Combination Delivery of Alpha-Tocopheryl Succinate and Curcumin Using a GSH-Sensitive Micelle (PAH-SS-PLGA) to Treat Pancreatic Cancer.

Tilahun Ayane Debele,Shang-Rung Wu,Yan-Shen Shan,Hung-Chang Wu,Wen-Pin Su

doi:10.3390/pharmaceutics12080778

Tilahun Ayane Debele, Shang-Rung Wu + Show 3 more

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https://doi.org/10.3390/pharmaceutics12080778

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Abstract

Pancreatic cancer is one of the highest causes of mortality throughout the world; thus, it requires an effective treatment strategy. Some chemotherapeutic agents used in the clinics or under clinical trials are hydrophobic and have poor aqueous solubility; consequently, they also have minimal systemic bioavailability. Nanoparticle-based drug delivery tactics have the potential for overcoming these limitations and enhancing their therapeutic efficacy. Herein, a glutathione (GSH)-sensitive micelle (PAH-SS-PLGA) was synthesized for the combined delivery of alpha-tocopheryl succinate (TOS) and curcumin to improve its therapeutic efficacy. The chemical structures of PAH-SS-PLGA were analyzed using Proton Nuclear Magnetic Resonance (1H-NMR) and Fourier Transform Infrared (FTIR) spectroscopy, whereas the particle size, zeta potential, and surface morphology were observed using dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release results revealed that more TOS and curcumin were released in the presence of GSH (5 mM) than the physiological pH value. Fluorescence microscopy images revealed that nanoformulated curcumin/rhodamine was uptaken by PAN02 pancreatic cancer cells. In vitro cytotoxicity assays showed higher cytotoxicity for nanoformulated TOS and/or curcumin than free TOS and/or curcumin. In addition, higher cytotoxicity was observed for combination drugs than free drugs alone. Most interestingly, at all tested concentrations of nanoformulated drugs (PAH-SS-PLGA, TOS, and curcumin), the calculated combination index (CI) value was less than one, which shows that TOS and curcumin have a synergistic effect on cellular proliferation inhibition. Overall, synthesized co-polymers are the best carriers for combination drugs, TOS, and curcumin, because they enhance the therapeutic efficacy and improve pancreatic cancer treatments.

Highlights

Nowadays, several targeted stimuli-sensitive nanocarrier-based drug delivery systems are of great interest for the treatment of cancers [1,2]
The poly(allylamine hydrochloride) (PAH)-SS-PLGA co-polymer was synthesized by conjugating the carboxyl group of poly(allylamine)-citraconic anhydride (PAH-Cit) with an amino group of PLGA-Cys in the presence of ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxy succinimide (NHS), as shown in Scheme 1
PAH-Cit was used as the backbone of the carriers, whereas cystamine were used as the GSH-sensitive segments

Summary

Introduction

Several targeted stimuli-sensitive nanocarrier-based drug delivery systems are of great interest for the treatment of cancers [1,2]. Nanocarriers enhance prolonged systemic circulation, improve the solubility of hydrophobic drugs, enhance metabolic stability, prevent premature release, and target delivery to the site of interest to minimize the systemic side effects associated with conventional drug formulations [2,3,4]. Once the GSH-sensitive micelles are taken up by cancer cells, disulfide bonds are cleaved, the micelles disassemble, and drugs are released in the cytosol. By taking this into consideration, several researchers have synthesized GSH-sensitive micelles using biocompatible polymers [15]

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