Prospects and Challenges of Phospholipid-Based Prodrugs.

Milica Markovic,Ellen Zimmermann,Shimon Ben-Shabat,Arik Dahan,Shahar Keinan,Aaron Aponick

doi:10.3390/pharmaceutics10040210

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.

Highlights

Prodrugs are bioreversible derivatives of active drug molecules used to overcome certain physiological barriers [1]
Lipidic prodrugs consist of two main parts: The drug moiety covalently attached to the lipid carrier, where the lipid carrier can be a fatty acid (FA), glyceride, steroid, or phospholipid (PL) [6]
The design of PL-based prodrugs includes either the active drug moiety linked to the phosphate group, or the drug moiety attached to the glyceride backbone replacing the sn-2 positioned FA, or less commonly, to the sn-1 position (Figure 1) [7]

Summary

Introduction

Prodrugs are bioreversible derivatives of active drug molecules used to overcome certain physiological barriers [1]. The focus of this work is the PL-based prodrugs approach; it is aimed to overview trends and uses, prospects and challenges, promising therapeutic applications, as well as modelling methods for improving their design. The modern prodrug approach focuses on enabling site specificity, by targeting a specific membrane transporter or an enzyme This “targeted” prodrug approach accounts for molecular and cellular factors such as influx/efflux of membrane transporters or cellular protein expression and distribution, thereby providing the opportunity for drug targeting, improving oral bioavailability, or selective organ/tissue activation [8,9,10,11,12,13]. PLA2 does not have specific fatty acid selectivity, an intelligent design of PL-drug conjugate can result in successful PLA2-mediated activation and consequent release of the parent drug from the conjugate complex at the site of overexpression. We aim to provide insights into the use of this approach that continuously grows and may aid in the development of better drug products

Processing Pathways of Phospholipids and Phospholipid-Based Prodrugs

Phospholipid-Based Prodrugs

Computational Modeling of PL-Based Prodrugs

Findings

Conclusions