Sustained and efficient porphyrin generation in vivo using dendrimer conjugates of 5-ALA for photodynamic therapy

JOURNAL OF CONTROLLED RELEASE

卷:135

Article

Casas, Adriana^2,3  Battah, Sinan¹  Di Venosa, Gabriela^2,3  Dobbin, Paul⁴  Rodriguez, Lorena^2,3  Fukuda, Haydee^2,3,5  Batlle, Alcira^2,3  MacRobert, Alexander J.¹ 

[1] UCL, Natl Med Laser Ctr, Sch Med, London W1W 7EJ, England

[2] Univ Buenos Aires, CONICET, CIPYP, Buenos Aires, DF, Argentina

[3] Univ Buenos Aires, Hosp Clin Jose San Martin, Buenos Aires, DF, Argentina

[4] Univ Essex, Dept Biol Sci, Colchester CO4 3SQ, Essex, England

[5] Univ Buenos Aires, Sch Sci, RA-1053 Buenos Aires, DF, Argentina

关键词: Aminolaevulinic acid;    ALA;    Dendrimer;    Nanoparticle;    Photodynamic therapy;    PDT;   

DOI  :  10.1016/j.jconrel.2009.01.002

来源: Elsevier

【 摘 要 】

The use of endogenous protoporphyrin IX (PpIX) after administration of 5-aminolaevulinic acid (ALA) has led to many applications in photodynamic therapy (PDT). However the efficacy of ALA-PDT is sub-optimal for thicker tumours and improved ALA delivery and therapeutic response are required. We have investigated the conjugation of ALA to a second-generation dxcendrimer for enhancing porphyrin synthesis in vitro and in vivo in a murine tumour model using systemic i.p. administration. In vitro, the dendrimer was more efficient than ALA for porphyrin synthesis at low concentrations in good correlation with higher cellular ALA dendrimer accumulation. In vivo, the porphyrin kinetics from ALA exhibited an early peak between 3 and 4 h in most tissues, whereas the dendrimer induced sustained porphyrin production for Over 24 h and basal values were not reached until 48 h after administration. Integrated porphyrin accumulation from the dendrimer and ALA, at equivalent molar ratios, was comparable showing that the majority of ALA residues were liberated from the dendrimer. The porphyrin kinetics appear to be governed by the rate of enzymatic cleavage of ALA from the dendrimer, which is consistent with in vitro results. ALA dendrimers may be useful for metronomic PDT, and Multiple low-dose ALA-PDT treatments. (c) 2009 Elsevier B.V. All rights reserved.

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