2018
DOI: 10.3390/pharmaceutics10040210
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Prospects and Challenges of Phospholipid-Based Prodrugs

Milica Markovic,
Shimon Ben-Shabat,
Shahar Keinan
et al.

Abstract: Nowadays, the prodrug approach is used already at the early stages of drug development. Lipidic prodrug approach is a growing field for improving a number of drug properties/delivery/therapy aspects, and can offer solutions for various unmet needs. This approach includes drug moiety bound to the lipid carrier, which can be triglyceride, fatty acids, steroid, or phospholipid (PL). The focus of this article is PL-based prodrugs, which includes a PL carrier covalently bound to the active drug moiety. An overview … Show more

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Cited by 25 publications
(18 citation statements)
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“…Various inflammatory diseases and cancers exhibit PLA 2 overexpression in the inflamed tissues, and this approach could be exploited for many potential conditions. [35][36][37] In summary, a set of new PL cyclosporine prodrugs was designed and prepared as the first step towards the goal of improving the site selectivity of cyclosporine to treat inflammatory bowel disease. In contrast to PLA 2 cleavage of less bulky phospholipid conjugates, PL-cyclosporine conjugates required long tethers for rapid release and the 12-carbon linker shows the most rapid hydrolysis of the potential cyclosporine prodrugs prepared here.…”
Section: Designmentioning
confidence: 99%
“…Various inflammatory diseases and cancers exhibit PLA 2 overexpression in the inflamed tissues, and this approach could be exploited for many potential conditions. [35][36][37] In summary, a set of new PL cyclosporine prodrugs was designed and prepared as the first step towards the goal of improving the site selectivity of cyclosporine to treat inflammatory bowel disease. In contrast to PLA 2 cleavage of less bulky phospholipid conjugates, PL-cyclosporine conjugates required long tethers for rapid release and the 12-carbon linker shows the most rapid hydrolysis of the potential cyclosporine prodrugs prepared here.…”
Section: Designmentioning
confidence: 99%
“…Our group studies PL-prodrugs consisting of the drug covalently bound to the sn-2 position of the PL. We aim to exploit the PLA 2 enzyme in order to hydrolyze the sn-2 bond of the prodrug, thereby releasing the drug specifically at the site of action, where the enzyme PLA 2 is overexpressed ( Figure 4A) [37]. Direct conjugation between the PL and the drug demonstrated lack of activation by PLA 2 [38], therefore, our PL-prodrugs contain different linker lengths between the PL backbone and the drug in the sn-2 position of the PL; different linker length resulted in different rate and extent of activation [8].…”
Section: Phospholipase a 2 (Pla 2 )mentioning
confidence: 99%
“…(A) Illustration of phospholipid (PL)-prodrug activation in phospholipase A 2 (PLA 2 )-rich inflamed intestinal tissues of Inflammatory Bowel Disease (IBD) patients; (B) Structure of PL-diclofenac prodrug; (C) Thermodynamic cycle used for relative binding free energy calculations of PL-diclofenac prodrugs in the transition state complex of PLA 2 ; and (D) In vitro/in silico correlation: binding free energies in PLA 2 transition state (kcal/mol) vs. in vitro activation for different PL-diclofenac prodrugs (% of intact complex). Reproduced with permission from[37,40].…”
mentioning
confidence: 99%
“…[16][17][18] However, the encapsulation of poorly lipophilic compounds, such as melatonin and metoclopramide, is challenging and leads to extremely low entrapment efficiency and relatively poor stability. 17,19 Two typical strategies have been proposed to improve the lipid solubility of drugs: modification of chemical structure and preparation of drug-phospholipid complexes. 20,21 Drug-phospholipid complexes are formed by non-covalent interactions between active compounds and the polar head of phospholipids.…”
Section: Introductionmentioning
confidence: 99%