5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy

Abstract

5-Aminolevulinic acid (ALA) is a naturally occurring amino acid synthesized in all nucleated mammalian cells. As a porphyrin precursor, ALA is metabolized in the heme biosynthetic pathway to produce protoporphyrin IX (PpIX), a fluorophore and photosensitizing agent. ALA administered exogenously bypasses the rate-limit step in the pathway, resulting in PpIX accumulation in tumor tissues. Such tumor-selective PpIX disposition following ALA administration has been exploited for tumor fluorescence diagnosis and photodynamic therapy (PDT) with much success. Five ALA-based drugs have now received worldwide approval and are being used for managing very common human (pre)cancerous diseases such as actinic keratosis and basal cell carcinoma or guiding the surgery of bladder cancer and high-grade gliomas, making it the most successful drug discovery and development endeavor in PDT and photodiagnosis. The potential of ALA-induced PpIX as a fluorescent theranostic agent is, however, yet to be fully fulfilled. In this review, we would like to describe the heme biosynthesis pathway in which PpIX is produced from ALA and its derivatives, summarize current clinical applications of ALA-based drugs, and discuss strategies for enhancing ALA-induced PpIX fluorescence and PDT response. Our goal is two-fold: to highlight the successes of ALA-based drugs in clinical practice, and to stimulate the multidisciplinary collaboration that has brought the current success and will continue to usher in more landmark advances.

Comparative Study of 5-Aminolevulinic Acid-Mediated Photodynamic Therapy and the Loop Electrosurgical Excision Procedure for the Treatment of Cervical High-Grade Squamous Intraepithelial Lesions

“…Exogenous supply of ALA to precancerous and cancerous lesions can lead to endogenous generation of potent photosensitizer PpIX. Its fluorescent and photodynamic properties offer unique theranostic tools for the examination and treatment of various precancerous and cancerous disorders [28,29]. ALA PDT has been used for cervical HPV infection, condyloma acuminatum, CIN, and other female genital disorders [13,30,31].…”

Current Photodynamic Therapy for Glioma Treatment: An Update

“…The third mechanism involves the activation of the immune response against cancer cells through acute inflammatory processes and the release of cytokines into the tumor. The advantage of one pathway over the other depends on the parameters used in therapy and the patient's health condition [102][103][104][105][106][107][108].…”

“…Clinical applications of PDT in dermatology, ophthalmology, urology, gastroenterology, gynecology, neurosurgery, and pneumology have shown encouraging results in the treatment of human cancers [103]. It is less invasive, target-specific, and has reduced cytotoxicity towards normal cells and tissues, which translates into fewer side effects [109][110][111].…”

Fluorescence-Enhanced Photodynamic Assessments for Human Breast Cancer Cell Characterizations

“…In comparison, the main emission interval (in this work) was around 420 to 600 nm (Figure 2) and 470-545 nm (Figure 6); hence, the fluorescence emission of PpIX is removed. It could be known to be pH-related [54,55] or link pathological status, and the gene expressions in vivo rely on a different aggregate of PpIX [56][57][58]. Also, other influential factors, such as temperature, incubation time, and added glucose of the culturing medium, influence the relative porphyrin concentrations, causing a faster photo-bleaching rate of the Pp spectrum [54,59,60].…”