Liposomal formulation of retinoids designed for enzyme triggered release.
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.
Pedersen
Palle J
PJ
Department of Chemistry, Technical University of Denmark, Kemitorvet, Building 201 and 207, DK-2800 Kgs. Lyngby, Denmark.
Adolph
Sidsel K
SK
Subramanian
Arun K
AK
Arouri
Ahmad
A
Andresen
Thomas L
TL
Mouritsen
Ole G
OG
Madsen
Robert
R
Madsen
Mogens W
MW
Peters
Günther H
GH
Clausen
Mads H
MH
D016923:Cell Death; D045744:Cell Line, Tumor; D003603:Cytotoxins; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008081:Liposomes / Q000737:chemistry* / Q000627:therapeutic use; D056004:Molecular Dynamics Simulation; D053758:Nanoparticles; D010316:Particle Size; D054467:Phospholipases A2 / Q000378:metabolism*; D010743:Phospholipids; D011355:Prodrugs / Q000378:metabolism*; D012176:Retinoids / Q000737:chemistry* / Q000627:therapeutic use
D003603:Cytotoxins; D008081:Liposomes; D010743:Phospholipids; D011355:Prodrugs; D012176:Retinoids; D054467:Phospholipases A2