Redox-sensitive micelles composed of disulfide-linked Pluronic-linoleic acid for enhanced anticancer efficiency of brusatol

Abstract

Brusatol (Bru) exhibits promising anticancer effects, with both proliferation inhibition and chemoresistance amelioration activity. However, the poor solubility and insufficient intracellular delivery of Bru greatly restrict its application. Herein, to simultaneously utilize the advantages of Pluronics as drug carriers and tumor microenvironment-responsive drug release profiles, a flexible amphiphilic copolymer with a polymer skeleton, that is, Pluronic ® F68 grafting with linoleic acid moieties by redox-reducible disulfide bonds (F68-SS-LA), was synthesized. After characterization by 1 H-nuclear magnetic resonance and Fourier transform infrared spectroscopy, the redox-sensitive F68-SS-LA micelles were self-assembled in a much lower critical micelle concentration than that of the unmodified F68 copolymer. Bru was loaded in micelles (Bru/SS-M) with high loading efficiency, narrow size distribution, and excellent storage stability. The redox-sensitive Bru/SS-M exhibited rapid particle dissociation and drug release in response to a redox environment. Based on the enhanced cellular internalization, Bru/SS-M achieved higher cytotoxicity in both Bel-7402 and MCF-7 cells compared with free Bru and nonreducible micelles. The improved anticancer effect was attributed to the remarkably decreased mitochondrial membrane potential and increased reactive oxygen species level as well as apoptotic rate. These results demonstrated that F68-SS-LA micelles possess great potential as an efficient delivery vehicle for Bru to promote its anticancer efficiency via an oxidation pathway.

Bruceine D induces lung cancer cell apoptosis and autophagy via the ROS/MAPK signaling pathway in vitro and in vivo

“…The seeds of Brucea javanica have been used to treat inflammation, malaria, and warts for many years 4 . Recently, growing evidence has indicated that Brucea javanica extracts exhibit potential anticancer activity [5][6][7] . BD, a quassinoid compound, can be extracted from the seeds of Brucea javanica.…”

pH-triggered charge-reversal and redox-sensitive drug release polymer micelles co-deliver doxorubicin and triptolide for prostate tumor therapy

“…[19][20][21] In addition, the concentration of glutathione (GSH) is different between the extracellular (~2.0-20 µM) and intracellular (~10 mM) environments. [22][23][24] Moreover, the concentration of GSH in many tumors has been reported to be fourfold higher than that of normal tissues. 18,25 Therefore, the pH-and redox-responsive drug delivery system has been widely used in cancer therapy.…”

<p>Fabrication of cRGD-modified reduction-sensitive nanocapsule via Pickering emulsion route to facilitate tumor-targeted delivery</p>

“…The stimuli-sensitive nanocarriers could respond to extra- and intracellular biological signal such as redox potential, pH, light, temperature 33. The reduction responsive due to its superior extracellular stability and rapid intracellular drug release hold great potential 34,35. The release of DOX from DOX-NCPE and DOX-ss-NCPE in vitro was monitored at 37°C in PBS (0.1 M, pH=7.4) with or without GSH (10 mM) to validate circulation stability and redox-sensitive intracellular delivery of nanocapsule.…”