Chapter 9 - Rational design of phospholipase-sensitive intelligent liposomal nanocarriers for prodrug and drug delivery in cancer therapy

Abstract

Phospholipases are ubiquitously distributed across mammalian, insect, bacterial, and fungal species. They play a crucial role in lipid metabolic pathways and signaling networks, and, hence, in progression of cancers, inflammation, infection, atherosclerosis, and several other pathological conditions. Overexpression on surface of several cancer cells, broad-spectrum substrate specificity toward lipids of varying chemical structure and surface charge, tendency for interfacial adsorption at lipid-water interface, and affinity of human secretory phospholipase A2 (sPLA2) for organized lipid superstructures enables exploitation of the specific phospholipase as a target in rational design of enzyme-sensitive, tumor-specific, lipid-based nanocarriers for delivery of prodrugs and drugs in cancer management. Design of sPLA2-cleavable and hydrolytically degradable lipid prodrugs to form active metabolites and, simultaneously, liposomal vesicular systems in situ is undoubtedly challenging but has immense potential. sPLA2-triggered release of classical anticancer payload from enzyme-sensitive liposomal systems is governed by several factors affecting cellular uptake of liposomes, enzyme-mediated hydrolytic breakdown of lipid bilayer, membrane destabilization induced by lysophospholipids and free fatty acids, site-specific drug release, and finally, in vivo stability of liposomes. Chemistry of the phospholipids, enzyme isoform, enzyme lag time, lipid-to-enzyme ratio, physical characteristics of the liposomes, and several other related parameters need to be monitored for achieving maximum pharmacological and pharmacokinetic benefits out of the enzyme-responsive, intelligent liposomal nanocarriers. Despite the significant progress in the field of prodrug and drug delivery from enzyme-sensitive liposomal nanocarriers in cancer management, there are still hurdles to be overcome in translation of the promising concept into economically viable, clinically acceptable, and marketable formulations.