5‐Aminolevulinic Acid Derivatives in Photomedicine: Characteristics, Application and Perspectives

Abstract

The introduction of lipophilic derivatives of the naturally occurring heme precursor 5-aminolevulinic acid (5-ALA) into photomedicine has led to a true revival of this research area. 5-ALA-mediated photodynamic therapy (PDT) and fluorescence photodetection (FD) of neoplastic disease is probably one of the most selective cancer treatments currently known in oncology. To date, this method has been assessed experimentally for the treatment of various medical indications. However, the limited local bioavailability of 5-ALA has widely prevented its use in daily clinical practice. Although researchers were already aware of this drawback early during the development of 5-ALA-mediated PDT, only recently have well-established concepts in pharmaceutical science been adapted to investigate ways to overcome this drawback. Recently, two derivatives of 5-ALA, methylaminolevulinate (MAL) and hexylaminolevulinate (HAL), gained marketing authorization from the regulatory offices in Europe and Australia. MAL is marketed under the trade name Metvix for the treatment of actinic keratosis and difficult-to-treat basal cell carcinoma. HAL has recently been launched under the trade name Hexvix to improve the detection of superficial bladder cancer in Europe. This review will first present the fundamental concepts underlying the use of 5-ALA derivatives in PDT and FD from a chemical, biochemical and pharmaceutical point of view. Experimental evidences from preclinical data on the improvements and limits observed with 5-ALA derivatives will then be introduced. The state-of-the-art from clinical studies with 5-ALA esters will be discussed, with special emphasis placed on the process that led to the development of MAL in dermatology and to HAL in urology. Finally, we will discuss promising medical fields in which use of 5-ALA derivatives might potentially lead to further use of this methodology in photomedicine.

The impact of fluorescence guidance on spinal intradural tumour surgery

“…5-ALA is a natural precursor for the heme biosynthesis [11]. After metabolization into the fluorescent molecule protoporphyrin IX (PpIX) strong fluorescence could be detected in malignant gliomas after illumination with violet-blue excitation light.…”

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

“…[16][17][18][19] Albeit improved in the terms of lipophilicity, ALA-Hex remains toxic with a poor systemic pharmacokinetic profile thus still not providing an optimal solution for the systemic administration. 20 In order to circumvent the problem of poor drug-like properties of 5-ALA and its esters, we recently reported new 5-ALA prodrugs where the amino group of ALA-Hex was modified with a phosphatase-sensitive linker.…”

Photodynamic inactivation of Klebsiella pneumoniae biofilms and planktonic cells by 5-aminolevulinic acid and 5-aminolevulinic acid methyl ester

“…One issue with the use of 5-ALA is that it does not transverse cell membranes and other biological barriers efficiently, and to counter this several more lipophilic derivatives have been developed to improve bioavailability [23]. Fotinos et al pneumoniae with 10 M MB.…”