- Department of Oral Medicine, School of Dentistry, Dental Science Research Institute, Chonnam National University, Bug-Gu, Gwangju, Korea
| | - Okjoon Kim
- Department of Oral Pathology, School of Dentistry, Dental Science Research Institute, Chonnam National University, Bug-Gu, Gwangju, Korea
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Wang KKH, Mitra S, Foster TH. Photodynamic dose does not correlate with long-term tumor response to mTHPC-PDT performed at several drug-light intervals. Med Phys 2008; 35:3518-26. [PMID: 18777912 DOI: 10.1118/1.2952360] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Meso-tetra-hydroxyphenyl-chlorin (mTHPC, Foscan), a promising photosensitizer for photodynamic therapy (PDT), is approved in Europe for the palliative treatment of head and neck cancer. Based on work in mice that investigated optimal tumor accumulation, clinical protocols with Foscan typically employ an interval of 96 h between systemic sensitizer administration and irradiation. However, recent studies in mouse tumor models have demonstrated significantly improved long-term tumor response when irradiation is performed at shorter drug-light intervals of 3 and 6 h. Using a previously published theoretical model of microscopic PDT dosimetry and informed by experimentally determined photophysical properties and intratumor sensitizer concentrations and distributions, we calculated photodynamic dose depositions following mTHPC-PDT for drug-light intervals of 3, 6, 24, and 96 h. Our results demonstrate that the singlet oxygen dose to the tumor volume does not track even qualitatively with tumor responses for these four drug-light intervals. Further, microscopic analysis of simulated singlet oxygen deposition shows that in no case do any subpopulations of tumor cells receive a threshold dose. Indeed, under the conditions of these simulations more than 90% of the tumor volume receives a dose that is approximately 20-fold lower than the threshold dose for mTHPC. Thus, in this evaluation of mTHPC-PDT at various drug-light intervals, any PDT dose metric that is proportional to singlet oxygen creation and/or deposition would fail to predict the tumor response. In situations like this one, other reporters of biological response to therapy would be necessary.
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Affiliation(s)
- Ken Kang-Hsin Wang
- Department of Physics and Astronomy, University of Rochester, Rochester, New York 14627, USA
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Fleshker S, Preise D, Kalchenko V, Scherz A, Salomon Y. Prompt Assessment of WST11-VTP Outcome Using Luciferase Transfected Tumors Enables Second Treatment and Increase in Overall Therapeutic Rate. Photochem Photobiol 2008; 84:1231-7. [DOI: 10.1111/j.1751-1097.2008.00340.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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41
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Chen B, Crane C, He C, Gondek D, Agharkar P, Savellano MD, Hoopes PJ, Pogue BW. Disparity between prostate tumor interior versus peripheral vasculature in response to verteporfin-mediated vascular-targeting therapy. Int J Cancer 2008; 123:695-701. [PMID: 18498134 DOI: 10.1002/ijc.23538] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Photodynamic therapy (PDT) is a light-based cancer treatment modality. Here we employed both in vivo and ex vivo fluorescence imaging to visualize vascular response and tumor cell survival after verteporfin-mediated PDT designed to target tumor vasculature. EGFP-MatLyLu prostate tumor cells, transduced with EGFP using lentivirus vectors, were implanted in athymic nude mice. Immediately after PDT with different doses of verteporfin, tumor-bearing animals were injected with a fluorochrome-labeled albumin. The extravasation of fluorescent albumin along with tumor EGFP fluorescence was monitored noninvasively with a whole-body fluorescence imaging system. Ex vivo fluorescence microscopy was performed on frozen sections of tumor tissues taken at different times after treatment. Both in vivo and ex vivo imaging demonstrated that vascular-targeting PDT with verteporfin significantly increased the extravasation of fluorochrome-labeled albumin in the tumor tissue, especially in the tumor periphery. Although PDT induced substantial vascular shutdown in interior blood vessels, some peripheral tumor vessels were able to maintain perfusion function up to 24 hr after treatment. As a result, viable tumor cells were typically detected in the tumor periphery in spite of extensive tumor cell death. Our results demonstrate that vascular-targeting PDT with verteporfin causes a dose- and time-dependent increase in vascular permeability and decrease in blood perfusion. However, compared to the interior blood vessels, peripheral tumor blood vessels were found less sensitive to PDT-induced vascular shutdown, which was associated with subsequent tumor recurrence in the tumor periphery.
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Affiliation(s)
- Bin Chen
- Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, PA 19104, USA.
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Barnes LD, Giuliano EA, Ota J, Cohn LA, Moore CP. The effect of photodynamic therapy on squamous cell carcinoma in a murine model: evaluation of time between intralesional injection to laser irradiation. Vet J 2008; 180:60-5. [PMID: 18294887 DOI: 10.1016/j.tvjl.2007.11.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2007] [Revised: 11/19/2007] [Accepted: 11/23/2007] [Indexed: 10/22/2022]
Abstract
Successful treatment of naturally occurring periocular squamous cell carcinoma (SCC) in horses with photodynamic therapy (PDT) has been performed by injecting residual tumor with verteporfin and applying laser irradiation immediately following injection. This study used a murine model to evaluate the influence of time between intralesional injection of verteporfin to laser irradiation on tumor growth inhibition with PDT. Mice were randomized into six groups (n=10/group). Each tumor was injected with either 0.1mg/cm(3) of verteporfin (Tx) or 5% dextrose in water (C). Tx and C groups 1, 2, and 3 were irradiated at 1, 30, and 180min after injection. Wilcoxon-rank sum test (P< or =0.05) was performed to determine the relative change in tumor volume (RCTV) between groups. Statistical significance was demonstrated between treatment groups. Although verteporfin-PDT treated mice in Tx1 and Tx2 demonstrated a lower RCTV compared to C1 and C2 mice, the differences were not statistically significant.
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Affiliation(s)
- Laura D Barnes
- Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, 900 East Campus Drive, Columbia, MO 65211, USA
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Attempt of photodynamic therapy on esophageal varices. Lasers Med Sci 2008; 24:167-71. [PMID: 18270762 DOI: 10.1007/s10103-008-0542-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2007] [Accepted: 01/03/2008] [Indexed: 12/19/2022]
Abstract
Small vessels gradually reappear within the esophageal wall after endoscopic injection sclerotherapy or endoscopic variceal ligation, which causes late recurrent bleeding. Additional ligation or a small amount of sclerotherapy of these thin and serpentine vessels is sometimes difficult to perform, and stenosis of the esophagus sometimes occurs after a small amount of sclerotherapy. In this study we attempted endoscopic photodynamic therapy on newly visible vessels and evaluated its ability to prevent recurrent bleeding. Fourteen patients with newly visible vessels within the esophageal wall were enrolled. All patients had esophageal varices secondary to hepatitis B and had their varices eliminated through endoscopic sclerotherapy before neovascularization. Seven patients received photodynamic therapy, and seven patients served as the control group. In the photodynamic therapy group, intravenous injection of 5 mg/kg of hematoporphyrin monomethyl ether was given and immediately followed by endoscopic irradiation of the newly visible vessels by copper vapor laser for 40 min with a power density of 150 mW/cm(2). Endoscopic examination was performed 3 months later to evaluate the therapeutic effect. The duration of non-bleeding was compared between the two groups. The number of newly visible vessels was found to have decreased after photodynamic therapy when compared with the control group (P < 0.001). Kaplan-Meier analyses demonstrated a longer period of non-bleeding in the photodynamic therapy group. The recurrent bleeding rate in the photodynamic therapy (PDT) group was lower than that in the control group (P = 0.027). One patient in the photodynamic therapy group suffered from facial dermatitis from shining direct light. Endoscopic photodynamic therapy seemed to be effective in the elimination of esophageal newly visible vessels and the prevention of recurrent bleeding.
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Zhou X, Chen B, Hoopes PJ, Hasan T, Pogue BW. Peptide-Induced Inflammatory Increase in Vascular Permeability Improves Photosensitizer Delivery and Intersubject Photodynamic Treatment Efficacy. Radiat Res 2007; 168:299-307. [PMID: 17705632 DOI: 10.1667/rr0804.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2006] [Accepted: 03/26/2007] [Indexed: 11/03/2022]
Abstract
Photodynamic therapy (PDT) treatment can exhibit high intersubject variability due to the inherent differences in drug delivery within the tissue to be treated. In this study, the increased perfusion of the lipid-associated photosensitizer verteporfin was studied using substance P, a peptide known to increase vascular permeability. The transvascular permeability coefficient was quantified before and after administration of substance P, and the mean value increased from 0.026 to 0.043 microm/s with the induced inflammation. Correspondingly, there was a 40-50% increase in uptake of verteporfin in the tumor parenchyma in tumors injected with substance P compared to those without. This increased drug uptake resulted in a modest increase in tumor doubling time from 4 days with regular PDT to 6.2 days with substance P and PDT. There was also a significant reduction in the interindividual variability in with substance P plus PDT from 64% to 13%. The resulting treatment was therefore more effective and there was less variability in dose between subjects.
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Affiliation(s)
- Xiaodong Zhou
- Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA
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Standish BA, Yang VXD, Munce NR, Wong Kee Song LM, Gardiner G, Lin A, Mao YI, Vitkin A, Marcon NE, Wilson BC. Doppler optical coherence tomography monitoring of microvascular tissue response during photodynamic therapy in an animal model of Barrett's esophagus. Gastrointest Endosc 2007; 66:326-33. [PMID: 17643708 DOI: 10.1016/j.gie.2007.02.040] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2006] [Accepted: 02/18/2007] [Indexed: 12/11/2022]
Abstract
BACKGROUND Doppler optical coherence tomography (DOCT) is an imaging modality that allows assessment of the microvascular response during photodynamic therapy (PDT) and may be a powerful tool for treatment monitoring/optimization in conditions such as Barrett's esophagus (BE). OBJECTIVE To assess the technical feasibility of catheter-based intraluminal DOCT for monitoring the microvascular response during endoluminal PDT in an animal model of BE. DESIGN Thirteen female Sprague-Dawley rats underwent esophagojejunostomy to induce enteroesophageal reflux for 35 to 42 weeks and the formation of Barrett's mucosa. Of these, 9 received PDT by using the photosensitizer Photofrin (12.5 mg/kg intravenous), followed by 635-nm intraluminal light irradiation 24 hours after drug administration. The remaining 4 surgical rats underwent light irradiation without Photofrin (controls). Another group of 5 normal rats, without esophagojejunostomy, also received PDT. DOCT imaging of the esophagus by using a catheter-based probe (1.3-mm diameter) was performed before, during, and after light irradiation in all rats. RESULTS Distinct microstructural differences between normal squamous esophagus, BE, and the transition zone between the 2 tissues were observed on DOCT images. Similar submucosal microcirculatory effects (47%-73% vascular shutdown) were observed during PDT of normal esophagus and surgically induced BE. Controls displayed no significant microvascular changes. CONCLUSIONS No apparent difference was observed in the PDT-induced vascular response between normal rat esophagus and the BE rat model. Real-time monitoring of PDT-induced vascular changes by DOCT may be beneficial in optimizing PDT dosimetry in patients undergoing this therapy for BE and other conditions.
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Affiliation(s)
- Beau A Standish
- Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Toronto, Ontario, Canada
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Zhou X, Chen B, Hoopes PJ, Hasan T, Pogue BW. Tumor vascular area correlates with photosensitizer uptake: analysis of verteporfin microvascular delivery in the Dunning rat prostate tumor. Photochem Photobiol 2007; 82:1348-57. [PMID: 17421078 DOI: 10.1562/2006-03-25-ra-858] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The parameters that limit supply of photosensitizer to the cancer cells in a solid tumor were systematically analyzed with the use of microvascular transport modeling and histology data from frozen sections. In particular, the vascular permeability transport coefficient and the effective interstitial diffusion coefficient were quantified for Verteporfin-for-Injection delivery of benzoporphyrin derivative (BPD). Orthotopic tumors had higher permeability and diffusion coefficients (Pd = 0.036 microm/s and D = 1.6 microm(2)/s, respectively) as compared to subcutaneously grown tumors (Pd = 0.025 microm/s and D = 0.9 microm2/s, respectively), likely due to the fact that the vessel patterns are more homogeneous orthotopically. In general, large intersubject and intratumor variability exist in the verteporfin concentration, in the range of 25% in plasma concentration and in the range of 20% for tissue concentrations, predominantly due to these microregional variations in transport. However, the average individual uptake of photosensitizer in tumor tissue was only correlated to the total vascular area within the tumor (R2 = 64.1%, P < 0.001). The data are consistent with a view that microregional variation in the vascular permeability and interstitial diffusion rate contribute the spatial heterogeneity observed in verteporfin uptake, but that average supply to the tissue is limited by the total area of perfused blood vessels. This study presents a method to systematically analyze micro-heterogeneity as well as possible methods to increase delivery and homogeneity of photosensitizer within tumor tissue.
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Affiliation(s)
- Xiaodong Zhou
- Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA
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Jarvi MT, Niedre MJ, Patterson MS, Wilson BC. Singlet oxygen luminescence dosimetry (SOLD) for photodynamic therapy: current status, challenges and future prospects. Photochem Photobiol 2007; 82:1198-210. [PMID: 16808593 DOI: 10.1562/2006-05-03-ir-891] [Citation(s) in RCA: 143] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
As photodynamic therapy (PDT) continues to develop and find new clinical indications, robust individualized dosimetry is warranted to achieve effective treatments. We posit that the most direct PDT dosimetry is achieved by monitoring singlet oxygen (1O2), the major cytotoxic species generated photochemically during PDT. Its detection and quantification during PDT have been long-term goals for PDT dosimetry and the development of techniques for this, based on detection of its near-infrared luminescence emission (1270 nm), is at a noteworthy stage of development. We begin by discussing the theory behind singlet-oxygen luminescence dosimetry (SOLD) and the seminal contributions that have brought SOLD to its current status. Subsequently, technology developments that could potentially improve SOLD are discussed, together with future areas of research, as well as the potential limitations of this method. We conclude by examining the major thrusts for future SOLD applications: as a tool for quantitative photobiological studies, a point of reference to evaluate other PDT dosimetry techniques, the optimal means to evaluate new photosensitizers and delivery methods and, potentially, a direct and robust clinical dosimetry system.
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Affiliation(s)
- Mark T Jarvi
- Department of Medical Biophysics, Ontario Cancer Institute and University of Toronto, Toronto, Ontario, Canada
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Standish BA, Jin X, Smolen J, Mariampillai A, Munce NR, Wilson BC, Vitkin IA, Yang VXD. Interstitial Doppler optical coherence tomography monitors microvascular changes during photodynamic therapy in a Dunning prostate model under varying treatment conditions. JOURNAL OF BIOMEDICAL OPTICS 2007; 12:034022. [PMID: 17614730 DOI: 10.1117/1.2744068] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
We measure the tumor vascular response to varying irradiance rates during photodynamic therapy (PDT) in a Dunning rat prostate model with interstitial Doppler optical coherence tomography (IS-DOCT). Rats are given a photosensitizer drug, Photofrin, and the tumors are exposed to light (635 nm) with irradiance rates ranging from 8 to 133 mWcm(2) for 25 min, corresponding to total irradiance of 12 to 200 Jcm(2) (measured at surface). The vascular index computed from IS-DOCT results shows the irradiance rate and total irradiance dependent microvascular shutdown in the tumor tissue during PDT. While faster rates of vascular shutdown were associated with increasing PDT irradiance rate and total irradiance, a threshold effect was observed as irradiance rates above 66 mWcm(2) (surface), where no further increase in vascular shutdown rate was detected. The maximum post-treatment vascular shutdown (81%) without immediate microcirculatory recovery was reached with the PDT condition of 33 mWcm(2) and 50 Jcm(2). Control groups without Photofrin show no significant microvascular changes. Microvascular shutdown occurs at different rates and shows correlation with PDT total irradiance and irradiance rates. These dependencies may play an important role in PDT treatment planning, feedback control for treatment optimization, and post-treatment assessment.
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Affiliation(s)
- Beau A Standish
- Ontario Cancer Institute, University of Toronto, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada.
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Zhou X, Pogue BW, Chen B, Hasan T. Analysis of Effective Molecular Diffusion Rates for Verteporfin in Subcutaneous Versus Orthotopic Dunning Prostate Tumors ¶. Photochem Photobiol 2007. [DOI: 10.1111/j.1751-1097.2004.tb00016.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Osaki T, Takagi S, Hoshino Y, Okumura M, Fujinaga T. Antitumor effects and blood flow dynamics after photodynamic therapy using benzoporphyrin derivative monoacid ring A in KLN205 and LM8 mouse tumor models. Cancer Lett 2007; 248:47-57. [PMID: 16837129 DOI: 10.1016/j.canlet.2006.05.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2006] [Revised: 05/24/2006] [Accepted: 05/31/2006] [Indexed: 10/24/2022]
Abstract
Photodynamic therapy (PDT) using benzoporphyrin derivative monoacid ring A (BPD-MA) induces direct tumor cell damage and microvascular injury. We administered BPD-MA at 3h or 15min before laser irradiation to KLN205 and LM8 tumors in murine models. Tumor growth delay was induced more effectively by 15-min-interval PDT than by 3-h-interval PDT. Vascularity and blood perfusion was significantly decreased by 15-min-interval PDT. We observed death of all tumor cells, except peripheral cells, in the 3-h-interval PDT group, and death of cells around the damaged tumor vasculature in the 15-min-interval PDT group. Thus, 15-min-interval PDT enhanced the antitumor effect by damaging tumor vasculature.
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MESH Headings
- Animals
- Antineoplastic Agents/therapeutic use
- Blood Flow Velocity/drug effects
- Blotting, Western
- Cell Line, Tumor
- Female
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Laser-Doppler Flowmetry
- Mice
- Mice, Inbred C3H
- Mice, Inbred DBA
- Neoplasms, Experimental/blood supply
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/pathology
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Photochemotherapy/methods
- Porphyrins/therapeutic use
- Time Factors
- Tumor Burden/drug effects
- Verteporfin
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Affiliation(s)
- Tomohiro Osaki
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido Kita 18, Nishi 9, Kita-ku, Sapporo 060-0818, Japan.
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