Cyclic Disulfide Liposomes for Membrane Functionalization and Cellular Delivery

Abstract

Liposomes are effective therapeutic delivery nanocarriers due to their ability to encapsulate and enhance the pharmacokinetic properties of a wide range of therapeutics. Two primary areas in which improvement is needed for liposomal drug delivery is to enhance the ability to infiltrate cells and to facilitate derivatization of the liposome surface. Herein, we report a liposome platform incorporating a cyclic disulfide lipid (CDL) for the dual purpose of enhancing cell entry and functionalizing the liposome membrane through thiol‐disulfide exchange. In order to accomplish this, CDL‐1 and CDL‐2, composed of lipoic acid (LA) or asparagusic acid (AA) appended to a lipid scaffold, were designed and synthesized. A fluorescence‐based microplate immobilization assay was implemented to show that these compounds enable convenient membrane decoration through reaction with thiol‐functionalized small molecules. Additionally, fluorescence microscopy experiments indicated dramatic enhancements in cellular delivery when CDLs were incorporated within liposomes. These results demonstrate that multifunctional CDLs serve as an exciting liposome system for surface decoration and enhanced cellular delivery.

Inhibition of Cell Motility by Cell-Penetrating Dynamic Covalent Cascade Exchangers: Integrins Participate in Thiol-Mediated Uptake

“…CAXs undergo dynamic covalent exchanges with membrane-bound protein thiols (or disulfides), where each exchange produces a new (or offers another) covalently tethered exchanger, that can continue exchanging until they are delivered into the cytosol . TMU has been realized with many classes of CAX for the cytosolic delivery of small molecules, , antibodies and other proteins, − genome editing machinery and other oligonucleotides, − polymers, liposomes, and nanoparticles ,, into various cellular targets including deep tissue, , living animals, , plant cells, and bacteria . Proteomics data, heatmap patterns, , and literature on oligonucleotide phosphorothioate , and viral uptake ,− all support that multipartner exchange networks are involved in how TMU brings matter into cells .…”

Asparagusic Acid – A Unique Approach toward Effective Cellular Uptake of Therapeutics: Application, Biological Targets, and Chemical Properties

“…[76,77] The enhanced liposome delivery decorated with asparagusic acid to mammary adenocarcinoma cells was observed, which makes the application of asparagusic acid moiety very promising in production of efficient therapeutic cargo for cancer therapy. [78]…”

Inclusive Pattern Generation Protocols to Decode Thiol-Mediated Uptake

“…Thiol-mediated uptake (TMU) refers to the cell-penetrating activity acquired by the attachment of thiol-reactive motifs to the substrates of interest (SOI), − such as probes, , drugs, proteins, ,,,− oligonucleotides, − liposomes, ,− quantum dots, nanoparticles, ,, and so on (Figure ). Since this process appears to operate with dynamic covalent exchange reactions with cellular thiols and disulfides, e.g., cysteine and cystine residues, it can be inhibited by other thiol-reactive agents, which is the hallmark of TMU.…”