Single-Molecule Kinetics of Growth and Degradation of Cell-Penetrating Poly(disulfide)s

Abstract

The delivery of therapeutic agents into target cells is a challenging task. Cell penetration and intracellular targeting were recently addressed with biodegradable cell-penetrating poly(disulfide)s (CPDs). Cellular localization is determined by the length of these polymers, emphasizing the significance of initial chain length and the kinetics of intracellular depolymerization for targeted delivery. In the present study, the kinetics of CPD polymer growth and degradation were monitored in a single-molecule nanoreactor. The chain lengths achievable under synthetic conditions with high concentrations of dithiolanes were then predicted by using the rate constants. For example, CPDs comprising 40 units are generated in 1 s at pH 7.4 and 0.3 s at pH 8.4 at dithiolane concentrations of 200 mM. The rate constants for degradation suggest that the main depolymerization pathway in the cell is by monomer removal by selfcyclization, rather than by intrachain cleavage by endogenous thiols. Communication pubs.acs.org/JACS

Thiol-Mediated Uptake

“…With single-channel current recordings of thiolated transmembrane pores, ring-opening polymerization as well as the reverse ring-closing depolymerization could be directly observed and characterized on the single-molecule level ( Figure 3 ). 68 …”

Dual closed-loop chemical recycling of synthetic polymers by intrinsically reconfigurable poly(disulfides)

“…[21][22][23] It should be noted that, in order to facilitate recyclability involving polymerization and depolymerization, reactions closer to equilibrium are needed and the intrinsically dynamic disulfide bond 24 within the five-membered ring of TA not only offers a chance to enable dynamic properties of polymers but also facilitates the control of polymerization and depolymerization by chemical means. [25][26][27][28][29][30][31] The naturally tailored structure of our monomer TA features a disulfide fivemembered ring, which facilitates reversible interconversion between monomers and polymers, as it is activated by strain in the five-membered ring, with intrinsic lower bond energy than is present in traditional open-chain disulfide bonds. 32 This allows TA to readily polymerize under conditions of (1) high concentration to favor intermolecular reactions, and (2) external stimulus to activate the disulfide bond, such as heat, 21,23,33,34 light, 32,35 and base.…”

Renewable and recyclable covalent adaptable networks based on bio-derived lipoic acid

“…Thioctic acid, or lipoic acid, is a naturally occurring carboxylic acid that contains a 5-membered cyclic disulfide which can be polymerised into a polydisulfide by ring-opening polymerisation (ROP). 24 The ROP of various strained cyclic disulfides to afford linear polydisulfides is well established and versatile as exemplified by numerous reaction pathways -such as thermal 25 , radical 26,27 or anionic (via thiolate) [28][29][30][31][32][33][34] . An exemplary feature of strained cyclic disulfides is their dynamic nature that results from facile thiol-disulfide exchange [35][36][37][38] and has been exploited to reversibly depolymerise (or chemically recycle) some of the aforementioned polydisulfides 27,[29][30][31]33 or to create functional supramolecular cyclic structures 39 .…”