title: Macromolecular delivery of 5-aminolaevulinic acid for photodynamic therapy using dendrimer conjugates.
abstract: Intracellular porphyrin generation following administration of 5-aminolaevulinic acid (5-ALA) has been widely used in photodynamic therapy. However, cellular uptake of 5-ALA is limited by its hydrophilicity, and improved means of delivery are therefore being sought. Highly branched polymeric drug carriers known as dendrimers present a promising new approach to drug delivery because they have a well-defined structure capable of incorporating a high drug payload. In this work, a dendrimer conjugate was investigated, which incorporated 18 aminolaevulinic acid residues attached via ester linkages to a multipodent aromatic core. The ability of the dendrimer to deliver and release 5-ALA intracellularly for metabolism to the photosensitizer, protoporphyrin IX, was studied in the transformed PAM 212 murine keratinocyte and A431 human epidermoid carcinoma cell lines. Up to an optimum concentration of 0.1 mmol/L, the dendrimer was significantly more efficient compared with 5-ALA for porphyrin synthesis. The intracellular porphyrin fluorescence levels showed good correlation with cellular phototoxicity following light exposure, together with minimal dark toxicity. Cellular uptake of the dendrimer occurs through endocytic routes predominantly via a macropinocytosis pathway. In conclusion, macromolecular dendritic derivatives are capable of delivering 5-ALA efficiently to cells for sustained porphyrin synthesis.
authors.affiliation: National Medical Laser Centre, University College London, Charles Bell House, 67-73 Riding House Street, London W1W 7EJ, United Kingdom.
authors.forename: Sinan
authors.initials: S
authors.lastname: Battah
authors.forename: Sherina
authors.initials: S
authors.lastname: Balaratnam
authors.forename: Adriana
authors.initials: A
authors.lastname: Casas
authors.forename: Sophie
authors.initials: S
authors.lastname: O'Neill
authors.forename: Christine
authors.initials: C
authors.lastname: Edwards
authors.forename: Alcira
authors.initials: A
authors.lastname: Batlle
authors.forename: Paul
authors.initials: P
authors.lastname: Dobbin
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: MacRobert
mesh_terms: D000622:Aminolevulinic Acid / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D046911:Macromolecular Substances; D051379:Mice; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000008:administration & dosage* / Q000737:chemistry; D011524:Protoporphyrins / Q000032:analysis / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D050091:Dendrimers; D046911:Macromolecular Substances; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D000622:Aminolevulinic Acid