Self‐Immolative Linkers Literally Bridge Disulfide Chemistry and the Realm of Thiol‐Free Drugs

Abstract

The ultimate goal of controlled, intracellulardrug delivery is to get the drug to the target cell without spilling the contents in transit and then release the entire payload upon cell entry. One of the most powerful platforms to achieve this relies on the intracellular disulfide reshuffling as a trigger for drug release form the engineered prodrugs. However, utility of disulfide reshuffling for drug release is naturally applicable only to the thiol containing molecules-ultimately leaving nearly all commercialized drugs beyond the scope of this platform. This is a drastic limitation. A cunning new tool of organic chemistry is fast entering the mainstream of prodrug design: the self-immolative linkers. This platform allows overcoming the natural chemical barrier and makes it possible to link virtually any drug to its carrier via a disulfide bond and engineer a specific intracellular release. It is a game-changing accomplishment of modern organic chemistry. The scope and limitations of this novel opportunity for medicinal chemistry and nanomedicine are outlined.

Triple Activity of Lamivudine Releasing Sulfonated Polymers against HIV-1

“…15 This technology offers a means to conjugate and control the release of any hydroxyl-, carboxylic acid or amine functionalized drug from a polymer and is mediated by a thiol such as GSH. 16,17 One of the limitations of drug delivery systems devised to date is the emergence of AZT drug resistant strains of HIV. For this reason, we hypothesized that an antiviral system that possesses inhibition efficacy against multiple stages of viral replication, 18 which additionally comprises a different reverse transcriptase inhibitor, lamivudine, would exhibit increased efficacy against HIV.…”

Templated Self-Assembly of a Covalent Polymer Network for Intracellular Protein Delivery and Traceless Release

“…However, this amino acid presents a challenge in that it is more difficult to functionalize them in a form, whereby they can be tracelessly liberated in the intracellular environment. We hypothesized that placing reactive side-chain functionalities in a polymer, with responsive self-immolation characteristics, 9 would result in a novel and general system that is capable of encapsulating proteins with high fidelity and tracelessly releasing them upon encountering a target microenvironment.…”

Macromolecular prodrugs of ribavirin: Polymer backbone defines blood safety, drug release, and efficacy of anti-inflammatory effects

“…2), allowing for the copolymerization to be performed under hydrophobic and hydrophilic conditions with either acrylate/acrylamide or methacrylate/methacrylamide containing monomers. In each case, the monomer structure also comprised a disulfide bond for intracellular degradation, coupled to a self-immolative linker for drug release [48].…”