ALA and ALA hexyl ester-induced porphyrin synthesis in chemically induced skin tumours: the role of different vehicles on improving photosensitization

Casas, Adriana; Perotti, Christian; Fukuda, Haydée; Rogers, Louis; Butler, Anthony R.; Batlle, Alcira

doi:10.1054/bjoc.2001.2156

Cited by 43 publications

(30 citation statements)

References 19 publications

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“…Through fiber-optic detection of porphyrins, we have observed that after topical application, ALA induced rapid diffusion of porphyrins to other distant sites within the skin, but this was not observed for the ALA peptides. Such a phenomenon has been previously remarked upon by us, along with a higher confinement of porphyrin synthesis from He-ALA to the application site (51). In our previous studies, a similar amount of porphyrins from ALA was synthesized in distant papillomas when compared with ALA-applied papillomas, demonstrating that either ALA itself and/or the porphyrins formed by synthesis can be distributed throughout the vasculature and accumulate in distant tumors, and though it is likely that ALA is the molecule diffusing to distant sites, we cannot discount the contribution of hydrophilic precursors of PpIX such as uroporphyrin and coproporphyrin.…”

Section: Discussionsupporting

confidence: 58%

The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy

Venosa

Vallecorsa

Giuntini

et al. 2015

Molecular Cancer Therapeutics

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The use of endogenous protoporphyrin IX generated after administration of 5-aminolaevulinic acid (ALA) has led to many applications in photodynamic therapy (PDT). However, the bioavailability of ALA is limited by its hydrophilic properties and limited cell uptake. A promising approach to optimize the efficacy of ALA-PDT is to deliver ALA in the form of prodrugs to mask its hydrophilic nature. The aim of this work was to evaluate the potential of two ALA dipeptide derivatives, N-acetyl terminated leucinyl-ALA methyl ester (Ac-Leu-ALA-Me) and phenylalanyl-ALA methyl ester (Ac-Phe-ALA-Me), for their use in PDT of cancer, by investigating the generation of protoporphyrin IX in an oncogenic cell line (PAM212-Ras), and in a subcutaneous tumor model. In our in vitro studies, both derivatives were more effective than ALA in PDT treatment, at inducing the same protoporphyrin IX levels but at 50-to 100-fold lower concentrations, with the phenylalanyl derivative being the most effective. The efficient release of ALA from Ac-Phe-ALA-Me appears to be consistent with the reported substrate and inhibitor preferences of acylpeptide hydrolase. In vivo studies revealed that topical application of the peptide prodrug Ac-Phe-ALA-Me gave greater selectivity than with ALA itself, and induced tumor photodamage, whereas systemic administration improved ALA-induced porphyrin generation in terms of equivalent doses administered, without induction of toxic effects. Our data support the possibility of using particularly Ac-Phe-ALA-Me both for topical treatment of basal cell carcinomas and for systemic administration. Further chemical fine-tuning of this prodrug template should yield additional compounds for enhanced ALA-PDT with potential for translation to the clinic. Mol Cancer Ther; 14(2); 440-51. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 58%

The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy

Venosa

Vallecorsa

Giuntini

et al. 2015

Molecular Cancer Therapeutics

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“…Nevertheless they both are similar to oil-in-water emulsion where Gantrez may be considered as the oil component and the PVP as the water component. Oil-in-water emulsions are known to enhance lipophilic ALA hexylester localization in tumour whereas saline-DMSO-ethanol composition enhances amphiphilic 5-ALA (zwitterions) localization (28). In this study it was observed that PME in Gel-1 exhibited statistically significant selectivity at all time-points.…”

Section: Discussionmentioning

confidence: 57%

A study comparing endogenous protoporphyrin IX induced by 5-ALA and ALA-methyl ester with exogenous PpIX and PpIX dimethyl ester in photodynamic diagnosis of human nasopharyngeal carcinoma xenografts

Manivasager

Yee²,

Heng³

et al. 2006

Int J Oncol

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Abstract. 5-Aminolevulinic acid (5-ALA) and its esters have been under intense investigation to enhance the endogenous production of protoporphyrin IX (PpIX) in tumour cells for the purpose of photodynamic diagnosis. In this study we have investigated the use of exogenous PpIX and its dimethyl ester (PME) and compared the results with endogenous PpIX produced via 5-ALA and ALA methyl ester (AME) in poorly differentiated NPC/CNE-2 nasopharyngeal carcinoma cells in both in vivo and in vitro systems. All prodrugs and photosensitizers were administered to tumour bearing balb/c nude mice either intravenously or topically. In vitro results show that 5-ALA induced more PpIX fluorescence when compared with AME in NPC/CNE-2 cells and PME showed better uptake than PpIX. In vivo results show that exogenous PpIX and PME show promise as good candidates as photosensitizers for photodynamic diagnosis as they exhibit significant selectivity between tumour tissue and normal tissue at 3 h. Modification of delivery vehicle used for application of exogenous PpIX and PME could allow for rapid uptake; better selectivity and localization of the photosensitizer.

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“…In conclusion, according to these results and those from Casas et al (2001b) when compared to ALA, only superficial skin lesions may be successfully treated with topical He-ALA PDT with the advantage of tumour selectivity; instead malignancies such as chest wall progression of breast cancer will probably fail this treatment. …”

Section: Discussionmentioning

confidence: 79%

“…However, in a previous work (Casas et al, 2001b) we have analysed porphyrin formation in chemically induced squamous papillomas, after topical application of ALA and He-ALA in cream and lotion formulations. Not only did we find porphyrin synthesis from ALA in these highly keratinised papillomas, but we also found porphyrin accumulation in internal organs, showing that the ALA-hexyl ester does reach the dermis in this tumour model.…”

Section: Discussionmentioning

confidence: 99%

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Topical application of ALA and ALA hexyl ester on a subcutaneous murine mammary adenocarcinoma: tissue distribution

et al. 2003

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Although 5-aminolevulinic acid (ALA)-based photodynamic therapy (PDT) has proven to be clinically beneficial for the treatment of certain cancers, including a variety of skin cancers, optimal tissue localisation still remains a problem. An approach to improve the bioavailability of protoporphyrin IX (PpIX) is the use of ALA derivatives instead of ALA. In this work, we employed a subcutaneous murine mammary adenocarcinoma to study the tissue distribution pattern of the ALA hexyl ester (He-ALA) in comparison with ALA after their topical application in different vehicles. He-ALA induced porphyrin synthesis in the skin overlying the tumour (SOT), but it did not reach the tumour tissue as efficiently. Only 5 h after He-ALA lotion application, tumour porphyrin levels surpassed control values. He-ALA delivered in cream induced a substantially lower porphyrin synthesis in SOT, reinforcing the importance of the vehicle in the use of topical PDT. Porphyrin levels in internal organs remained almost within control values when He-ALA was employed. The addition of DMSO to ALA formulation slightly increased tumour and SOT porphyrin biosynthesis, but it did not when added to He-ALA lotion.

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ALA and ALA hexyl ester-induced porphyrin synthesis in chemically induced skin tumours: the role of different vehicles on improving photosensitization

Cited by 43 publications

References 19 publications

The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy

The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy

A study comparing endogenous protoporphyrin IX induced by 5-ALA and ALA-methyl ester with exogenous PpIX and PpIX dimethyl ester in photodynamic diagnosis of human nasopharyngeal carcinoma xenografts

Topical application of ALA and ALA hexyl ester on a subcutaneous murine mammary adenocarcinoma: tissue distribution

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