Lipases, liposomes and lipid-prodrugs

Lipid prodrug nanocarriers in cancer therapy

“…[137] Despite the described anticancer and anti-inflammatory properties of butyric acid, a member of the short-chain fatty acids family, its pharmacokinetic characteristics (i.e., rapid plasma clearance, first pass hepatic metabolism, side effects such as anemia, nausea, diarrhea) limit its clinical application [138]. The feasibility of the prodrug approach applied to butyrate was demonstrated by clinical investigation of various derivatives, which revealed more favorable toxicological, pharmacological, and pharmaceutical properties compared to the parent molecule [139][140].…”

Peptidophospholipids: Synthesis, phospholipase A2 catalyzed hydrolysis, and application to development of phospholipid prodrugs

“…Secretory PLA 2 s are present extensively in a number of mammalian tissues including pancreas, kidney, and cancer (Arouri et al, 2013). In addition, it has been found that sPLA 2 enzymes, particularly subtype IIA, are overexpressed in several cancer types, specifically in prostate, pancreas, breast, and colon cancers (Yamashita et al, 1994), and that they may also be associated with tumorigenesis and tumor metastasis (Tribler et al, 2007, Scott, et al, 2010).…”

“…In addition, it has been found that sPLA 2 enzymes, particularly subtype IIA, are overexpressed in several cancer types, specifically in prostate, pancreas, breast, and colon cancers (Yamashita et al, 1994), and that they may also be associated with tumorigenesis and tumor metastasis (Tribler et al, 2007, Scott, et al, 2010). Thus, with the recognition that phospholipase A 2 activity has been demonstrated in a number of pathological conditions, the idea of designing sPLA 2 -targeted prodrugs seemed a promising approach to improve the pharmacodynamic properties of tissue-directed drugs (Arouri et al, 2013). The concept was originally based upon replacement of the sn -2-ester group of the natural phospholipid 1 , (Figure 1), by an ester group carrying the pharmacophore, directed at the tissue specific sPLA 2 isozyme, with the objective that hydrolysis by the enzyme will release the drug.…”

“…The concept was originally based upon replacement of the sn -2-ester group of the natural phospholipid 1 , (Figure 1), by an ester group carrying the pharmacophore, directed at the tissue specific sPLA 2 isozyme, with the objective that hydrolysis by the enzyme will release the drug. Along these lines a number of sPLA 2 -targeted prodrugs have been prepared, with the main emphasis on incorporation of pharmacophores with anticancer activities (Andresen et al, 2005, Arouri et al, 2013). One of the recently developed methods of delivery involved the use of phospholipid prodrugs capable of liposome formation, that were pre-mixed with natural phospholipids to provide enhanced formulation stability and performance (Arouri and Mouritsen, 2012), This strategy has been developed as an improved alternative to conventional liposome delivery that circumvents issues of limited efficiency of drug loading, and premature and uncontrolled drug release.…”

Lipid-Based Drug Carriers for Prodrugs to Enhance Drug Delivery

“…Therefore, several different strategies utilized to enable the targeting capabilities of liposomes, which were recently reviewed in detail (66), can also be applied to lipid prodrugs. The two main approaches are the addition of targeting ligands or antibodies on the liposome surface (i.e., active targeting methods) (67,68) or incorporation of a bio-responsive modality to specifically release the liposome contents at the target site (56,66,69). The ligands or antibodies utilized in active targeting methods target overexpressed or uniquely expressed antigens or receptors located in the target site.…”