Aminolevulinic Acid Derivatives and Liposome Delivery as Strategies for Improving 5-Aminolevulinic Acid- Mediated Photodynamic Therapy

Abstract

Photodynamic Therapy employing 5-aminolevulinic acid (ALA) as a precursor of the photosensitizer Protoporphyrin IX has become a promising approach to treat superficial cancers. However, the hydrophilic nature of the ALA molecule somewhat limits the penetration through the skin as well as all cell membranes. Different attempts are currently under investigation to enhance ALA penetration, such as the development of new synthetic and more lipophilic molecules derived from ALA and the incorporation of ALA into lipophilic vehicles such as liposomes. Among the new synthesized molecules, we can find ALA esters, ALA aminoacid derivatives and ALA dendrimers. In general, there is consensus that the promising results obtained in vitro with ALA esters cannot be reproduced in vivo. However, ALA methyl ester (1) has been widely used for treatment of skin malignancies and ALA hexyl ester (15) proved to be more powerful than ALA in bladder imaging. ALA aminoacid derivatives have been designed to use specific cellular aminopeptidases to targeting tumors, and it was shown that they can be metabolized to ALA with some specificity.

5-Aminolaevulinic acid peptide prodrugs enhance photosensitization for photodynamic therapy

“…5A) for both exposure times (5 and 24 h). The porphyrin fluorescence was highest in the epidermis as we have observed previously using ALA in rat skin explants (16). These results also show that enzymes are available, as discussed further below, to metabolize the peptide prodrug in pig skin.…”

“…To overcome this problem, several chemical approaches have been attempted to improve the incorporation of ALA and also its selectivity. One approach has been to use more lipophilic ALA derivatives, such as alkyl or ethylene glycol esters, which are potential substrates for cellular esterases (8 -11), or different delivery systems including dendrimers (12 -14) or liposomes (15,16). The use of alkyl esters of ALA results in a nonspecific distribution of ALA in all cell types, but with an increased PpIX production (10,17) in tumor cells.…”

Protoporphyrin IX enhancement by 5-aminolaevulinic acid peptide derivatives and the effect of RNA silencing on intracellular metabolism

“…To overcome this problem, several chemical approaches have been attempted to improve the incorporation of ALA and also its selectivity. One approach has been to use more lipophilic ALA derivatives, such as alkyl or ethyleneglycol esters, which are potential substrates for cellular esterases (Kloek and Beijersbergen, 1996;Gaullier et al, 1997;Berger et al, 2000;Uehlinger et al, 2000), or different delivery systems including dendrimers (Battah et al, 2001Di Venosa et al, 2006), or liposomes (Casas et al, 2002;Casas and Batlle, 2006). 5-Aminolaevulinic acid prodrug ester derivatives have been widely studied (Kloek and Beijersbergen, 1996;Peng et al, 1996;Gaullier et al, 1997;Kloek et al, 1998;Casas et al, 1999;Eleouet et al, 2000;Brunner et al, 2003;Lopez et al, 2004), in particular the methyl and hexyl ester derivatives, and approval has been granted for the treatment of actinic keratosis and basal cell carcinoma using the methyl ester derivative in Europe and Australia.…”

5-aminolevulinic acid-incorporated nanoparticles of methoxy poly(ethylene glycol)-chitosan copolymer for photodynamic therapy

“…12 Otherwise, the high aqueous solubility of 5-ALA and its low bioavailability have frequently been discussed as drawbacks to its clinical application. 1,2,6,10 To overcome these problems, chemical modification of 5-ALA, 5-ALA-incorporated nanocolloid, patch-based delivery system, or liposomal carriers were tried, in order to improve delivery of 5-ALA. 14,15,18,19 Chitosan has been extensively investigated as a geneor drug-delivery carrier. [25][26][27][28][33][34][35] In particular, chitosan is known to enhance mucosal transport or delivery of bioactive agents.…”

“…[14][15][16] Drug delivery strategies using colloidal drug carriers such as polymeric nanoparticles and liposomes have also been studied for their enhancement of 5-ALA cellular uptake. [17][18][19][20] Among them, nanoscopic vehicles such as polymeric micelles and nanoparticles have been investigated as ideal carriers for drugs, including photosensitizers. [20][21][22] Nanoparticles are regarded as ideal vehicles for targeting solid tumors, because of their favorable biodistribution, excellent bioavailability, and reduction of the intrinsic toxicity of the drugs.…”