Reversible Covalent Chemistry in Drug Delivery

Abstract

The targeting of drugs specifically to their sites of action is an important strategy for increasing drug efficacy. Chemists have come up with many elegant schemes that aim to convert drugs into magic bullets. This review focuses on the chemistry that underlies these schemes, with particular emphasis on two types of cleavable covalent bonds that are frequently used to link drugs to their various carriers: disulfide bonds and hydrazone bonds. These linkages have been used to release drugs under specific conditions; in the case of disulfides, cleavage is triggered by the mildly reducing environment found in intracellular fluids, and in the case of hydrazones, the acidic conditions that prevail in endosomes cause release of the drug. The applications of these chemistries in drug delivery are reviewed.

Intracellular Cleavable CpG Oligodeoxynucleotide-Antigen Conjugate Enhances Anti-tumor Immunity

“…The lower pH of the endo-lysosome system has also been used as an intracellular trigger for cleavage of hydrazone linkers. 13,15 To confirm that these conjugates are not cleaved by a physiological pH trigger, the conjugates were incubated in buffer at pH 7.4, 6, and 5 for 18 hr at 37 C. HR-SEC analysis showed no change in the chromatographs at either of the pH conditions tested for all three conjugates (data not shown). These in vitro cleavage studies showed that the HYN conjugate was not cleaved by either a reduction (GSH) or a pH trigger and it is therefore a suitable stable control conjugate.…”

“…In order to achieve targeted release of the antigen from the adjuvant inside the cell, an intracellular trigger such as reduction-oxidation (redox) potential, pH, or a specific enzyme can be used. [13][14][15][16][17][18][19] These triggers have been used in a number of devices to enhance the targeted delivery of a drug. 20,21 Triggerable formulations for immunotherapy have been investigated for intracellular targeting to APCs.…”

“…The disulphide bond can be cleaved through the thiol-disulphide exchange reactions with a redox molecule such as glutathione (GSH), which is found at millimolar concentrations (0.5-10 mM) in intracellular compartments, while its concentration is much lower in extracellular milieu (2-40 mM). 15,29 The large redox potential difference between intracellular and extracellular compartments is believed to render an effective trigger that can cleave the disulphide linkage once it enters the high redox intracellular environment. Although there is a large variation in reducing agent concentration between extra-and intracellular compartments, the susceptibility of the disulphide bond to reduction has been shown to be dependent upon the neighboring chemical substituents to the disulphide bond.…”

Nanoparticulate formulations of mithramycin analogs for enhanced cytotoxicity

“…Drug binding linkers are normally designed to degrade in response to pH, enzymatic activity, light, or heat. 24 The hydrazone bond, involved in many biomolecular events, is stable at physiological Ph (7.4), yet is cleaved in acidic conditions (pH , 7.0) in a pH-dependent manner. Such a unique degradation pattern has been employed to design pH-controlled drug-delivery systems that can trigger drug release in intracellular lysosomal compartments (pH 5.0), following the cellular uptake of drug carriers.…”

A walk along DNA using bipedal migration of a dynamic and covalent crosslinker

“…Advances in this topic have directly benefitted from past success in the broader field of dynamic combinatorial chemistry involving reversible covalent forces to assemble new materials and devices from pools of competing subunits [12][13][14][15][16] . Only a limited number of covalent bonds have yet demonstrated sufficient reversibility to support these types of applications and most involve exchange through disulfide bonds, iminium ions, hydrazones or boronate complexes 17 . Metal-ligand interactions have also been used for exchange within dynamic mixtures 18 , and a few examples suggest that Michael reactions have a potential for reversible assembly of macromolecules as well 19,20 .…”