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Liposomal formulation of retinoids designed for enzyme triggered release.

Journal of medicinal chemistry (2010-04-22)
Palle J Pedersen, Sidsel K Adolph, Arun K Subramanian, Ahmad Arouri, Thomas L Andresen, Ole G Mouritsen, Robert Madsen, Mogens W Madsen, Günther H Peters, Mads H Clausen
ABSTRACT

The design of retinoid phospholipid prodrugs is described based on molecular dynamics simulations and cytotoxicity studies of synthetic retinoid esters. The prodrugs are degradable by secretory phospholipase A(2) IIA and have potential in liposomal drug delivery targeting tumors. We have synthesized four different retinoid phospholipid prodrugs and shown that they form particles in the liposome size region with average diameters of 94-118 nm. Upon subjection to phospholipase A(2), the lipid prodrugs were hydrolyzed, releasing cytotoxic retinoids and lysolipids. The formulated lipid prodrugs displayed IC(50) values in the range of 3-19 microM toward HT-29 and Colo205 colon cancer cells in the presence of phospholipase A(2), while no significant cell death was observed in the absence of the enzyme.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Stearic acid, ≥95%, FCC, FG
Sigma-Aldrich
Stearic acid, Grade I, ≥98.5% (capillary GC)
Sigma-Aldrich
Stearic acid, reagent grade, 95%
Supelco
Stearic acid, analytical standard
Supelco
Melting Point Standard 69-71°C, analytical standard
Supelco
Stearic acid, certified reference material, TraceCERT®
Sigma-Aldrich
Retinoic acid, ≥98% (HPLC), powder
Sigma-Aldrich
Stearic acid 50, tested according to Ph. Eur.