Prospects and Challenges of Phospholipid-Based Prodrugs

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 of relevant physiological lipid processing pathways and absorption barriers is provided, followed by drug delivery/therapeutic application of PL-drug conjugates, as well as computational modeling techniques, and a modern bioinformatics tool that can aid in the optimization of PL conjugates. PL-based prodrugs have increased lipophilicity comparing to the parent drug, and can therefore significantly improve the pharmacokinetic profile and overall bioavailability of the parent drug, join the endogenous lipid processing pathways and therefore accomplish drug targeting, e.g., by lymphatic transport, drug release at specific target site(s), or passing the blood-brain barrier. Moreover, an exciting gateway for treating inflammatory diseases and cancer is presented, by utilizing the PL sn-2 position in the prodrug design, aiming for PLA2-mediated activation. Overall, a PL-based prodrug approach shows great potential in improving different drug delivery/therapy aspects, and is expected to grow.

Phospholipid Cyclosporine Prodrugs Targeted at Inflammatory Bowel Disease (IBD) Treatment: Design, Synthesis, and in Vitro Validation

“…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.…”

Computational Simulations to Guide Enzyme-Mediated Prodrug Activation

“…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].…”

“…(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].…”

<p>Self-Assembled Lecithin/Chitosan Nanoparticles Based on Phospholipid Complex: A Feasible Strategy to Improve Entrapment Efficiency and Transdermal Delivery of Poorly Lipophilic Drug</p>

“…[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.…”