Aminolevulinic Acid (ALA) as a Prodrug in Photodynamic Therapy of Cancer

Abstract

Aminolevulinic acid (ALA) is an endogenous metabolite normally formed in the mitochondria from succinyl-CoA and glycine. Conjugation of eight ALA molecules yields protoporphyrin IX (PpIX) and finally leads to formation of heme. Conversion of PpIX to its downstream substrates requires the activity of a rate-limiting enzyme ferrochelatase. When ALA is administered externally the abundantly produced PpIX cannot be quickly converted to its final product - heme by ferrochelatase and therefore accumulates within cells. Since PpIX is a potent photosensitizer this metabolic pathway can be exploited in photodynamic therapy (PDT). This is an already approved therapeutic strategy making ALA one of the most successful prodrugs used in cancer treatment.

Organoiridium Photosensitizers Induce Specific Oxidative Attack on Proteins within Cancer Cells

“…[1] Indeed, this procedure has been widely used in the last 40 years,l argely as photodynamic therapy (PDT) in which absorption of light by ap hotosensitizer (e.g., ap orphyrin) promotes formation of at riplet state which can polarize the spins of the ground-state 3 O 2 to generate highly toxic 1 O 2 . Surface cancers are particularly accessible to PDT,b ut light can also be directed to ar ange of other tissues using,f or example,f iber optics.E xamples of clinical photosensitizers include hematoporphyrin derivatives (Photofrin) [2] and aminolevulinic acid (ALA, ap orphyrin precursor).…”

Photodynamic Therapy As a Promising Method Used in the Treatment of Oral Diseases

“…It is applied topically and, like most photosensitizers given locally, does not have the ability to penetrate deep in the tissues. Intralesional injections often cause significant pain to the patient and systemic administration may cause side-effects [35], such as headache, nausea, fatigue and paraesthesia [36,37]. Repeated systemic application of ALA may also cause damage to hepatocytes and impairment of hepatic functions [38].…”

Natural product as a source of prodrug

“…Aminolevulinic acid (44) light that leads to excitation of photosensitizer and production of reactive oxygen species which produced the cytotoxic effects (Wachowska et al, 2011).…”