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Partition Coefficients
determination of 5-ALA ester derivatives to cutaneous delivery in PDT
Tedesco, Antonio 1,
Pierre, Maria2, Rotta, Jeane1,
Machetti, Juliana2 and Bentley, Maria Vitoria2
Faculdade de Filosofia Ciências e Letras de Rib. Preto- FFCLRP- Universidade
de São Paulo1
Faculdade de Ciências Farmacêuticas de Rib.Preto- FCFRP-Universidade de
São Paulo2
Abstract-
Exogenous 5-aminolevulinic acid (5-ALA) is becoming widely used as an
inducer of endogenous synthesis of PpIX, a photosensitizer used in PDT.
Topically ALA-based PDT has been used in cutaneous disease and clinical
results have been obtained in the treatment of non-melanoma skin cancers.
One of the limitations of this technique may be the extent to which
5-ALA can penetrate the epidermis. Hence, improving the uptake of 5-ALA
would be expected to increase the efficiency of PDT. Because the limited
penetration of 5-ALA itself, hydrophobic derivatives are now under investigation.
Some lipophilic molecules, such as esterified 5-ALA derivatives, have
been used both in human cell carcinomas, in nude mouse skin and in human
tumors cell lines, and a higher and more homogenous tissue distribution
can be produced, compared to those of free 5-ALA-induced porphyrins.
This work has proposed the synthesis of two 5-ALA lipophilic derivatives
(n-hexyl ester and n-octyl ester) in order to improve the skin penetration
of 5-ALA. The octanol/water (KO/W) and skin/water (KS/W) partition coefficients
were determined in order to verify the lipophilic characteristic and
the skin affinity of 5-ALA derivatives, respectively. The ester derivatives
of 5-ALA with long alkyl chain were synthesized through reaction with
the respective aliphatic alcohol (hexanol and octhanol). The KO/W for
the 5-ALA and its ester derivatives were determined in the aqueous phase
after equilibrium with octhanol. The KS/W were determined in the aqueous
phase after mixing 5-ALA or 5-ALA derivatives solutions with approximately
300 mg excised hairless mouse skin. In both experiments, the aqueous
phase before (C1) and after partition (C2), was assayed by derivation
reaction, followed by HPLC with fluorescence detection. The KO/W values
for the ALA-n-hexyl ester was approximately 3.75 times higher than 5-ALA,
whereas ALA-n-octyl ester this value represented ten times higher compared
to 5-ALA. The KS/W derivatives values were approximately 10.0 times
(ALA-n-hexyl ester) and 30.0 times (ALA-n-octyl ester) higher than 5-ALA.
The results showed 5-ALA ester derivatives showed higher lipophilicity
and skin affinity, which is a desirable characteristic for drug cutaneous
delivery, especially 5-ALA in the topical PDT. SUPPORTED BY FAPESP
Keywords: 5-ALA
ester derivative, Photodynamic Therapy, Skin Cancer
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