Chemical instability of 5-aminolevulinic acid used in the fluorescence diagnosis of bladder tumours

Novo, Mercedes; Hüttmann, Gereon; Diddens, H.

doi:10.1016/1011-1344(96)07285-5

Cited by 73 publications

(78 citation statements)

References 8 publications

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“…Furthermore, the unprotected 5-amino group makes the molecule chemically unstable at physiological pH found in bloodstream leading to its degradation and irreversible formation of cyclic dimers that are not able to enter the heme cycle. 29,30 Although different strategies have been employed in order to protect the 5-amino group of 5-ALA while keeping some pharmacological activity, they did not really provide any promising candidates for further development. 31,32 Our approach to protect the amino group in 5-ALA from degradation by integration of phosphatase-sensitive moieties aims at providing the stability needed for the systemic administration of 5-ALA whilst keeping the toxicity profile low.…”

Section: Discussionmentioning

confidence: 99%

Activity of phosphatase-sensitive 5-aminolevulinic acid prodrugs in cancer cell lines

Herceg

Lange

Allémann

et al. 2017

Journal of Photochemistry and Photobiology B: Biology

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Section: Discussionmentioning

confidence: 99%

Activity of phosphatase-sensitive 5-aminolevulinic acid prodrugs in cancer cell lines

Herceg

Lange

Allémann

et al. 2017

Journal of Photochemistry and Photobiology B: Biology

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“…[5] Formulating vehicles that are of sufficiently low pH to allow short-term ALA stability but not so acidic that they cause irritation have also been reported. [12,16] The aim of this work was to formulate a stable and benign formulation that could enhance ALA stability and enable topical delivery. Of particular interest was the incorporation of ALA into microparticles prepared using an aerosol-based procedure adapted from methods described for the encapsulation of indometacin [17] and 17b-estradiol.…”

Section: Introductionmentioning

confidence: 99%

Aminolevulinic acid-loaded Witepsol microparticles manufactured using a spray congealing procedure: implications for topical photodynamic therapy

Al-Kassas¹,

Donnelly²,

McCarron³

2009

j pharm pharmacol

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Objectives The aim was to enhance aminolevulinic acid (ALA) stability by incorporation into low-melting microparticles prepared using a spray congealing procedure and to evaluate temperature-triggered release, allowing topical bioavailability following melting at skin temperature. Methods ALA-loaded Witepsol microparticles were prepared using a novel spray congealing technique. Entrapment efficiency was compared with conventional emulsionbased methods and modelled drug release profiles determined using a membrane separation technique. Raised receiver medium temperature was used to determine triggered release. Bioavailability and lipid-mediated enhancement of ALA penetration were determined in excised murine skin. Key findings ALA-loaded Witepsol microparticles were spherical, with a mean diameter of 20 mm. Loading and stability studies demonstrated effective encapsulation, ranging from 91% to 100%, with no evidence of degradation to pyrazine derivatives. ALA release correlated with dissolution medium temperature, triggered at temperatures close to that of skin. Results suggested that molten Witepsol enhanced cutaneous permeation, whereas incorporation of microparticles in a semi-solid vehicle attenuated ALA penetration. Optimal use was direct application under occlusion. Conclusions Spray congealing is superior to the emulsion-based procedures with respect to encapsulation efficiency of ALA in Witepsol matrices, providing temperature-triggered release, enhanced stability and improved penetration of ALA through keratinised skin. These features could improve ALA delivery to superficial lesions as part of photodynamic therapy.

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“…Almost all of these possible disadvantages accompanying the use of ALA can be ascribed to the physical-chemical properties of the molecule itself. Applied under physiological conditions, ALA is a zwitterion (Novo et al, 1996). Because the lipid bilayer of biological membranes is relatively impermeable to charged molecules, the cellular uptake of ALA is shallow.…”

mentioning

confidence: 99%

Photodetection of early human bladder cancer based on the fluorescence of 5-aminolaevulinic acid hexylester-induced protoporphyrin IX: a pilot study

et al. 1999

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Fluorescence photodetection (PD) and photodynamic therapy (PDT) are techniques currently under clinical assessment for both visualization and local destruction of malignant tumours and premalignant lesions. One drawback of these methods found with some photosensitizers is a more or less long-term cutaneous photosensitivity (Wagnières et al, 1998;Dougherty et al, 1990). A more recent strategy for administering photosensitizers involves the application of 5-aminolaevulinic acid (ALA) in order to stimulate the formation of protoporphyrin IX (PpIX) in situ. The exogenous ALA bypasses the negative feedback control from haem to ALA synthase that catalyses the condensation of glycine and succinyl-coenzyme A (CoA). Given in excess, exogenous ALA thus can result in a temporary accumulation of PpIX, in particular, in cells with higher metabolic turnover. Since PPIX has fairly good photosensitizing properties (Cox et al, 1982;Kennedy et al, 1990) proposed ALA as a possible photodynamic agent. Following this pioneering work, this treatment modality has been widely studied for various cancers (Kennedy et al, 1992;Peng et al, 1992;Svanberg et al, 1994).As well as for the PDT of malignant or premalignant lesions, ALA-induced PpIX is now being used for the detection of such lesions. This technique has been shown to work, among other applications, in urology, where easy instillation in the bladder, combined with the fact that this organ is readily accessible endoscopically, makes it an ideal object. Alongside classical techniques such as cytology or white light examination, fluorescence PD by ALA-induced PpIX provides some advantages (Leveckis et al, 1994;Kriegmair et al, 1996;Jichlinski et al, 1997). This inspection modality allows an exact mapping which pinpoints, with a high level of sensitivity and specificity, the locations of carcinoma in situ (CIS) as well as early stages of cancer-like dysplasias, which are normally difficult to recognize under white light examination.However, when using topically instilled ALA for the PDT of CIS and precancerous lesions, this modality appears to be limited by the amount of ALA that enter the target cells or by the tissue penetration and the distribution of the resulting PpIX in the targeted tissue. Almost all of these possible disadvantages accompanying the use of ALA can be ascribed to the physical-chemical properties of the molecule itself. Applied under physiological conditions, ALA is a zwitterion (Novo et al, 1996). Because the lipid bilayer of biological membranes is relatively impermeable to charged molecules, the cellular uptake of ALA is shallow. Consequently, in order to increase the transport across cellular membranes, fairly high drug doses and increased administration times have to be used. This deficiency results in a low penetration depth (Warloe et al, 1992;Loh et al, 1993;Peng et al, 1995) and an ALA-induced PpIX distribution, which is not optimized for the PDT of the deep layers of nodular lesions in the urothelium (Iinuma et al, 1995;Chang et al, 1996) after topical A...

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Chemical instability of 5-aminolevulinic acid used in the fluorescence diagnosis of bladder tumours

Cited by 73 publications

References 8 publications

Activity of phosphatase-sensitive 5-aminolevulinic acid prodrugs in cancer cell lines

Activity of phosphatase-sensitive 5-aminolevulinic acid prodrugs in cancer cell lines

Aminolevulinic acid-loaded Witepsol microparticles manufactured using a spray congealing procedure: implications for topical photodynamic therapy

Photodetection of early human bladder cancer based on the fluorescence of 5-aminolaevulinic acid hexylester-induced protoporphyrin IX: a pilot study

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