Reduction‐Triggered Transformation of Disulfide‐Containing Micelles at Chemically Tunable Rates

Abstract

A dilemma exists between the circulation stability and cargo release/mass diffusion at desired sites when designing delivery nanocarriers and in vivo nanoreactors. Reported herein are disulfide-crosslinked (DCL) micelles exhibiting reduction-triggered switching of crosslinking modules and synchronized hydrophobic-to-hydrophilic transition. Tumor cell targeted DCL micelles undergo cytoplasmic milieu triggered disulfide cleavage and self-immolative decaging reactions at chemically adjustable rates, generating primary amine moieties. Extensive amidation reactions with neighboring ester moieties then occur because of the high local concentration and suppression of the apparent amine pK value within the hydrophobic cores, thus leading to the transformation of crosslinking modules and formation of tracelessly crosslinked (TCL) micelles, with hydrophilic cores, inside live cells. We further integrate this design principle with theranostic nanocarriers for selective intracellular drug transport guided by enhanced magnetic resonance (MR) imaging performance.

Base‐Sequence‐Independent Efficient Redox Switching of Self‐Assembled DNA Nanocages

“…Nevertheless, the DNA part was limited to an i‐motif. Disulfide crosslinking has exhibited great potential in drug delivery and controlled release due to its responsiveness to versatile in vivo redox environments . Recently, redox‐responsive DNA nanostructures were realized by synthetic incorporation of disulfide linkages in DNA strands .…”

Emerging Applications of Fluorogenic and Non‐fluorogenic Bifunctional Linkers

“…We previously reported the design of poly‐prodrug amphiphiles as a polymeric drug‐delivery platform by using self‐immolative hetero‐bifunctional linkers (HO‐PB‐MA, HO‐SS‐MA, and HO‐SSB‐MA) and controlled polymerization of prodrug monomers. Intracellular reductive media (e.g., cytosolic GSH) cleave disulfide bonds, followed by the release of intact CPT or IND through the self‐immolative cyclization mechanism (Figure b) . In addition, a variety of self‐immolative hetero‐bifunctional linkers involving the cleavable disulfide motif have been used for the fabrication of antibody–drug bioconjugates, nanoparticle–drug conjugates, and protein cross‐linked nanocapsules .…”

“…Intracellular reductivem edia (e.g.,c ytosolicG SH) cleave disulfide bonds, followed by the releaseo fi ntact CPT or IND throught he self-immolativec yclization mechanism (Figure 5b). [5,43] In addition, av ariety of self-immolative hetero-bifunctional linkersi nvolving the cleavable disulfide motif have been used for the fabricationo fa ntibody-drug bioconjugates, nanoparticle-drug conjugates, and protein cross-linked nanocapsules. [44] Pillow and co-workersr ecently reported the use of self-immolative hetero-bifunctional linkers (Cl-CV-MC, Cl-Csq-MC, and Cl-SS-NPy;F igure 5c)t oc onstruct quaternary ammonium-based ADCs, whichr eleased av ariety of active drugs containing tertiary and heteroaryl amines upon applying reductiveo re nzymatic triggers.…”

“…On the other hand, in the field of synthetic polymer chemistry, linker chemistries are also quite useful towards the synthesis of block and graft copolymers, polymer brushes, polymer conjugates, and polymers with other nonlinear chain topologies . Their successful synthesis provides numerous possibilities to regulate and optimize advanced functions of polymeric materials ,,.…”

Synthesis of light and dual‐redox triple‐stimuli‐responsive core‐crosslinked micelles as nanocarriers for controlled release

“…The disulfide bonds are stable in physiological environments, but are quickly cleaved in the presence of a high concentration of glutathione (GSH) . GSH is a thiol‐containing peptide, and the tested tumor tissues had at least fourfold higher concentration than normal tissues, even 100 to 1000 times in some cancer cells (e.g., colon, breast, and pancreatic cancer cells) . Thus, many polymeric micelles containing disulfide bonds as drug delivery systems have been demonstrated.…”