ALA and its clinical impact, from bench to bedside

Abstract

ALA-induced protoporphyrin IX (PpIX) is used for fluorescence diagnosis (ALA-FD) and for fluorescence-guided resection of both (pre)malignant and non-malignant diseases. ALA is also applied in photodynamic therapy (ALA-PDT) of superficial (pre)malignant lesions in dermatology, urology, neurosurgery, otorhinolaryngology, gynecology and gastroenterology. Today, ALA is approved as Levulan for actinic keratoses, the ALA-methyl ester Metvix for actinic keratoses and basal cell carcinoma, the ALA-hexyl ester Hexvix for the diagnosis of bladder cancer and Gliolan for malignant glioma. The use of ALA for PDT and FD was established around 25 years ago, with most of the fundamental knowledge gained at the "bench" and implemented at the "bedside" due to the diligence of a few researchers within the first 10 years of research. After 1993 ALA research was taken up by many groups. For patient treatment, several factors are relevant. Administered mainly in a topical or oral form, ALA penetrates tissue in a sub-optimal way, which is currently improved by special techniques and the use of ALA-esters. PpIX accumulation is elevated in many malignant tissues, several tissue abnormalities, and in mucosa. It is also found at elevated levels in macrophages, dendritic cells and activated lymphocytes. Following sufficient PpIX accumulation in the target cells, irradiation is carried out which may be accompanied by a burning sensation at the treatment site. Due to a saturation process of PpIX formation and rapid photobleaching during irradiation the risk of overtreatment is relatively low. Pharmacokinetical studies have demonstrated a low systemic photosensitivity and excretion of PpIX via natural routes.

Monitoring the accumulation and dissipation of the photosensitizer protoporphyrin IX during standard dermatological methyl-aminolevulinate photodynamic therapy utilizing non-invasive fluorescence imaging and quantification

“…The clinical clearance rates are similar to standard treatment methodologies for these conditions (e.g. surgical excision and curettage) (9)(10)(11)(12)(13)(14)(15)(16). Furthermore PDT negates several other issues that commonly arise in the standard treatment of these indications, including lesion size and multiplicity as well as also resulting in a better cosmetic outcome (17).…”

Surgery with molecular fluorescence imaging using activatable cell-penetrating peptides decreases residual cancer and improves survival

“…From a molecular-imaging perspective, ACPPDs have several advantages over other targeted fluorescent probes previously described in the literature for use in a surgical system (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Molecular fluorescence-guided surgery demands that a given probe (a), works for a wide variety of tumor types (b), offers ample signal with low background (c), binds tightly to the tumor, and (d), is not affected by the physical trauma of surgery.…”

“…These probes are applicable to a wide range of tumors but are limited by contrast and nonspecificity. Other options that offer similar fluorescence contrast to ACPPD are the dequenching probes designed by Weissleder's group (19,20), peptide-based probes that target an abundant ligand such as the αvβ3 integrin (21), or 5-aminolevulinic acid (5-ALA) and derivatives, which get converted to fluorescent protoporphyrin IX in many tumors (22,23). All of these alternatives are limited to fluorescence readout, whereas ACPPD also allows MRI, whose noninvasive depth penetration and tomographic accuracy are ideally complementary to the high spatial resolution, real-time capability, and surgical compatibility of fluorescence.…”

Photodynamic Therapy with Aminolevulinic Acid: a novel therapeutic Target in the Management of Gastrointestinal Malignancies

“…Recently, aminolevulinic acid (ALA) has been used as photosensitizer for PDT [4,5]. ALA is first committed intermediate in the heme synthesis pathway ( Figure 1) [6].…”