Metronomic Photodynamic Therapy as a New Paradigm for Photodynamic Therapy: Rationale and Preclinical Evaluation of Technical Feasibility for Treating Malignant Brain Tumors¶
Abstract
The concept of metronomic photodynamic therapy (mPDT) is presented, in which both the photosensitizer and light are delivered continuously at low rates for extended periods of time to increase selective tumor cell kill through apoptosis. The focus of the present preclinical study is on mPDT treatment of malignant brain tumors, in which selectivity tumor cell killing versus damage to normal brain is critical. Previous studies have shown that low-dose PDT using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) can induce apoptosis in tumor cells without causing necrosis in either tumor or normal brain tissue or apoptosis in the latter. On the basis of the levels of apoptosis achieved and model calculations of brain tumor growth rates, metronomic delivery or multiple PDT treatments, such as hyperfractionation, are likely required to produce enough tumor cell kill to be an effective therapy. In vitro studies confirm that ALA-mPDT induces a higher incidence of apoptotic (terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate, sodium salt nick-end labeling positive) cells as compared with an acute, high-dose regimen (ALA-aPDT). In vivo, mPDT poses two substantial technical challenges: extended delivery of ALA and implantation of devices for extended light delivery while allowing unencumbered movement. In rat models, ALA administration via the drinking water has been accomplished at very high doses (up to 10 times therapeutic dose) for up to 10 days, and ex vivo spectrofluorimetry of tumor (9L gliosarcoma) and normal brain demonstrates a 3-4 fold increase in the tumor-to-brain ratio of PpIX concentration, without evidence of toxicity. After mPDT treatment, histological staining reveals extensive apoptosis within the tumor periphery and surrounding microinvading colonies that is not evident in normal brain or tumor before treatment. Prototype light sources and delivery devices were found to be practical, either using a laser diode or light-emitting diode (LED) coupled to an implanted optical fiber in the rat model or a directly implanted LED using a rabbit model. The combined delivery of both drug and light during an extended period, without compromising survival of the animals, is demonstrated. Preliminary evidence of selective apoptosis of tumor under these conditions is presented.
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Low-dose PDT often induces apoptosis and high-dose PDT typically results in necrosis.
“The dose of ALA and light as well as the light dose (fluence) rate may also determine how cells die of PDT, with low-dose PDT often inducing apoptosis and high-dose PDT typically resulting in necrosis [32,33].”
From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [32]
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- Authors
- Bisland, S. K., Lilge, L., Lin, A., Rusnov, R., & Wilson, B. C.
- Affiliations
- University Health Network (CA)
- Venue
- Photochemistry and Photobiology
- Publisher
- Wiley
- Published
- 2004
- Volume
- 80
- Issue
- 1
- Pages
- 22
- ISSN
- 0031-8655 (ISSN-L)
- OpenAlex
- W2065744257
- Cited by
- 173
- References
- 39
- Citations by year
- 2025: 1 · 2024: 8 · 2023: 10 · 2022: 5 · 2021: 7 · 2020: 12 · 2019: 7 · 2018: 7 · 2017: 4 · 2016: 10 · 2015: 5 · 2014: 16 · 2013: 4 · 2012: 7
- FWCI
- 8.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Photochemistry and Photobiology (publishedVersion)
- PubMed (publishedVersion)
- BioOne Complete (BioOne) (submittedVersion)
- Funders
- National Cancer Institute (P01 CA43892, P01CA043892)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Photodynamic Therapy Research Studies
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- malignant brain tumors, 5-aminolevulinic acid, protoporphyrin IX, apoptosis, hyperfractionated radiotherapy, 9L gliosarcoma, tumor growth modeling, fluorescence spectroscopy
- MeSH terms
- Brain Neoplasms, Clinical Trials as Topic, Humans, Photochemotherapy, Apoptosis
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