Biodegradable mixed MPEG-SS-2SA/TPGS micelles for triggered intracellular release of paclitaxel and reversing multidrug resistance

Abstract

In this study, a type of multifunctional mixed micelles were prepared by a novel biodegradable amphiphilic polymer (MPEG-SS-2SA) and a multidrug resistance (MDR) reversal agent ( d -α-tocopheryl polyethylene glycol succinate, TPGS). The mixed micelles could achieve rapid intracellular drug release and reversal of MDR. First, the amphiphilic polymer, MPEG-SS-2SA, was synthesized through disulfide bonds between poly (ethylene glycol) monomethyl ether (MPEG) and stearic acid (SA). The structure of the obtained polymer was similar to poly (ethylene glycol)-phosphatidylethanolamine (PEG-PE). Then the mixed micelles, MPEG-SS-2SA/TPGS, were prepared by MPEG-SS-2SA and TPGS through the thin film hydration method and loaded paclitaxel (PTX) as the model drug. The in vitro release study revealed that the mixed micelles could rapidly release PTX within 24 h under a reductive environment because of the breaking of disulfide bonds. In cell experiments, the mixed micelles significantly inhibited the activity of mitochondrial respiratory complex II, also reduced the mitochondrial membrane potential, and the content of adenosine triphosphate, thus effectively inhibiting the efflux of PTX from cells. Moreover, in the confocal laser scanning microscopy, cellular uptake and 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assays, the MPEG-SS-2SA/TPGS micelles achieved faster release and more uptake of PTX in Michigan Cancer Foundation-7/PTX cells and showed better antitumor effects as compared with the insensitive control. In conclusion, the biodegradable mixed micelles, MPEG-SS-2SA/TPGS, could be potential vehicles for delivering hydrophobic chemotherapeutic drugs in MDR cancer therapy.

Recent Advances in the Application of Vitamin E TPGS for Drug Delivery

“…Mitochondrial respiratory complex Ⅱ, also called succinate dehydrogenase, plays an important role in mitochondrial electron transport, which is an essential part in the tricarboxylic acid cycle as well as the mitochondrial respiratory chain 35 . TPGS can bind with mitochondrial respiratory complex Ⅱ and induce subsequent mitochondrial dysfunction, resulting in significant depletion of intracellular energy 20 , 36 . TPGS can accumulate in mitochondria and inhibit the activity of complex Ⅱ, and consequently disrupt the electron transfer and activate calcium channel, which would result in the overload of calcium and ensuing dysfunction of mitochondria.…”

“…The micelles exhibited 6-fold decrease of IC 50 in MCF-7/ADR cells and more efficient tumor inhibition in MCF-7/ADR bearing nude mice compared with free DOX. Moreover, Dong et al 36 designed PTX loaded mixed micelles, which were prepared with disulfide bond-linked MPEG and stearic acid (MPEG-SS-2SA), and TPGS. PTX can be rapidly released within 24 h under the reductive environment.…”

<p>Regulating intracellular ROS signal by a dual pH/reducing-responsive nanogels system promotes tumor cell apoptosis</p>

“…TPGS was employed as the other ROS inducer in this system, which was a derivative of vitamin E and composed of polyethylene glycol and α-tocopheryl succinate (α-TOS) 24. α-TOS is the major function group of TPGS, which increases the intracellular ROS level through interfering with the function of the mitochondrial electron transport chain, thereby inducing apoptosis 25,26. Youk et al, found that TPGS generated more ROS to induce apoptosis, and effectively inhibited the growth of human lung carcinoma cells implanted in nude mice compared with TOS 27.…”

Icariin protects against sodium azide—induced neurotoxicity by activating the PI3K/Akt/GSK-3β signaling pathway

“…A total of 0.5 ml culture medium and 0.5 ml JC-1 staining solution were added and incubated at 37 C for 20 min. Carbonyl cyanide 3-chlorophenylhydrazone (CCCP) was used as the control of MMP decrease (Dong et al, 2016). The cells were rinsed with binding buffer twice and observed under an inverted fluorescence microscope (IX73; Olympus TM , Shinjuku City, Tokyo, Japan).…”