Design of Bifunctional Dendritic 5‑Aminolevulinic Acid and Hydroxypyridinone Conjugates for Photodynamic Therapy

• Published in: Bioconjugate chemistry Vol. 29; no. 10; pp. 3411 - 3428
• Main Authors: Zhou, Tao, Battah, Sinan, Mazzacuva, Francesca, Hider, Robert C, Dobbin, Paul, MacRobert, Alexander J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 17.10.2018; Amer Chemical Soc
• Subjects: Aminolevulinic Acid; Biochemical Research Methods; Biochemistry; Biochemistry & Molecular Biology; Cancer; Cell Line, Tumor; Chelating agents; Chemistry; Chemistry, Multidisciplinary; Chemistry, Organic; Dendrimers; Dendrimers - administration & dosage; Dendrimers - chemistry; Drug Carriers; Fluorescence; Heme; Humans; Intracellular; Iron; Levulinic Acids - chemistry; Levulinic Acids - pharmacokinetics; Levulinic Acids - pharmacology; Life Sciences & Biomedicine; Photochemotherapy; Photodynamic therapy; Photosensitizing Agents - chemistry; Photosensitizing Agents - pharmacokinetics; Photosensitizing Agents - pharmacology; Photosynthesis; Phototoxicity; Physical Sciences; Protoporphyrin; Protoporphyrin IX; Protoporphyrins - biosynthesis; Pyridones - chemistry; Science & Technology; Tumor cell lines; FLUORESCENCE; DELTA-AMINOLEVULINIC-ACID; IRON CHELATOR CP94; DRUG-DELIVERY; ALA-PDT; PORPHYRIN ACCUMULATION; DENDRIMERS; PROTOPORPHYRIN IX PRODUCTION; DERIVATIVES; CANCER
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/acs.bioconjchem.8b00574

Iron chelators have recently attracted interest in the field of photo­dynamic therapy (PDT) owing to their role in enhancement of intra­cellular proto­porphyrin IX (PpIX) generation induced by 5-amino­levulinic acid (ALA) via the biosynthetic heme cycle. Although ALA is widely used in PDT, cellular uptake of ALA is limited by its hydro­philicity. In order to improve ALA delivery and enhance the PpIX production, several dendrimers incorporating both ALA and 3-hydroxy-4-pyridinone (HPO) were synthesized. The ability of the dendrimers to enter cells and be metabolized to the PpIX photosensitizer was studied in several human cancer cell lines. The dendrimers were found to be significantly more efficient than ALA alone in PpIX production. The higher intra­cellular PpIX levels showed a clear correlation with enhanced cellular photo­toxicity following light exposure. Dendritic derivatives are therefore capable of efficiently delivering both ALA and HPO, which act synergistically to amplify in vitro PpIX levels and enhance PDT efficacy.