Characterization of Endogenous Protoporphyrin IX Induced by δ-Aminolevulinic Acid in Resting and Activated Peripheral Blood Lymphocytes by Four-Color Flow Cytometry

Hryhorenko, Eric A.; Rittenhouse-Diakun, Kate; Harvey, Nishikant S.; Morgan, Janet; Stewart, Carleton C.; Oseroff, Allan R.

doi:10.1111/j.1751-1097.1998.tb09456.x

Cited by 34 publications

(5 citation statements)

References 29 publications

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“…In the present study, the activated CD3 + T cells with a high CD71 expression had a higher ALA-derived PpIX production than the resting CD3 + T cells with a low CD71 expression. Similar results were also obtained by others [19,27].…”

Section: Discussionsupporting

confidence: 92%

“…Hence, substantial interest has been aimed at developing a PDT modality that utilizes an endogenously synthesized photosensitizer [16,17]. The production and accumulation of endogenous protoporphyrin IX (PpIX) in highly proliferative cells by exogenous 5-aminolevulinic acid (ALA) are well described in the literature [16][17][18][19]. Such PpIX synthesis takes place in the mitochondria of cells due to an increased capacity of porphobilinogen deaminase and a limited activity of ferrochelatase in the heme biosynthesis pathway [16,17].…”

Section: Introductionmentioning

confidence: 99%

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Selective Killing of Activated T Cells by 5-Aminolevulinic Acid Mediated Photodynamic Effect: Potential Improvement of Extracorporeal Photopheresis

Darvekar

Juzenas

Oksvold

et al. 2020

Cancers

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Extracorporeal photopheresis (ECP), a modality that exposes isolated leukocytes to the photosensitizer 8-methoxypsoralen (8-MOP) and ultraviolet-A (UV-A) light, is used to treat conditions such as cutaneous T-cell lymphoma and graft-versus-host disease. However, the current procedure of ECP has limited selectivity and efficiency; and produces only partial response in the majority of treated patients. Additionally, the treatment is expensive and time-consuming, so the improvement for this modality is needed. In this study, we used the concept of photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA), a precursor of an endogenously synthesized photosensitizer protoporphyrin IX (PpIX) in combination with blue light to explore the possibility of targeting activated human blood T cells ex vivo. With various T-cell activation protocols, a high ALA-induced PpIX production took place in activated CD3+, CD4+CD25+, and CD8+ T cell populations with their subsequent killing after blue light exposure. By contrast, resting T cells were much less damaged by the treatment. The selective and effective killing effect on the activated cells was also seen after co-cultivating activated and resting T cells. Under our clinically relevant experimental conditions, ALA-PDT killed activated T cells more selectively and efficiently than 8-MOP/UV-A. Monocyte-derived dendritic cells (DCs) were not affected by the treatment. Incubation of ALA-PDT damaged T cells with autologous DCs induced a downregulation of the co-stimulatory molecules CD80/CD86 and also upregulation of interleukin 10 (IL-10) and indoleamine 2,3-dioxygenase expression, two immunosuppressive factors that may account for the generation of tolerogenic DCs. Overall, the data support the potential use of ALA-PDT strategy for improving ECP by selective and effective killing of activated T cells and induction of immune tolerance.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Selective Killing of Activated T Cells by 5-Aminolevulinic Acid Mediated Photodynamic Effect: Potential Improvement of Extracorporeal Photopheresis

Darvekar

Juzenas

Oksvold

et al. 2020

Cancers

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“…It is worth noting that ALA-PDT is able to selectively kill activated T cells including CD4 and CD8 cells. This is because PpIX is preferentially accumulated only in activated T cells but not resting T cells without activation after ALA incubation, resulting in the selective killing of activated T cells by PDT [ 159 , 160 ]. However, in antigen-presenting cells such as dendritic cells and macrophages, PpIX accumulation can occur regardless of cell activation [ 161 , 162 ].…”

Section: Strategies For Enhancing Ala-ppix Fluorescence and Ala-pdt R...mentioning

confidence: 99%

5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy

2023

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5-Aminolevulinic acid (ALA) is a naturally occurring amino acid synthesized in all nucleated mammalian cells. As a porphyrin precursor, ALA is metabolized in the heme biosynthetic pathway to produce protoporphyrin IX (PpIX), a fluorophore and photosensitizing agent. ALA administered exogenously bypasses the rate-limit step in the pathway, resulting in PpIX accumulation in tumor tissues. Such tumor-selective PpIX disposition following ALA administration has been exploited for tumor fluorescence diagnosis and photodynamic therapy (PDT) with much success. Five ALA-based drugs have now received worldwide approval and are being used for managing very common human (pre)cancerous diseases such as actinic keratosis and basal cell carcinoma or guiding the surgery of bladder cancer and high-grade gliomas, making it the most successful drug discovery and development endeavor in PDT and photodiagnosis. The potential of ALA-induced PpIX as a fluorescent theranostic agent is, however, yet to be fully fulfilled. In this review, we would like to describe the heme biosynthesis pathway in which PpIX is produced from ALA and its derivatives, summarize current clinical applications of ALA-based drugs, and discuss strategies for enhancing ALA-induced PpIX fluorescence and PDT response. Our goal is two-fold: to highlight the successes of ALA-based drugs in clinical practice, and to stimulate the multidisciplinary collaboration that has brought the current success and will continue to usher in more landmark advances.

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“…Finally, perhaps the largest biological effect that factors into PDT treatment is the subsequent immunological responses, and changes that occur in expression pathways of the surviving cells (De Goeij et al 1975, Canti et al 1994, Hryhorenko et al 1998, Wong et al 2003, Brackett 2011, Kammerer et al 2011, Shams et al 2015. Although these reactions have been well documented in recent decades, our understanding of these effects across a range of tumor lines is still not at a level that can be applied to clinical treatment.…”

Section: Biological Modifiers Of Dose Responsementioning

confidence: 99%

Revisiting photodynamic therapy dosimetry: reductionist & surrogate approaches to facilitate clinical success

et al. 2016

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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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Characterization of Endogenous Protoporphyrin IX Induced by δ-Aminolevulinic Acid in Resting and Activated Peripheral Blood Lymphocytes by Four-Color Flow Cytometry

Cited by 34 publications

References 29 publications

Selective Killing of Activated T Cells by 5-Aminolevulinic Acid Mediated Photodynamic Effect: Potential Improvement of Extracorporeal Photopheresis

Selective Killing of Activated T Cells by 5-Aminolevulinic Acid Mediated Photodynamic Effect: Potential Improvement of Extracorporeal Photopheresis

5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy

Revisiting photodynamic therapy dosimetry: reductionist & surrogate approaches to facilitate clinical success

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