Improving nucleoside analogs via lipid conjugation: Is fatter any better?

Abstract

In the past few decades, nucleoside analog drugs have been used to treat a large variety of cancers. These antimetabolite drugs mimic nucleosides and interfere with chain lengthening upon incorporation into the DNA or RNA of actively replicating cells. However, efficient delivery of these drugs is limited due to their pharmacokinetic properties, and tumors often develop drug resistance. In addition, nucleoside analogs are generally hydrophilic, resulting in poor bioavailability and impaired blood-brain barrier penetration. Conjugating these drugs to lipids modifies their pharmacokinetic properties and may improve in vivo efficacy. This review will cover recent advances in the field of conjugation of phospholipids to nucleoside analogs. This includes conjugation of myristic acid, 12-thioethyldodecanoic acid, 5-elaidic acid esters, phosphoramidate, and self-emulsifying formulations. Relevant in vitro and in vivo data will be discussed for each drug, as well as any available data from clinical trials.

Recent Advances in the Design of Self‐Delivery Amphiphilic Drugs and Vaccines

“…However, no significant differences were observed in overall survival, response rate in multiple tumor types . Enocitabine is another lipid‐nucleoside analog that has shown clinical benefit when combined with other chemotherapeutic agents . In a different study, Hong et.al.…”

Molecular Modeling-Guided Design of Phospholipid-Based Prodrugs

“…One of the main advantages of attaching the drug moiety to the phosphate group is avoiding hydrolysis by PLA 2 . Such a conjugation may provide an altered pharmacological effect, higher blood–brain barrier permeability, and may help in overcoming multidrug resistance (e.g., of nucleoside analogs) [28,29,30,31]. On the other hand, attaching the drug to the sn -2 position takes advantage of the PLA 2 -mediated activation, which results in the hydrolysis of the sn -2 fatty acyl bond and the liberation of the lysophospholipid and fatty acid [15,16,19,32,33,34].…”

Prospects and Challenges of Phospholipid-Based Prodrugs

“…Majority of the drugs conjugated this way are nucleosides with antiviral or antineoplastic pharmacological effect, which are characterized by poor absorption and suboptimal pharmacokinetic behavior. Resistance towards nucleoside analogs is very common, attributable to either decreased expression of transport proteins, which leads to lower uptake of drugs (i.e., human equilibrative nucleoside transporter 1 (hENT1), loss of deoxycytidine kinase (dCK) expression and consequent decrease in drug activation, P-glycoprotein (P-gp) increased efflux activity, and cytidine deaminase loss of function (cytarabine, gemcitabine) or nuclear exonucleases/ribonucleotide reductase (fludarabine) [67,68]. Conjugation with PL can improve passive permeability of such hydrophilic drugs, and bypass active ligand transport mechanisms and transport resistance barriers [5,68].…”

“…One way to overcome drug resistance is reducing the drug efflux via transporters e.g., the multi drug resistance (MDR) transporters, resulting in increased accumulation within the cell [33]. In some cases PL-nucleoside conjugates can overcome possible deficiencies in nucleoside kinase activity by liberating the drug moiety in a monophosphate form inside the cell, to avoid dependency on dCK activation [67,68].…”