Liposomal Formulation of Retinoids Designed for Enzyme Triggered Release

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.

The antitumor activity of tumor-homing peptide-modified thermosensitive liposomes containing doxorubicin on MCF-7/ADR: in vitro and in vivo

“…11 In fact, the ability to control and produce a burst release of the encapsulated drug from liposomes would be extremely advantageous and may prove to be an essential step in providing effective levels of drug in the tumor. 12 Several approaches for triggered drug release from liposomes have been investigated, such as enzyme-activated, 13,14 pH-sensitive, 15,16 lightsensitive, 17,18 ultrasound-triggered, [19][20][21] and thermosensitive liposomes. [22][23][24][25][26][27][28][29][30] Thermosensitive liposomes can be prepared from phospholipids that exhibit a sharp gel-to-liquid crystalline transition.…”

Enzymatic action of phospholipase A2 on liposomal drug delivery systems

“…The differences between venom and human sPLA 2 in terms of activity and substrate specificity have been the subject of several earlier studies (Buckland and Wilton, 2000;Leidy et al, 2006;Pedersen et al, 2010). It appears that the major difference between venom and human sPLA 2 refers in the substrate specificity, whereas their global behavior and activity are essentially comparable.…”

“…The feasibility of this platform has been demonstrated before for doxorubicin-and cisplatin-loaded liposomes (Andresen et al, 2005;de Jonge et al, 2010), liposome-forming lipid-like anticancer prodrugs Pedersen et al, 2009Pedersen et al, , 2010, as well as certain double lipid-prodrug systems Mouritsen, 2011, 2012). Several studies have postulated that the hydrolytic products, i.e., fatty acids and lysolipids, due to their membraneperturbing effects, can reduce the permeability barrier of the target cancer cell membrane and thereby enhance the drug cellular uptake (Andresen et al, 2005;Davidsen et al, 2002Davidsen et al, , 2003Jespersen et al, 2012).…”

“…The major difference between CsPLA 2 and human sPLA 2 (HsPLA 2 ) is in their substrate specificity, namely HsPLA 2 needs a certain threshold of anionic lipids for activity (Buckland and Wilton, 2000;Leidy et al, 2006;Pedersen et al, 2010). Therefore, in order to allow for testing single-component liposomes, i.e., DPPC, CsPLA 2 was used in these experiments.…”

Model Answers to Lipid Membrane Questions

“…On accumulation in the tumor of intravenously administered liposomes with encapsulated anticancer drugs, the phospholipase opens the liposomal carrier and the drugs leak out Andresen et al 2005). This latter system can furthermore be expanded to include lipid prodrugs or double prodrugs that are turned into drugs by the action of the phospholipase, precisely at the target (Pedersen et al 2010).…”