Mechanisms of 5‐aminolevulic acid ester uptake in mammalian cells

Rodríguez, Lorena; Batlle, Alcira; Venosa, Gabriela Di; Battah, Sinan; Dobbin, Paul S.; MacRobert, Alexander J.; Casas, Adriana

doi:10.1038/sj.bjp.0706668

Cited by 62 publications

(54 citation statements)

References 34 publications

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“…Porphyrin production was severely suppressed when cells were incubated with compound 1 at 4jC compared with 37jC, which is consistent with endocytic uptake. Because the molecular weight of compound 1 is <500, endocytic uptake is unlikely; therefore, the low temperature effect would be consistent with an active uptake mechanism being a major factor, as also found with ALA (22,35). Further studies using specific inhibitors should enable identification of the active transport mechanism.…”

Section: Discussionmentioning

confidence: 63%

5-Aminolaevulinic acid peptide prodrugs enhance photosensitization for photodynamic therapy

Bourré

Giuntini²,

Eggleston³

et al. 2008

Molecular Cancer Therapeutics

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Intracellular porphyrin generation following administration of 5-aminolaevulinic acid (ALA) has been widely used in photodynamic therapy for a range of malignant and nonmalignant lesions. However, ALA is relatively hydrophilic and lacks stability at physiologic pH, limiting its bioavailability. We have investigated more lipophilic, uncharged ALA-peptide prodrugs based on phenylalanyl-ALA conjugates, which are water soluble and chemically stable for improving ALA delivery. Pharmacokinetics of the induced protoporphyrin IX (PpIX) were studied in transformed PAM212 keratinocyte cells and pig skin explants. The intracellular porphyrin production was substantially increased with Ac-L-Phe-ALA-Me (compound 1) and Ac-LPhe-ALA (compound 3) compared with equimolar ALA: after 6-h incubation, the PpIX fluorescence measured using 0.01 mmol/L of compound 1 was enhanced by a factor of 5 compared with ALA. Phototoxicity results showed good correlation with PpIX levels, giving a LD 50 (2.5 J/cm 2 ) of 25 Mmol/L for ALA, 6 Mmol/L for 5-aminolaevulinic hexyl ester, and 2.6 Mmol/L for compound 1, which exhibited the highest phototoxicity. However, these results were stereospecific because the corresponding D-enantiomer, Ac-D-Phe-ALA-Me (compound 2), induced neither porphyrin synthesis nor phototoxicity. PpIX levels were considerably reduced when cells were incubated with compound 1 at low temperatures, consistent with active transport. In pig skin explants, compound 1 induced higher porphyrin fluorescence than ALA by a factor of 3. These results show that water-soluble peptide prodrugs of ALA can greatly increase its cellular uptake, generating more intracellular PpIX and improved tumor cell photosensitization. The derivatives are comparable in efficacy with 5-aminolaevulinic hexyl ester but less toxic and more stable at physiologic pH. [Mol Cancer Ther 2008;7(6):1720 -9]

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Section: Discussionmentioning

confidence: 63%

5-Aminolaevulinic acid peptide prodrugs enhance photosensitization for photodynamic therapy

Bourré

Giuntini²,

Eggleston³

et al. 2008

Molecular Cancer Therapeutics

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“…The cellular uptake of ALA has been studied by several groups and is mediated via active transport mechanisms, whereas passive diffusion is also significant for small ALA esters (31)(32)(33). Much larger molecules, such as ALA dendrimers, however, may be taken up through endocytic pathways.…”

Section: Discussionmentioning

confidence: 99%

Macromolecular delivery of 5-aminolaevulinic acid for photodynamic therapy using dendrimer conjugates

Battah

Balaratnam

Casas

et al. 2007

Molecular Cancer Therapeutics

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Intracellular porphyrin generation following administration of 5-aminolaevulinic acid (5-ALA) has been widely used in photodynamic therapy. However, cellular uptake of 5-ALA is limited by its hydrophilicity, and improved means of delivery are therefore being sought. Highly branched polymeric drug carriers known as dendrimers present a promising new approach to drug delivery because they have a well-defined structure capable of incorporating a high drug payload. In this work, a dendrimer conjugate was investigated, which incorporated 18 aminolaevulinic acid residues attached via ester linkages to a multipodent aromatic core. The ability of the dendrimer to deliver and release 5-ALA intracellularly for metabolism to the photosensitizer, protoporphyrin IX, was studied in the transformed PAM 212 murine keratinocyte and A431 human epidermoid carcinoma cell lines. Up to an optimum concentration of 0

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“…The drawback of this approach lies in the biological need to have the ester cleaved by cellular enzymes before ALA can enter the heme biosynthetic pathway. Thus, some ALA esters, especially MAL, have been shown to induce less PpIX compared with ALA after the same incubation time [57][58][59]. Additionally, the concentration of short-chained ALA-esters (C1-C3), which is required to induce half-maximal PpIX accumulation, was clearly higher in several cell lines than the corresponding concentration of ALA [56].…”

Section: Enhancing Pdt With Nanoemulsion Technologymentioning

confidence: 99%

A review of BF-200 ALA for the photodynamic treatment of mild-to-moderate actinic keratosis

Reinhold¹

2017

Future Oncol.

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BF-200 ALA is a combination of a nanoscale-lipid vesicle formulation and the prodrug 5-aminolevulinic acid (5-ALA). The nanoemulsion stabilizes the prodrug and enhances its penetration through the stratum corneum. It has shown excellent therapeutic results in both lesion and field-directed photodynamic therapy of actinic keratosis (AK). AK is an early form of epidermal neoplasia and a precursor of invasive cutaneous squamous cell carcinoma. It is characterized by the combination of visible neoplastic lesions and surrounding tissue also harboring tumorigenic UV-induced mutations: a concept called field cancerization. A selective, field-directed treatment is ideal to meet the requirements of field change. Here, we review the clinical data on BF-200 ALA for AK along with a summary of molecular mechanisms and future perspectives. Actinic keratosis (AK), also known as solar keratosis, is caused by chronic exposure to sunlight or other ultraviolet light sources [1,2] and may progress to invasive squamous cell carcinoma (SCC) [3]. It is the most common lesion with malignant potential to arise on the skin. AK is mostly seen in Caucasians in skin areas that have extensive sun exposure throughout their lives [4]. Epidemiological data show a high occurrence rate of AK. Regions with higher ultraviolet exposure have a higher prevalence of AK. For the USA, the prevalence was estimated to range from 11 to 26%, while in Australia it ranged from 40 to 60%. In Europe, a prevalence of 15% in men and 6% in women has been documented [5]. Over the age of 70 years, 34% of men and 18% of women were found to have actinic keratotic lesions [6]. Next to fair skin type, an advanced age and lifelong sun exposure immunosuppression/-deficiency plays another important risk factor [5].Mostly, AK develops slowly and early in the disease process, they may disappear only to reappear later. Recurrence of the disease may include partial elimination of the initial lesion, subclinical lesion progression to visible status, or development of new lesions [7]. On top of this, an AK may progress to invasive SCC, the second-most common form of skin cancer [8,9]. The actual percentage of progress to invasive SCC remains unknown, and estimates vary from 5 to 20% within 10 to 25 years with reported annual transformation rates varying greatly from as low as 0.25% to as high as 16% [10]. The regression rate for a single untreated lesion is 15 to 63% after a year; recurrence rates range from 15 to 53% [11]. In general patients develop multiple AKs in one area and predicting which course each individual lesion will follow is impossible. Nonetheless, AK lesions are reliable markers for patients who are most predisposed to developing invasive SCC [4,[12][13].AK lesions typically appear in areas most frequently exposed to the sun such as the face, back of the hands, or bald scalp; 75% of lesions are found on the head, neck and forearms [14]. The lesions vary in appearance as well as size and can include erythematous scaly macules, rough pigmented patches and hyperker...

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Mechanisms of 5‐aminolevulic acid ester uptake in mammalian cells

Cited by 62 publications

References 34 publications

5-Aminolaevulinic acid peptide prodrugs enhance photosensitization for photodynamic therapy

5-Aminolaevulinic acid peptide prodrugs enhance photosensitization for photodynamic therapy

Macromolecular delivery of 5-aminolaevulinic acid for photodynamic therapy using dendrimer conjugates

A review of BF-200 ALA for the photodynamic treatment of mild-to-moderate actinic keratosis

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