Abstract
The ability of polymeric micelles to self-assemble into nanosized particles has created interest in their application as potential anticancer drug delivery systems. A poly(ethylene glycol)-cholesteryl conjugate (Chol-ss-PEG-ss-Chol) connected by cleavable disulfide linkages was synthesized and used as a nanocarrier for in vitro release of doxorubicin (DOX). Owing to its amphiphilic structure, Chol-ss-PEG-ss-Chol was able to self-assemble into micelles with an average diameter 18.6 nm in aqueous solution. The micelles formed large aggregates due to the shedding of the PEG shell through cleavage of disulfide bonds in a reductive environment. The in vitro release studies revealed that Chol-ss-PEG-ss-Chol micelles released 80% and approximately 9% of the encapsulated DOX within 6 h under reductive and non-reductive conditions, respectively. The glutathione (GSH)-mediated intracellular drug delivery was investigated in a KB cell line. The cytotoxicity of DOX-loaded micelles indicated a higher cellular anti-proliferative effect against GSH-pretreated than untreated KB cells. Furthermore, confocal laser scanning microscopy (CLSM) measurement demonstrated that Chol-ss-PEG-ss-Chol micelles exhibited faster drug release in GSH-pretreated KB cells than untreated KB cells. These results suggest the potential usefulness of disulfide-based polymeric micelles as controlled drug delivery carriers.
Highlights
Polymeric micelles have attracted significant attention as anticancer drug carriers because they can self-assemble into nanosized micelles in water [1,2,3]
Among the various types of micelles, amphiphilic copolymers comprised of poly(ethylene glycol) (PEG) as the hydrophilic segments and polyesters including poly(D,L-lactic acid) (PDLLA), poly(glycolic acid) (PGA), and poly(ε-caprolactone) (PCL) as the hydrophobic segments have been extensively investigated as drug carriers due to their excellent biocompatibility and biodegradability [7,8,9,10,11,12,13]
We evaluated poly(ethylene glycol)-cholesteryl conjugate (Chol-ss-PEG-ss-Chol)based shell-sheddable micelles containing a disulfide bond at the junction of the hydrophilic corona and hydrophobic core
Summary
Polymeric micelles have attracted significant attention as anticancer drug carriers because they can self-assemble into nanosized micelles in water [1,2,3]. We evaluated poly(ethylene glycol)-cholesteryl conjugate (Chol-ss-PEG-ss-Chol)based shell-sheddable micelles containing a disulfide bond at the junction of the hydrophilic corona and hydrophobic core. This amphiphile was prepared using facile synthetic procedures. We investigated the disintegration or destabilization of Chol-ss-PEG-ss-Chol micelles following cleavage of disulfide in the presence of DTT using NMR, gel permeation chromatography (GPC), and dynamic light scattering (DLS) Their destabilization enhanced the release of encapsulated doxorubicin (DOX), a hydrophobic anticancer drug. Their GSH-responsive destabilization was investigated in KB cell lines using confocal laser scanning microscopy (CLSM) to monitor cellular uptake as well as cell viability assays to evaluate anticancer efficacy
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