title: Multifunctional Nanoparticles Loading with Docetaxel and GDC0941 for Reversing Multidrug Resistance Mediated by PI3K/Akt Signal Pathway.
abstract: The polylactic-co-glycolic acid polyethylene glycol conjugated with cell penetrating peptide R7(PLGA-PEG-R7)/polysulfadimethoxine-folate nanoparticles loaded with docetaxel (DTX) and GDC0941 (R7/PSD-Fol NPs) were prepared to overcome multidrug resistance (MDR) and enhance the antitumor activity. First, polysulfadimethoxine-folate was synthesized to construct the R7/PSD-Fol NPs. The R7/PSD-Fol NPs were prepared with the abilities of effective entrapment and drug loading. Due to the pH-sensitive effect of PSD-folate, the releasing of DTX and GDC0941 from the R7/PSD-Fol NPs was lower in pH 7.4 buffer solution than that in pH 5.0 buffer solution. The half maximal inhibitory concentration (IC50) of MCF-7 and resistant to doxorubicin (MCF-7/Adr) cells illustrated the cytotoxicity of R7/PSD-Fol nanoparticles by using the MTT method. The uptake of R7/PSD-Fol NPs was visualized by using the fluorescence of Rh-123 to detect the targeting effect of folate on the surface of R7/PSD-Fol NPs. The results of the cell apoptosis and the depolarization of mitochondrial membrane potential (MMP) were adopted to show the cytotoxicity of the R7/PSD-Fol NPs on MCF-7/Adr cells. The Western blot revealed the inhibition of PI3K/Akt pathway in MCF-7/Adr cells induced by R7/PSD-Fol NPs. Finally, both in vivo distribution and in vivo antitumor showed the R7/PSD-Fol NPs displayed the better distribution at tumor site and the stronger suppression of tumor growth in the tumor bearing nude mice compared with control group. It was concluded that R7/PSD-Fol NPs loaded with DTX and GDC0941 could overcome MDR and enhance the antitumor effect further.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Yiyue
authors.identifier: 0000-0002-7564-0067
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Jing Jing
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Gao
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Zun
authors.initials: Z
authors.lastname: Huang
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Shen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004337:Drug Carriers / Q000737:chemistry; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D005260:Female; D005492:Folic Acid / Q000737:chemistry; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D004337:Drug Carriers; D007191:Indazoles; D011091:Polyesters; D013449:Sulfonamides; D043823:Taxoids; D000077143:Docetaxel; D011100:Polyglycolic Acid; D011092:Polyethylene Glycols; C033616:poly(lactide); D005492:Folic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: DTX; folate; multidrug resistance; nanoparticles; p-Akt