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Patel N, Held I, Trzcinska A, Wasman J, Alagramam KN, Oleinick NL, Maronian N, Howard NS. Mucosal Injection of the Silicon Phthalocyanine Pc 4 in a Rabbit Model-A Pilot Study. Laryngoscope 2025; 135:270-276. [PMID: 39206668 DOI: 10.1002/lary.31738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 07/24/2024] [Accepted: 08/08/2024] [Indexed: 09/04/2024]
Abstract
OBJECTIVE The silicon phthalocyanine Pc 4 is a photosensitizing agent previously shown to be a promising treatment for cutaneous neoplasms using photodynamic therapy (PDT). Based on prior preclinical studies, we believe Pc 4-PDT has potential as a targeted treatment of human recurrent respiratory papillomatosis or laryngeal leukoplakia by direct injection into mucosal surfaces. METHODS This was a proof-of-concept pilot study assessing direct mucosal injection of Pc 4 into buccal and vocal fold mucosae in a rabbit model. Five New Zealand white rabbits underwent tattooing of bilateral buccal mucosae to delineate injection sites, followed by submucosal injections of control and Pc 4 solutions. Rabbits were monitored for post-injection tolerance. Punch biopsies were obtained from injected mucosa and assessed histopathologically. Once the buccal mucosa was found to be tolerant, vocal folds of three rabbits were injected. The rabbits were then sacrificed, and laryngeal tissue was assessed histopathologically. RESULTS All rabbits tolerated injection of Pc 4 and control solutions into buccal mucosa with no evidence of gross visual inflammatory changes and no changes in behavior or masticatory function. Histopathologic analysis of Pc 4 injected buccal and control mucosal tissue revealed mild focal histological changes and no stigmata of diffuse inflammatory reactions. The histopathologic analysis of Pc 4 injected into laryngeal tissue revealed similar findings with addition of mild eosinophilia in one sample. CONCLUSION Direct mucosal injection of Pc 4 in rabbit buccal and vocal fold mucosae appears to be well tolerated with no gross inflammatory changes, and only mild histopathologic inflammatory changes observed. LEVEL OF EVIDENCE NA Laryngoscope, 135:270-276, 2025.
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Affiliation(s)
- Nilam Patel
- Department of Otolaryngology-Head and Neck Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio, U.S.A
- Case Western Reserve University School of Medicine, Cleveland, Ohio, U.S.A
| | - Isabel Held
- Case Western Reserve University School of Medicine, Cleveland, Ohio, U.S.A
| | - Anna Trzcinska
- Case Western Reserve University School of Medicine, Cleveland, Ohio, U.S.A
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, U.S.A
| | - Jay Wasman
- Case Western Reserve University School of Medicine, Cleveland, Ohio, U.S.A
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, U.S.A
| | - Kumar N Alagramam
- Department of Otolaryngology-Head and Neck Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio, U.S.A
- Case Western Reserve University School of Medicine, Cleveland, Ohio, U.S.A
| | - Nancy L Oleinick
- Case Western Reserve University School of Medicine, Cleveland, Ohio, U.S.A
| | - Nicole Maronian
- Department of Otolaryngology-Head and Neck Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio, U.S.A
- Case Western Reserve University School of Medicine, Cleveland, Ohio, U.S.A
| | - Nelson S Howard
- Department of Otolaryngology-Head and Neck Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio, U.S.A
- Case Western Reserve University School of Medicine, Cleveland, Ohio, U.S.A
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Crous A, Abrahamse H. Photodynamic therapy of lung cancer, where are we? Front Pharmacol 2022; 13:932098. [PMID: 36110552 PMCID: PMC9468662 DOI: 10.3389/fphar.2022.932098] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
Lung cancer remains the leading threat of death globally, killing more people than colon, breast, and prostate cancers combined. Novel lung cancer treatments are being researched because of the ineffectiveness of conventional cancer treatments and the failure of remission. Photodynamic therapy (PDT), a cancer treatment method that is still underutilized, is a sophisticated cancer treatment that shows selective destruction of malignant cells via reactive oxygen species production. PDT has been extensively studied in vitro and clinically. Various PDT strategies have been shown to be effective in the treatment of lung cancer. PDT has been shown in clinical trials to considerably enhance the quality of life and survival in individuals with incurable malignancies. Furthermore, PDT, in conjunction with the use of nanoparticles, is currently being researched for use as an effective cancer treatment, with promising results. PDT and the new avenue of nanoPDT, which are novel treatment options for lung cancer with such promising results, should be tested in clinical trials to determine their efficacy and side effects. In this review, we examine the status and future potentials of nanoPDT in lung cancer treatment.
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Affiliation(s)
- Anine Crous
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, Johannesburg, South Africa
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Ma CH, Yang J, Mueller JL, Huang HC. Intratumoral Photosensitizer Delivery and Photodynamic Therapy. ACTA ACUST UNITED AC 2021; 11. [PMID: 34484435 DOI: 10.1142/s179398442130003x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Photodynamic therapy (PDT) is a two-step procedure that involves the administration of special drugs, commonly called photosensitizers, followed by the application of certain wavelengths of light. The light activates these photosensitizers to produce reactive molecular species that induce cell death in tissues. There are numerous factors to consider when selecting the appropriate photosensitizer administration route, such as which part of the body is being targeted, the pharmacokinetics of photosensitizers, and the formulation of photosensitizers. While intravenous, topical, and oral administration of photosensitizers are widely used in preclinical and clinical applications of PDT, other administration routes, such as intraperitoneal, intra-arterial, and intratumoral injections, are gaining traction for their potential in treating advanced diseases and reducing off-target toxicities. With recent advances in targeted nanotechnology, biomaterials, and light delivery systems, the exciting possibilities of targeted photosensitizer delivery can be fully realized for preclinical and clinical applications. Further, in light of the growing burden of cancer mortality in low and middle-income countries and development of low-cost light sources and photosensitizers, PDT could be used to treat cancer patients in low-income settings. This short article introduces aspects of interfaces of intratumoral photosensitizer injections and nano-biomaterials for PDT applications in both high-income and low-income settings but does not present a comprehensive review due to space limitations.
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Affiliation(s)
- Chen-Hua Ma
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA
| | - Jeffrey Yang
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA
| | - Jenna L Mueller
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA.,Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Huang-Chiao Huang
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA.,Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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Pinto A, Marangon I, Méreaux J, Nicolás-Boluda A, Lavieu G, Wilhelm C, Sarda-Mantel L, Silva AKA, Pocard M, Gazeau F. Immune Reprogramming Precision Photodynamic Therapy of Peritoneal Metastasis by Scalable Stem-Cell-Derived Extracellular Vesicles. ACS NANO 2021; 15:3251-3263. [PMID: 33481565 DOI: 10.1021/acsnano.0c09938] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
The dissemination of tumor metastasis in the peritoneal cavity, also called peritoneal metastasis (PM) or carcinomatosis, represents a late stage of gastrointestinal and gynecological cancer with very poor prognosis, even when cytoreductive surgery is effective, due to residual microscopic disease. Photodynamic therapy (PDT) in the management of peritoneal metastasis has been clinically limited by the low tumor selectivity of photosensitizers (PS) and important adverse effects. Here, we propose extracellular nanovesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) as the fourth generation of immune active PS vectors that are able to target peritoneal metastasis with superior selectivity, potentiate PDT cytotoxicity at the tumor site without affecting healthy tissues, modulate the tumor microenvironment of immunocompetent colorectal and ovarian carcinomatosis models, and promote an antitumor immune response. A pioneering strategy was developed for high yield, large-scale production of MSC-EVs encapsulating the drug meta(tetrahydroxyphenyl)chlorin (mTHPC) (EVs-mTHPC) that is compatible with requirements of clinical translation and also preserves the topology and integrity of naturally produced EVs. Intraperitoneal injection of EVs-mTHPC showed an impressive enhancement of tumoral selectivity in comparison to the free drug and to the liposomal formulation Foslip (mean ratio of PS in tumors/organs of 40 for EVs-mTHPC versus 1.5 for the free PS and 5.5 for Foslip). PDT mediated by EVs-mTHPC permitted an important tumoral necrosis (55% of necrotic tumoral nodules versus 18% for Foslip (p < 0.0001)) and promoted antitumor immune cell infiltration, mainly proinflammatory M1-like CD80+ and CD8+ T cell effector. Intratumor proliferation was significantly decreased after PDT with EVs-mTHPC. Overall EVs vectorization of mTHPC afforded important tumoral selectivity while overcoming the PDT toxicity of the free drug and prolonged mice survival in the colorectal carcinomatosis model. MSC-EVs produced by our scalable manufacturing method appears like the clinically relevant fourth-generation PDT vehicle to overcome current limitations of PDT in the treatment of peritoneal metastasis and promote a hot tumor immune environment in PM.
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Affiliation(s)
- Amandine Pinto
- Inserm UMR 1275 CAP Paris-Tech, Université de Paris, F-75010 Paris, France
- Service de Chirurgie Digestive et Cancérologique, Hôpital Lariboisière AP-HP, 2 rue Ambroise Paré, F-75010 Paris, France
| | - Iris Marangon
- Laboratoire MSC Matière et Systèmes Complexes, CNRS UMR 7057, Université de Paris, 10 Rue Alice Domon et Léonie Duquet, 75205 Paris Cedex 13, France
| | - Julie Méreaux
- Inserm UMR 1275 CAP Paris-Tech, Université de Paris, F-75010 Paris, France
- Service de Chirurgie Digestive et Cancérologique, Hôpital Lariboisière AP-HP, 2 rue Ambroise Paré, F-75010 Paris, France
| | - Alba Nicolás-Boluda
- Laboratoire MSC Matière et Systèmes Complexes, CNRS UMR 7057, Université de Paris, 10 Rue Alice Domon et Léonie Duquet, 75205 Paris Cedex 13, France
| | - Grégory Lavieu
- Laboratoire MSC Matière et Systèmes Complexes, CNRS UMR 7057, Université de Paris, 10 Rue Alice Domon et Léonie Duquet, 75205 Paris Cedex 13, France
| | - Claire Wilhelm
- Laboratoire MSC Matière et Systèmes Complexes, CNRS UMR 7057, Université de Paris, 10 Rue Alice Domon et Léonie Duquet, 75205 Paris Cedex 13, France
| | - Laure Sarda-Mantel
- Service de Médecine Nucléaire, Université de Paris, Hôpital Lariboisière AP-HP, 2 rue Ambroise Paré, F-75010 Paris, France
| | - Amanda K A Silva
- Laboratoire MSC Matière et Systèmes Complexes, CNRS UMR 7057, Université de Paris, 10 Rue Alice Domon et Léonie Duquet, 75205 Paris Cedex 13, France
| | - Marc Pocard
- Inserm UMR 1275 CAP Paris-Tech, Université de Paris, F-75010 Paris, France
- Service de Chirurgie Digestive et Cancérologique, Hôpital Lariboisière AP-HP, 2 rue Ambroise Paré, F-75010 Paris, France
| | - Florence Gazeau
- Laboratoire MSC Matière et Systèmes Complexes, CNRS UMR 7057, Université de Paris, 10 Rue Alice Domon et Léonie Duquet, 75205 Paris Cedex 13, France
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Park W, Cho S, Kang D, Han JH, Park JH, Lee B, Lee J, Kim DH. Tumor Microenvironment Targeting Nano-Bio Emulsion for Synergistic Combinational X-Ray PDT with Oncolytic Bacteria Therapy. Adv Healthc Mater 2020; 9:e1901812. [PMID: 32529747 PMCID: PMC7523430 DOI: 10.1002/adhm.201901812] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 05/16/2020] [Indexed: 11/08/2022]
Abstract
Various cancer therapies have been developed, but tumor recurrence with incomplete tumor killing and remaining tumor cells/tissues is frequent in monotherapies. Herein, a nano-bio therapeutic emulsion formulated with multifunctional nanoscintillators and anaerobic Clostridium novyi-NT spores for synergistic image-guided combinational cancer therapy is reported. MRI visible nanoscintillators (NSs) are synthesized with a NaGdF4 :Tb,Ce@NaGdF4 core/shell structure for an image-guided X-ray photodynamic therapy (PDT) of the normoxic peripheral tumor. An anaerobic oncolytic bacterium (C. novyi-NT) therapy is combined to treat the hypoxic central tumor tissues. Photosensitizer-coated NSs (PS-NSs) and C. novyi-NT spores are emulsified with clinically available ethiodized oil (Lipiodol) to be the nano-bio therapeutic emulsion and injected into the tumor with computed tomography image guidance. The distribution of nano-bio therapeutic emulsion, including PS-NSs and anaerobic C. novyi-NT spores in the tumor site, is confirmed by both X-ray and T1 -weighted magnetic resonance imaging. Following the image-guided X-ray PDT and anaerobic C. novyi- NT combination treatment, apoptotic cell death in cancer tissues, including both peripheral and central tumor regions, is significantly higher than in the control groups. This combination therapy approach using a nano-bio therapeutic emulsion is expected to overcome the limitations of conventional cancer therapy, resulting in increased cancer-therapeutic efficacy.
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Affiliation(s)
- Wooram Park
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Department of Biomedical-Chemical Engineering, The Catholic University of Korea, 43 Jibong-ro, Bucheon-si, Gyeonggi 14662, Republic of Korea
| | - Soojeong Cho
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Dongkyu Kang
- Molecular Recognition Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Jun-Hyeok Han
- Department of Biomedical-Chemical Engineering, The Catholic University of Korea, 43 Jibong-ro, Bucheon-si, Gyeonggi 14662, Republic of Korea
| | - Jung-Hoon Park
- Biomedical Engineering Research Center, Asan Institute for Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Byeongdu Lee
- X-ray Science Division, Argonne National Laboratory, Argonne, Illinois 60439, USA
| | - Joonseok Lee
- Molecular Recognition Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- Department of HY-KIST Bio-convergence, Hanyang University, Seoul 04763, Republic of Korea
| | - Dong-Hyun Kim
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL 60611, USA
- Department of Biomedical Engineering, McCormick School of Engineering, Evanston, IL 60208, USA
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Celasun S, Maron E, Börner HG. Peptide‐Assisted Design of Precision Polymer Sequences: On the Relevance of the Side‐Chain Sequences and the Variability of the Backbone. Macromol Biosci 2019; 20:e1900244. [DOI: 10.1002/mabi.201900244] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 08/09/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Sensu Celasun
- Laboratory for Organic Synthesis of Functional SystemsDepartment of ChemistryHumboldt‐Universität zu Berlin Brook‐Taylor‐Str. 2 12489 Berlin Germany
| | - Eva Maron
- Laboratory for Organic Synthesis of Functional SystemsDepartment of ChemistryHumboldt‐Universität zu Berlin Brook‐Taylor‐Str. 2 12489 Berlin Germany
| | - Hans G. Börner
- Laboratory for Organic Synthesis of Functional SystemsDepartment of ChemistryHumboldt‐Universität zu Berlin Brook‐Taylor‐Str. 2 12489 Berlin Germany
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Hameed S, Mo S, Mustafa G, Bajwa SZ, Khan WS, Dai Z. Immunological Consequences of Nanoparticle‐Mediated Antitumor Photoimmunotherapy. ADVANCED THERAPEUTICS 2019. [DOI: 10.1002/adtp.201900101] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Sadaf Hameed
- Department of Biomedical EngineeringCollege of EngineeringPeking University Beijing 100871 China
| | - Shanyan Mo
- Department of Biomedical EngineeringCollege of EngineeringPeking University Beijing 100871 China
| | - Ghulam Mustafa
- Department of SciencesBahria University Lahore Lahore 54000 Pakistan
| | - Sadia Z. Bajwa
- Nanobiotech GroupNational Institute for Biotechnology and Genetic Engineering (NIBGE) P.O. Box No. 577, Jhang Road Faisalabad 44000 Pakistan
| | - Waheed S. Khan
- Nanobiotech GroupNational Institute for Biotechnology and Genetic Engineering (NIBGE) P.O. Box No. 577, Jhang Road Faisalabad 44000 Pakistan
| | - Zhifei Dai
- Department of Biomedical EngineeringCollege of EngineeringPeking University Beijing 100871 China
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Ji Y, Li J, Zhao J, Shan S, Chu CC. A light-facilitated drug delivery system from a pseudo-protein/hyaluronic acid nanocomplex with improved anti-tumor effects. NANOSCALE 2019; 11:9987-10003. [PMID: 31080976 DOI: 10.1039/c9nr01909j] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Reduction-sensitive nanomedicine is a promising strategy to achieve controlled release of payloads in response to intracellular reductive milieu. However, endolysosomal sequestration of internalized carriers and insufficient redox potential in endolysosomes may delay the release of payloads and impact their therapeutic efficacy. Photochemical internalization (PCI), which takes advantage of light-induced endolysosomal rupture, is an effective technique for endosomal escape and cytosolic release of cargos. In this study, a biodegradable and reduction-sensitive nanocomplex was developed from arginine based poly(ester amide)s and hyaluronic acid (HA), and the PCI-photosensitizer AlPcS2a was conjugated to the surface of the nanocomplex (ArgPEA-ss-HA(AP)). This nanocomplex was used for the co-delivery of both PCI-photosensitizers and therapeutic agents to eliminate the biodistribution discrepancy resulting from the separated administration of free therapeutics. The PCI effect of the ArgPEA-ss-HA(AP) nanocomplex was validated in both monolayers and 3D spheroid models of MDA-MB-231 breast cancer cells. Synergism was detected between the PCI effect and doxorubicin-loaded nanocomplex in the inhibition of MDA-MB-231 cells. In addition, the ArgPEA-ss-HA(AP) nanocomplex also provided enhanced intratumoral penetration in 3D spheroids compared to free AlPcS2a. The in vivo results suggested that the conjugation of AlPCs2a in the nanocomplex enabled the consistent and preferential accumulation of both doxorubicin and AlPcS2a in tumor sites. A light-enhanced anti-tumor effect was observed for the doxorubicin-loaded nanocomplex at well-tolerable dosage. The ArgPEA-ss-HA(AP) nanocomplex, as a reduction-responsive delivery vehicle, can hold great potential to achieve spatio-temporally controllable anti-tumor effects.
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Affiliation(s)
- Ying Ji
- Department of Fiber Science and Apparel Design, Cornell University, Ithaca, New York 14853-4401, USA.
| | - Juan Li
- Key Laboratory of Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Science, Beijing 100049, PR China
| | - Jihui Zhao
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Shuo Shan
- Biomedical Engineering Field. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York 14853-4401, USA
| | - Chih-Chang Chu
- Department of Fiber Science and Apparel Design, Cornell University, Ithaca, New York 14853-4401, USA. and Biomedical Engineering Field. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York 14853-4401, USA
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Hlapisi N, Motaung TE, Linganiso LZ, Oluwafemi OS, Songca SP. Encapsulation of Gold Nanorods with Porphyrins for the Potential Treatment of Cancer and Bacterial Diseases: A Critical Review. Bioinorg Chem Appl 2019; 2019:7147128. [PMID: 31182957 PMCID: PMC6515112 DOI: 10.1155/2019/7147128] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 02/04/2019] [Indexed: 01/23/2023] Open
Abstract
Cancer and bacterial diseases have been the most incidental diseases to date. According to the World Health Report 2018, at least every family is affected by cancer around the world. In 2012, 14.1 million people were affected by cancer, and that figure is bound to increase to 21.6 million in 2030. Medicine therefore sorts out ways of treatment using conventional methods which have been proven to have many side effects. Researchers developed photothermal and photodynamic methods to treat both cancer and bacterial diseases. These methods pose fewer effects on the biological systems but still no perfect method has been synthesized. The review serves to explore porphyrin and gold nanorods to be used in the treatment of cancer and bacterial diseases: porphyrins as photosensitizers and gold nanorods as delivery agents. In addition, the review delves into ways of incorporating photothermal and photodynamic therapy aimed at producing a less toxic, more efficacious, and specific compound for the treatment.
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Affiliation(s)
- Nthabeleng Hlapisi
- Department of Chemistry, University of Zululand, X1001, KwaDlangezwa, KwaZulu-Natal, South Africa
| | - Tshwafo E. Motaung
- Department of Chemistry, University of Zululand, X1001, KwaDlangezwa, KwaZulu-Natal, South Africa
| | - Linda Z. Linganiso
- Department of Chemistry, University of Zululand, X1001, KwaDlangezwa, KwaZulu-Natal, South Africa
| | - Oluwatobi S. Oluwafemi
- Department of Applied Chemistry, University of Johannesburg, P.O. Box 17011, Doornfontein, Johannesburg 2028, South Africa
- Centre for Nanomaterials Science Research, University of Johannesburg, Johannesburg, South Africa
| | - Sandile P. Songca
- Department of Chemistry, University of Kwazulu Natal, Kwazulu Natal, South Africa
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Shen YJ, Cao J, Sun F, Cai XL, Li MM, Zheng NN, Qu CY, Zhang Y, Shen F, Zhou M, Chen YW, Xu LM. Effect of photodynamic therapy with (17R,18R)-2-(1-hexyloxyethyl)-2-devinyl chlorine E6 trisodium salt on pancreatic cancer cells in vitro and in vivo. World J Gastroenterol 2018; 24:5246-5258. [PMID: 30581273 PMCID: PMC6295833 DOI: 10.3748/wjg.v24.i46.5246] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/28/2018] [Accepted: 11/13/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the antitumor effects and underlying mechanisms of (17R,18R)-2-(1-hexyloxyethyl)-2-devinyl chlorine E6 trisodium salt (YLG-1)-induced photodynamic therapy (PDT) on pancreatic cancer in vitro and in vivo.
METHODS YLG-1 is a novel photosensitizer extracted from spirulina. Its phototoxicity, cellular uptake and localization, as well as its effect on reactive oxygen species (ROS) production, apoptosis, and expression of apoptosis-associated proteins were detected in vitro. An in vivo imaging system (IVIS), the Lumina K imaging system, and mouse models of subcutaneous Panc-1-bearing tumors were exploited to evaluate the drug delivery pathway and pancreatic cancer growth in vivo.
RESULTS YLG-1 was localized to the mitochondria, and the appropriate incubation time was 6 h. Under 650 nm light irradiation, YLG-1-PDT exerted a potent cytotoxic effect on pancreatic cancer cells in vitro, which could be abolished by the ROS scavenger N-acetyl-L-cysteine (NAC). The death mode caused by YLG-1-PDT was apoptosis, accompanied by upregulated Bax and cleaved Caspase-3 and decreased Bcl-2 expression. The results from the IVIS images suggested that the optimal administration route was intratumoral (IT) injection and that the best time to conduct YLG-1-PDT was 2 h post-IT injection. Consistent with the results in vitro, YLG-1-PDT showed great growth inhibition effects on pancreatic cancer cells in a mouse model.
CONCLUSION YLG-1 is a potential photosensitizer for pancreatic cancer PDT via IT injection, the mechanisms of which are associated with inducing ROS and promoting apoptosis.
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Affiliation(s)
- Yu-Jie Shen
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Jia Cao
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Fang Sun
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xiao-Lei Cai
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Ming-Ming Li
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Nan-Nan Zheng
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Chun-Ying Qu
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yi Zhang
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Feng Shen
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Min Zhou
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Ying-Wei Chen
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Lei-Ming Xu
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
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Baran TM. Photofrin ® photodynamic therapy with intratumor photosensitizer injection provides similar tumor response while reducing systemic skin photosensitivity: Pilot murine study. Lasers Surg Med 2017; 50:476-482. [PMID: 29214668 DOI: 10.1002/lsm.22774] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/23/2017] [Indexed: 12/18/2022]
Abstract
OBJECTIVES The goal of this study was to compare tumor response to Photofrin® photodynamic therapy using intravenous and intratumoral injection of photosensitizer. Systemic skin photosensitivity and photosensitizer distribution were also compared between the two delivery methods. METHODS SCCVII tumors were initiated in the hind legs of female C3H mice and grown to a volume of ∼1,000 mm3 . Photofrin® was delivered intravenously via the tail vein at a concentration of 2 mg/kg or intratumorally at concentrations ranging from 0.5-2 mg/kg. A 630 nm laser illumination was delivered via interstitial diffuser placement at a fluence rate of 400 mW/cm and fluence of 100 J/cm. Mice were maintained under normal room lighting for 24 hours after treatment, at which point photographs were captured for assessment of skin photosensitivity. Animals were then sacrificed, and their tumors were excised, sectioned, imaged, and stained with hematoxylin and eosin (H&E). H&E slides were imaged to assess necrosis post-PDT, and skin photographs were evaluated by two blinded reviewers for quantification of skin photosensitivity. Whole-body fluorescence imaging was performed before and after photodynamic therapy. RESULTS Tumor necrosis was not significantly different based on treatment group (P = 0.33), while skin photosensitivity was significantly reduced in animals that received Photofrin® intratumorally (P = 0.0005). Fluorescence imaging revealed similar photosensitizer fluorescence in excised tumors for intratumor and intravenous injection of Photofrin® (P = 0.48), although fluorescence decreased significantly with decreasing intratumor injection concentration (P= 0.01). CONCLUSIONS This pilot study shows that intratumoral administration of Photofrin® has the potential to produce similar tumor outcomes, while reducing systemic skin photosensitivity. Further studies are warranted to characterize and optimize intratumor delivery. Lasers Surg. 50:476-482, 2018. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Timothy M Baran
- Departments of Imaging Sciences and Biomedical Engineering, University of Rochester, 601 Elmwood Ave., Box 648, Rochester, New York, 14642
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12
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Penjweini R, Kim MM, Liu B, Zhu TC. Evaluation of the 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH) mediated photodynamic therapy by macroscopic singlet oxygen modeling. JOURNAL OF BIOPHOTONICS 2016; 9:1344-1354. [PMID: 27653233 PMCID: PMC5159301 DOI: 10.1002/jbio.201600121] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 07/12/2016] [Accepted: 08/21/2016] [Indexed: 05/02/2023]
Abstract
Photodynamic therapy (PDT) is known as a non-invasive treatment modality that is based on photochemical reactions between oxygen, photosensitizer, and a special wavelength of light. However, a dosimetric predictor for PDT outcome is still elusive because current dosimetric quantities do not account for the differences in the PDT oxygen consumption rate for different fluence rates. In this study, we evaluate several dose metrics, total fluence, photobleaching ratio, PDT dose, and mean reacted singlet oxygen (mean [1 O2 ]rx ) for predicting the PDT outcome and a clinically relevant tumor re-growth endpoint. For this reason, radiation-induced fibrosarcoma (RIF) mice tumors are treated with 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH) and different in-air fluences (30 J/cm2 , 50 J/cm2 , 135 J/cm2 , 250 J/cm2 , and 350 J/cm2 ) and in-air fluence rates (20, 50, 75, 150 mW/cm2 ). Explicit measurements of HPPH and oxygen concentration as well as tissue optical properties are performed pre- and post-treatment. Then, this information is incorporated into a macroscopic model to calculate the photobleaching, PDT dose, and mean [1 O2 ]rx . Changes in tumor volume are tracked following the treatment and compared with the dose metrics. The correlation demonstrates that mean [1 O2 ]rx serves as a better dosimetric quantity for predicting treatment outcome and a clinically relevant tumor re-growth endpoint.
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Affiliation(s)
| | | | - Baochang Liu
- University of Pennsylvania, School of Medicine, Department of Radiation Oncology, 3400 Civic Center Boulevard TRC 4W, hiladelphia, Pennsylvania 19104, USA
| | - Timothy C. Zhu
- University of Pennsylvania, School of Medicine, Department of Radiation Oncology, 3400 Civic Center Boulevard TRC 4W, hiladelphia, Pennsylvania 19104, USA
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13
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Synthesis, Photophysical and Photochemical Properties of a Set of Silicon Phthalocyanines Bearing Anti-Inflammatory Groups. J Fluoresc 2016; 27:407-416. [PMID: 27858301 DOI: 10.1007/s10895-016-1969-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 11/03/2016] [Indexed: 01/19/2023]
Abstract
In this study, a series of novel silicon (IV) phthalocyanines conjugated axially with anti-inflammatory (sulindac) and triethylene glycol groups has been synthesized. Different synthetic strategies were attempted to obtain the targeted molecules in high yield. The compounds were fully characterized by using different analyses techniques. Our objectives were to generate a system with sulindac group which enhances the singlet oxygen generation and exhibits anti-cancer effect. Therefore, photophysical and photochemical properties of these compounds were investigated in different solvents. The substituent effect on fluorescence quantum yield and singlet oxygen generation was evaluated for efficiency in photodynamic therapy (PDT) as photosensitizer. The molecules exhibited no aggregation tendency, solubility in common organic solvents, high singlet oxygen quantum yield and high photostability in DMSO so these favourable properties make them good candidates as photosensitizer for PDT. In addition, their stabilities were investigated in DMSO, THF, acetonitrile and DMF.
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14
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Ahn MY, Yoon HE, Moon SY, Kim YC, Yoon JH. Intratumoral Photodynamic Therapy With Newly Synthesized Pheophorbide a in Murine Oral Cancer. Oncol Res 2016; 25:295-304. [PMID: 27629775 PMCID: PMC7841246 DOI: 10.3727/096504016x14732527645922] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Photodynamic therapy (PDT) is a therapeutic alternative for malignant tumors that uses a photosensitizer. Our group recently synthesized photosensitizer pheophorbide a (Pa) from chlorophyll-a. The present study investigated the therapeutic effect of PDT using intratumoral administration of the synthetic photosensitizer Pa in an in vivo murine oral squamous cell carcinoma (OSCC) animal model. Pa accumulation was measured using the fluorescence spectrum and imaging in living C3H mice. Intratumoral treatment of Pa-PDT (IT Pa-PDT) significantly inhibited the growth of transplanted OSCC cells. Histopathological examination of tumor tissues showed that PCNA expression was significantly decreased, while TUNEL-stained cells were markedly increased in the IT Pa-PDT group compared to controls. IT Pa-PDT-induced apoptosis was confirmed by immunoblot. Reduction of Bcl-2 and cleavage of caspase 3 and PARP were observed in IT Pa-PDT. These data demonstrate that IT Pa-PDT inhibited tumor cell proliferation and induced apoptosis, which is correlated with the anticancer activity of IT Pa-PDT. These potent antitumor activities of IT Pa-PDT were observed in both the immunohistochemistry and Western blot experiments. Our findings suggest the intratumoral therapeutic potential of Pa-PDT on OSCC. Additionally, demonstrated detection of Pa using a fluorescence spectroscopy system or molecular imaging system provides a means for simultaneous diagnosis and treatment of OSCC.
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Affiliation(s)
- Mee-Young Ahn
- College of Medical and Life Sciences, Division of Bio-industry, Major in Pharmaceutical Engineering, Silla University, Busan, South Korea
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15
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Clark AJ, Petty HR. WO3/Pt nanoparticles promote light-induced lipid peroxidation and lysosomal instability within tumor cells. NANOTECHNOLOGY 2016; 27:075103. [PMID: 26788907 DOI: 10.1088/0957-4484/27/7/075103] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Although metal-metal oxide nanoparticles have attracted considerable interest as catalysts, they have attracted little interest in nanomedicine. This is likely due to the fact that metal oxide semiconductors generally require biologically harmful ultraviolet excitation. In contrast, this study focuses upon WO3/Pt nanoparticles, which can be excited by visible light. To optimize the nanoparticles' catalytic performance, platinization was performed at alkaline pH. These nanoparticles destroyed organic dyes, consumed dissolved oxygen and produced hydroxyl radicals. 4T1 breast cancer cells internalized WO3/Pt nanoparticles within the membrane-bound endo-lysosomal compartment as shown by electron and fluorescence microscopy. During visible light exposure, but not in darkness, WO3/Pt nanoparticles manufacture reactive oxygen species, promote lipid peroxidation, and trigger lysosomal membrane disruption. As cells of the immune system degrade organic molecules, produce reactive oxygen species, and activate the lipid peroxidation pathway within target cells, these nanoparticles mimic the chemical attributes of immune effector cells. These biomimetic nanoparticles should become useful in managing certain cancers, especially ocular cancer.
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Affiliation(s)
- Andrea J Clark
- Department of Ophthalmology and Visual Sciences, 1000 Wall Street, University of Michigan Medical School, Ann Arbor, MI 48105, USA
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16
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Clark AJ, Coury EL, Meilhac AM, Petty HR. WO3/Pt nanoparticles are NADPH oxidase biomimetics that mimic effector cells in vitro and in vivo. NANOTECHNOLOGY 2016; 27:065101. [PMID: 26683660 DOI: 10.1088/0957-4484/27/6/065101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
To provide a means of delivering an artificial immune effector cell-like attack on tumor cells, we report the tumoricidal ability of inorganic WO3/Pt nanoparticles that mimic a leukocyte's functional abilities. These nanoparticles route electrons from organic structures and electron carriers to form hydroxyl radicals within tumor cells. During visible light exposure, WO3/Pt nanoparticles manufacture hydroxyl radicals, degrade organic compounds, use NADPH, trigger lipid peroxidation, promote lysosomal membrane disruption, promote the loss of reduced glutathione, and activate apoptosis. In a model of advanced breast cancer metastasis to the eye's anterior chamber, we show that WO3/Pt nanoparticles prolong the survival of 4T1 tumor-bearing Balb/c mice. This new generation of inorganic photosensitizers do not photobleach, and therefore should provide an important therapeutic advance in photodynamic therapy. As biomimetic nanoparticles destroy targeted cells, they may be useful in treating ocular and other forms of cancer.
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Affiliation(s)
- Andrea J Clark
- Department of Ophthalmology and Visual Sciences, 1000 Wall Street, University of Michigan Medical School, Ann Arbor, MI 48105, USA
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17
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Zhang P, Yang Y, Liu Y, Rodriguez ME, Kenney ME. Studies directed towards nonyl acridine orange analogues having the potential to act as FRET donors with the PDT drug Pc 4. RSC Adv 2016. [DOI: 10.1039/c5ra28126a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Analogues of nonyl acridine orange (NAO) were made by quaternization of substituted acridine oranges. The Pc 4-FRET occurrence of these NAO analogues in cells was investigated.
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Affiliation(s)
- Ping Zhang
- Department of Chemistry
- Case Western Reserve University
- Cleveland
- USA
| | - Yang Yang
- Department of Chemistry
- Case Western Reserve University
- Cleveland
- USA
| | - Yun Liu
- Department of Chemistry
- Case Western Reserve University
- Cleveland
- USA
| | - Myriam E. Rodriguez
- Department of Radiation Oncology
- School of Medicine
- Case Western Reserve University
- USA
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18
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Fourier transform infrared spectroscopy (FTIR) characterization of the interaction of anti-cancer photosensitizers with dendrimers. Anal Bioanal Chem 2015; 408:535-44. [DOI: 10.1007/s00216-015-9125-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 10/02/2015] [Accepted: 10/16/2015] [Indexed: 11/25/2022]
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19
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Zhen Z, Tang W, Zhang W, Xie J. Folic acid conjugated ferritins as photosensitizer carriers for photodynamic therapy. NANOSCALE 2015; 7:10330-10333. [PMID: 25998995 PMCID: PMC4885642 DOI: 10.1039/c5nr01833a] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
We coupled folic acid as a tumour targeting ligand to the surface of ferritins and loaded them with ZnF16Pc. The resulting nanoconjugates can efficiently hone in on 4T1 tumours in vivo, and, with photoirradiation, leading to suppressed tumour growth and tumour metastasis.
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Affiliation(s)
- Zipeng Zhen
- Department of Chemistry, University of Georgia, Athens, Georgia 30602, United States
- Bio-Imaging Research Center, University of Georgia, Athens, Georgia 30602, United States
| | - Wei Tang
- Department of Chemistry, University of Georgia, Athens, Georgia 30602, United States
- Bio-Imaging Research Center, University of Georgia, Athens, Georgia 30602, United States
| | - Weizhong Zhang
- Department of Chemistry, University of Georgia, Athens, Georgia 30602, United States
- Bio-Imaging Research Center, University of Georgia, Athens, Georgia 30602, United States
| | - Jin Xie
- Department of Chemistry, University of Georgia, Athens, Georgia 30602, United States
- Bio-Imaging Research Center, University of Georgia, Athens, Georgia 30602, United States
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20
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Zhu TC, Liu B, Penjweini R. Study of tissue oxygen supply rate in a macroscopic photodynamic therapy singlet oxygen model. JOURNAL OF BIOMEDICAL OPTICS 2015; 20:038001. [PMID: 25741665 PMCID: PMC4479436 DOI: 10.1117/1.jbo.20.3.038001] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 02/04/2015] [Indexed: 05/07/2023]
Abstract
An appropriate expression for the oxygen supply rate (Γ(s)) is required for the macroscopic modeling of the complex mechanisms of photodynamic therapy (PDT). It is unrealistic to model the actual heterogeneous tumor microvascular networks coupled with the PDT processes because of the large computational requirement. In this study, a theoretical microscopic model based on uniformly distributed Krogh cylinders is used to calculate Γ(s) = g (1 - [³O₂]/[³O₂]₀) that can replace the complex modeling of blood vasculature while maintaining a reasonable resemblance to reality; g is the maximum oxygen supply rate and [³O₂]/[³O₂]₀ is the volume-average tissue oxygen concentration normalized to its value prior to PDT. The model incorporates kinetic equations of oxygen diffusion and convection within capillaries and oxygen saturation from oxyhemoglobin. Oxygen supply to the tissue is via diffusion from the uniformly distributed blood vessels. Oxygen can also diffuse along the radius and the longitudinal axis of the cylinder within tissue. The relations of Γ(s) to [³O₂]/[³O₂]₀ are examined for a biologically reasonable range of the physiological parameters for the microvasculature and several light fluence rates (ϕ). The results show a linear relationship between Γ(s) and [³O₂]/[³O₂]₀, independent of ϕ and photochemical parameters; the obtained g ranges from 0.4 to 1390 μM/s.
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Affiliation(s)
- Timothy C. Zhu
- University of Pennsylvania, School of Medicine, Department of Radiation Oncology, Philadelphia, Pennsylvania 19104, United States
- Address all correspondence to: Timothy C. Zhu,
| | - Baochang Liu
- University of Pennsylvania, School of Medicine, Department of Radiation Oncology, Philadelphia, Pennsylvania 19104, United States
| | - Rozhin Penjweini
- University of Pennsylvania, School of Medicine, Department of Radiation Oncology, Philadelphia, Pennsylvania 19104, United States
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21
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Penjweini R, Liu B, Kim MM, Zhu TC. Explicit dosimetry for 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a-mediated photodynamic therapy: macroscopic singlet oxygen modeling. JOURNAL OF BIOMEDICAL OPTICS 2015; 20:128003. [PMID: 26720883 PMCID: PMC4698734 DOI: 10.1117/1.jbo.20.12.128003] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 11/18/2015] [Indexed: 05/07/2023]
Abstract
Type II photodynamic therapy (PDT) is based on the photochemical reactions mediated through an interaction between a photosensitizer, ground-state oxygen ([(3)O2]), and light excitation at an appropriate wavelength, which results in production of reactive singlet oxygen ([(1)O2]rx). We use an empirical macroscopic model based on four photochemical parameters for the calculation of [(1)O2]rx threshold concentration ([(1)O2]rx,sh) causing tissue necrosis in tumors after PDT. For this reason, 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH)-mediated PDT was performed interstitially on mice with radiation-induced fibrosarcoma (RIF) tumors. A linear light source at 665 nm with total energy released per unit length of 12 to 100 J/cm and source power per unit length (LS) of 12 to 150 mW/cm was used to induce different radii of necrosis. Then the amount of [(1)O2]rx calculated by the macroscopic model incorporating explicit PDT dosimetry of light fluence distribution, tissue optical properties, and HPPH concentration was correlated to the necrotic radius to obtain the model parameters and [(1)O2]rx,sh. We provide evidence that [(1)O2]rx is a better dosimetric quantity for predicting the treatment outcome than PDT dose, which is proportional to the time integral of the products of the photosensitizer concentration and light fluence rate.
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Affiliation(s)
- Rozhin Penjweini
- University of Pennsylvania, School of Medicine, Department of Radiation Oncology, 3400 Civic Center Boulevard TRC 4W, Philadelphia, Pennsylvania 19104, United States
| | - Baochang Liu
- University of Pennsylvania, School of Medicine, Department of Radiation Oncology, 3400 Civic Center Boulevard TRC 4W, Philadelphia, Pennsylvania 19104, United States
| | - Michele M. Kim
- University of Pennsylvania, School of Medicine, Department of Radiation Oncology, 3400 Civic Center Boulevard TRC 4W, Philadelphia, Pennsylvania 19104, United States
| | - Timothy C. Zhu
- University of Pennsylvania, School of Medicine, Department of Radiation Oncology, 3400 Civic Center Boulevard TRC 4W, Philadelphia, Pennsylvania 19104, United States
- Address all correspondence to: Timothy C. Zhu, E-mail:
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22
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Li J, Yang Y, Zhang P, Sounik JR, Kenney ME. Synthesis, properties and drug potential of the photosensitive alkyl- and alkylsiloxy-ligated silicon phthalocyanine Pc 227. Photochem Photobiol Sci 2014; 13:1690-8. [DOI: 10.1039/c4pp00321g] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Photolysis of Pc 227 yields the extensively studied photodynamic therapy drug Pc 4. The photolytic pathway is a homolysis involving a phthalocyanine π radical and low bond dissociation energy.
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Affiliation(s)
- Jun Li
- Department of Chemistry
- Case Western Reserve University
- Cleveland, USA
| | - Yang Yang
- Department of Chemistry
- Case Western Reserve University
- Cleveland, USA
| | - Ping Zhang
- Department of Chemistry
- Case Western Reserve University
- Cleveland, USA
| | - James R. Sounik
- Department of Chemistry
- Case Western Reserve University
- Cleveland, USA
| | - Malcolm E. Kenney
- Department of Chemistry
- Case Western Reserve University
- Cleveland, USA
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23
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Mitra S, Modi KD, Foster TH. Enzyme-activatable imaging probe reveals enhanced neutrophil elastase activity in tumors following photodynamic therapy. JOURNAL OF BIOMEDICAL OPTICS 2013; 18:101314. [PMID: 23897439 PMCID: PMC3726228 DOI: 10.1117/1.jbo.18.10.101314] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Revised: 05/31/2013] [Accepted: 06/27/2013] [Indexed: 06/02/2023]
Abstract
We demonstrate the use of an enzyme-activatable fluorogenic probe, Neutrophil Elastase 680 FAST (NE680), for in vivo imaging of neutrophil elastase (NE) activity in tumors subjected to photodynamic therapy (PDT). NE protease activity was assayed in SCC VII and EMT6 tumors established in C3H and BALB/c mice, respectively. Four nanomoles of NE680 was injected intravenously immediately following PDT irradiation. 5 h following administration of NE680, whole-mouse fluorescence imaging was performed. At this time point, levels of NE680 fluorescence were at least threefold greater in irradiated versus unirradiated SCC VII and EMT6 tumors sensitized with Photofrin. To compare possible photosensitizer-specific differences in therapy-induced elastase activity, EMT6 tumors were also subjected to 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH)-PDT. NE levels measured in HPPH-PDT-treated tumors were twofold higher than in unirradiated controls. Ex vivo labeling of host cells using fluorophore-conjugated antibodies and confocal imaging were used to visualize Gr1+ cells in Photofrin-PDT-treated EMT6 tumors. These data were compared with recently reported analysis of Gr1+ cell accumulation in EMT6 tumors subjected to HPPH-PDT. The population density of infiltrating Gr1+ cells in treated versus unirradiated drug-only control tumors suggests that the differential in NE680 fold enhancement observed in Photofrin versus HPPH treatment may be attributed to the significantly increased inflammatory response induced by Photofrin-PDT. The in vivo imaging of NE680, which is a fluorescent reporter of NE extracellular release caused by neutrophil activation, demonstrates that PDT results in increased NE levels in treated tumors, and the accumulation of the cleaved probe tracks qualitatively with the intratumor Gr1+ cell population.
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Affiliation(s)
- Soumya Mitra
- University of Rochester Medical Center, Department of Imaging Sciences, Rochester, New York 14642, USA.
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Mitra S, Mironov O, Foster TH. Confocal fluorescence imaging enables noninvasive quantitative assessment of host cell populations in vivo following photodynamic therapy. Theranostics 2012; 2:840-9. [PMID: 23082097 PMCID: PMC3475210 DOI: 10.7150/thno.4385] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Accepted: 06/14/2012] [Indexed: 12/18/2022] Open
Abstract
We report the use of optical imaging strategies to noninvasively examine photosensitizer distribution and physiological and host responses to 2-[1-hexyloxyethyl]-2 devinyl pyropheophorbide-a (HPPH)-mediated photodynamic therapy (PDT) of EMT6 tumors established in the ears of BALB/c mice. 24 h following intravenous (IV) administration of 1 μmol kg(-1) HPPH, wide-field fluorescence imaging reveals tumor selectivity with an approximately 2-3-fold differential between tumor and adjacent normal tissue. Confocal microscopy demonstrates a relatively homogeneous intratumor HPPH distribution. Labeling of host cells using fluorophore-conjugated antibodies allowed the visualization of Gr1(+)/CD11b(+) leukocytes and major histocompatibility complex class II (MHC-II)(+) cells in vivo. Imaging of the treated site at different time-points following irradiation shows significant and rapid increases in Gr1(+) cells in response to therapy. The maximum accumulation of Gr1(+) cells is found at 24 h post-irradiation, followed by a decrease at the 48 h time-point. Using IV-injected FITC-conjugated dextran as a fluorescent perfusion marker, we imaged tissue perfusion at different times post-irradiation and found that the reduced Gr1(+ )cell density at 48 h correlated strongly with functional damage to the vasculature as reported via decreased perfusion status. Dual color confocal imaging experiments demonstrates that about 90% of the anti-Gr1 cell population co-localized with anti-CD11b labeling, thus indicating that majority of the Gr1-labeled cells were neutrophils. At 24 h post-PDT, an approximately 2-fold increase in MHC-II+ cells relative to untreated control is also observed. Co-localization analysis reveals an increase in the fraction of Gr1(+) cells expressing MHC-II, suggesting that HPPH-PDT is stimulating neutrophils to express an antigen-presenting phenotype.
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Affiliation(s)
| | | | - Thomas H. Foster
- Department of Imaging Sciences, University of Rochester Medical Center, Rochester, NY 14642, USA
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Baran TM, Foster TH. Fluence rate-dependent photobleaching of intratumorally administered Pc 4 does not predict tumor growth delay. Photochem Photobiol 2012; 88:1273-9. [PMID: 22582826 DOI: 10.1111/j.1751-1097.2012.01171.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
We examined effects of fluence rate on the photobleaching of the photosensitizer Pc 4 during photodynamic therapy (PDT) and the relationship between photobleaching and tumor response to PDT. BALB/c mice with intradermal EMT6 tumors were given 0.03 mg kg(-1) Pc 4 by intratumor injection and irradiated at 667 nm with an irradiance of 50 or 150 mW cm(-2) to a fluence of 100 J cm(-2). While no cures were attained, significant tumor growth delay was demonstrated at both irradiances compared with drug-only controls. There was no significant difference in tumor responses to these two irradiances (P = 0.857). Fluorescence spectroscopy was used to monitor the bleaching of Pc 4 during irradiation, with more rapid bleaching with respect to fluence shown at the higher irradiance. No significant correlation was found between fluorescence photobleaching and tumor regrowth for the data interpreted as a whole. Within each treatment group, weak associations between photobleaching and outcome were observed. In the 50 mW cm(-2) group, enhanced photobleaching was associated with prolonged growth delay (P = 0.188), while at 150 mW cm(-2) this trend was reversed (P = 0.308). Thus, it appears that Pc 4 photobleaching is not a strong predictor of individual tumor response to Pc 4-PDT under these treatment conditions.
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Affiliation(s)
- Timothy M Baran
- The Institute of Optics, University of Rochester, Rochester, NY, USA
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Baran TM, Giesselman BR, Hu R, Biel MA, Foster TH. Factors influencing tumor response to photodynamic therapy sensitized by intratumor administration of methylene blue. Lasers Surg Med 2011; 42:728-35. [PMID: 20848552 DOI: 10.1002/lsm.20962] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND AND OBJECTIVES We examined tumor response to methylene blue (MB)-mediated photodynamic therapy (PDT) in a murine tumor model. The goal was to investigate the effects of drug-light interval (DLI), injection vehicle, and fluence on tumor destruction. Fluorescence and reflectance spectroscopy informed our understanding. MATERIALS AND METHODS EMT6 tumor cells were implanted intradermally on the backs of female BALB/c mice and grown to ∼4-mm diameter. Mice were given a 35 µl, single site, intratumor injection of 500 µg/ml MB administered in either a water or a 5% ethanol-5% Cremophor-90% saline vehicle. PDT was begun either immediately or after a 1-hour DLI with a fluence rate of 60 mW/cm(2). Each animal received a fluence of 240 or 480 J/cm(2). Fluorescence and reflectance spectra were captured before and during irradiation. RESULTS A protocol consisting of the Cremophor-based vehicle, 0 DLI, and a fluence of 480 J/cm(2) was the most effective, with a 55% cure rate as measured by no evidence of tumor 90 days after PDT. Use of the water vehicle with this fluence and DLI reduced the cure rate to 20%. Reducing the fluence to 240 J/cm(2) similarly reduced treatment efficacy with 0 and 1-hour DLIs. Univariate Cox proportional hazards analysis identified increased fluence, 0 versus 1-hour DLI, and the Cremophor versus water vehicle as highly significant independent predictors of long term tumor control (P < 0.01 in each case). Multivariate analysis with model selection revealed fluence and injection vehicle as the best predictors of survival hazards. Fluorescence spectroscopy in vivo showed that MB fluorescence decreased monotonically during a 2-hour dark interval but was restored by irradiation. Reflectance spectroscopy revealed that MB at this injected concentration attenuates the treatment beam significantly. CONCLUSION Sensitizer delivery vehicle, drug-light interval, and fluence contribute significantly to the tumor response to MB-mediated PDT.
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Affiliation(s)
- Timothy M Baran
- Institute of Optics, University of Rochester, Rochester, New York 14627, USA
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