TY - JOUR
T1 - Combination delivery of alpha-tocopheryl succinate and curcumin using a gsh-sensitive micelle (Pah-ss-plga) to treat pancreatic cancer
AU - Debele, Tilahun Ayane
AU - Wu, Hung Chang
AU - Wu, Shang Rung
AU - Shan, Yan Shen
AU - Su, Wen Pin
N1 - Funding Information:
4.ConcA GSH-sensitivelusions copolymer, PAH-SS-PLGA, was synthesized after the modification of highly A GSH-sensitive copolymer, PAH-SS-PLGA, was synthesized after the modification of highly amphiphilic nature and tends to encapsulate hydrophobic drugs, TOS and curcumin, in its core region during micelle synthesis in the aqueous medium. The drug release study revealed higher drug release region during micelle synthesis in the aqueous medium. The drug release study revealed higher drug release in the presence of 5 mM GSH than at physiological pH value. Fluorescence microscopy pancreatic cancer cells. The in vitro cytotoxicity results revealed that combination treatments enhanced PAN02 pancreatic cancer cells. The in vitro cytotoxicity results revealed that combination treatments enhanced anti-cancer therapeutic efficacy compared to free TOS or curcumin. In addition, at all tested doses, nanoformulated drugs showed synergistic effects, whereas antagonistic effects were seen at a lower dose combination of free drugs. Overall, a synthesized co-polymer would be a promising carrier for TOS/curcumin to enhance its therapeutic efficiency. Author Contributions: Conceptualization, T.A.D. and W.-P.S.; Data curation, T.A.D. and S.-R.W.; Formal analysis, T.A.D. and H.-C.W.; Funding acquisition, W.-P.S. and H.-C.W.; Investigation, T.A.D.; Methodology, T.A.D.; Supervision, W.-P.S.; Validation, T.A.D.; Writing—original draft, T.A.D.; Writing—review and editing, T.A.D., Ya.n-Sa.lSy.saisn,dTW.A..-DP..Sa. nAdllHau.-tCho.Wrs.;hFauvnedreinagd ancqduaisgirteioend,tWo t.h-Pe.Sp.uabnlidshHed.-Cve.Wrs.i;oInnovfesthtiegamtiaonu,sTc.rAip.Dt..; Methodology, T.A.D.; Supervision, W.-P.S.; Validation, T.A.D.; Writing—original draft, T.A.D.; Writing—review and editing, MT.OAS.DT.,1 Y08.-S2.8S1.1a-nBd-0 W06-.-5P0.1S,.MAOllSaTut1h0o8r-s2 8h1a1v-eB -r0e0a6d- 5a2n5d, MagOreSeTd1t0o6-t2h3e1 p4-uBb-l0i0sh6-e0d74v-eMrsYio3n, MofO tShTe m10a9n-2u3s1c4r-iBp-t0. 06-078, and MOST 109-2314-B-006-084-MY3; National Cheng Kung University, the grant number: HUA 109-3-7-156; National Cheng Kung University Hospital, grant number: NCKUH-10902034 and Chi Mei Medical Center for financial support the grants number: CMNCKU10505, CMNCKU10609 and CMNCKU10715.
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PY - 2020/8
Y1 - 2020/8
N2 - 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 (1 H-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.
AB - 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 (1 H-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.
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U2 - 10.3390/pharmaceutics12080778
DO - 10.3390/pharmaceutics12080778
M3 - Article
AN - SCOPUS:85089703419
SN - 1999-4923
VL - 12
SP - 1
EP - 17
JO - Pharmaceutics
JF - Pharmaceutics
IS - 8
M1 - 0778
ER -