Sustained and efficient porphyrin generation in vivo using dendrimer conjugates of 5-ALA for photodynamic therapy.
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.
Casas
Adriana
A
Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET and Hospital de Clínicas José de San Martín, University of Buenos Aires, Buenos Aires, Argentina.
Battah
Sinan
S
Di Venosa
Gabriela
G
Dobbin
Paul
P
Rodriguez
Lorena
L
Fukuda
Haydée
H
Batlle
Alcira
A
MacRobert
Alexander J
AJ
D000230:Adenocarcinoma / Q000188:drug therapy; D000622:Aminolevulinic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents / Q000378:metabolism; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D007279:Injections, Subcutaneous; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D008970:Molecular Weight; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D011166:Porphyrins / Q000378:metabolism*; D011524:Protoporphyrins / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D004396:Coloring Agents; D050091:Dendrimers; D017319:Photosensitizing Agents; D011166:Porphyrins; D011524:Protoporphyrins; D013778:Tetrazolium Salts; D013844:Thiazoles; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX; C022616:thiazolyl blue