Topical Photodynamic Therapy Using Different Porphyrin Precursors Leads to Differences in Vascular Photosensitization and Vascular Damage in Normal Mouse Skin

Abstract

Different distributions of hexyl aminolevulinate (HAL), aminolevulinic acid (ALA) and methyl aminolevulinate (MAL) in the superficial vasculature are not well studied but they are hypothesized to play an important role in topical photodynamic therapy (PDT). The colocalization of fluorescent CD31 and protoporphyrin IX (PpIX) was calculated using confocal microscopy of mouse skin sections to investigate the vascular distribution after topical application. Vascular damage leads to disruption of the normal endothelial adherens junction complex, of which CD144 is an integral component. Therefore, normal CD31 combined with loss of normal fluorescent CD144 staining was visually scored to assess vascular damage. Both the vascular PpIX concentration and the vascular damage were highest for HAL, then ALA and then MAL. Vascular damage in MAL was not different from normal contralateral control skin. This pattern is consistent with literature data on vasoconstriction after PDT, and with the hypothesis that the vasculature plays a role in light fractionation that increases efficacy for HAL and ALA-PDT but not for MAL. These findings indicate that endothelial cells of superficial blood vessels synthesize biologically relevant PpIX concentrations, leading to vascular damage. Such vascular effects are expected to influence the oxygenation of tissue after PDT which can be important for treatment efficacy.

Treatment of superficial basal cell carcinoma by topical photodynamic therapy with fractionated 5-aminolaevulinic acid 20% vs. two-stage topical methyl aminolaevulinate: results of a randomized controlled trial

“…reported a higher accumulation of PpIX in endothelial vessel walls after ALA application, compared with MAL. After illumination more endothelial damage was observed . Despite these various hypotheses, the exact explanation for the enhanced efficacy has not yet been fully elucidated.…”

“…After illumination more endothelial damage was observed. 28 Despite these various hypotheses, the exact explanation for the enhanced efficacy has not yet been fully elucidated.…”

Blood flow dynamics during local photoreaction in a head and neck tumor model

“…In this study, we focused on several metrics related to the blood flow dynamics such as the final value of the blood flow at the completion of the treatment, the blood FRR, the light dose interval when the blood flow reached the highest and lowest values, and the delivered light dose while the blood flow values were effectively high during the treatment. These parameters indicated substantial differences with respect to the administered PDT treatment light fluence rates, which were confirmed with the CD31 staining and STAT3 crosslinking studies [54][55][56][57]. Figure 10 proposes the mechanistic basis for the different outcomes of low and high fluence rate PDT.…”

“…For technical reasons, the microvessel density could only be determined for post-PDT tumor tissue because removing a portion of the tumor before PDT would cause bleeding, interfering with the blood flow measurements. As previously already demonstrated, an accurate measure for vasculature shutdown is the change in microvessel density [10,17,19,[54][55][56][57][58][59][60][61][62].…”

Therapeutic Considerations and Conjugated Polymer‐Based Photosensitizers for Photodynamic Therapy

“…Tumor vessels are vital factors in the process of cancer development . Selectively damaging existing vasculature or inhibiting the formation of new vessels has been demonstrated as effective way for cancer treatment . After treated with PDT, vascular endothelium and the subendothelial cells are destroyed, and the endothelial cell junctions become widen, then activated platelet and exposure of vascular intima leads to platelet aggregation, thrombosis, and vascular obstruction.…”